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Wang Q, Fu H, Zhang Y, Zhang M, Xu J, Fu J. Bibliometric and Visualization Analysis of DprE1 Inhibitors to Combat Tuberculosis. Drug Des Devel Ther 2025; 19:2577-2596. [PMID: 40196755 PMCID: PMC11974558 DOI: 10.2147/dddt.s515049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Accepted: 03/18/2025] [Indexed: 04/09/2025] Open
Abstract
Background Tuberculosis (TB) poses a serious threat to public health, particularly owing to the increase in multidrug-resistant tuberculosis (MDR-TB) and extremely drug-resistant tuberculosis (XDR-TB); thus, there is an imperative need for novel treatments to tackle this issue. Decaprenylphosphoryl-β-D-ribose 2'-epimerase (DprE1) is essential for mycobacterial cell wall integrity and viability. As no relevant bibliometric study has been reported, we performed bibliometric and visual analyses to depict the knowledge framework of research related to the involvement of DprE1 in TB. Methods Relevant studies were sourced from the Web of Science Core Collection database. VOSviewer, CiteSpace, and bibliometrics (http://bibliometric.com/) were used to construct networks based on an analysis of journals, countries, funding, institutions, authors, references, and keywords. Results A total of 184 publications were retrieved; the total citations were 3405 times and the mean citation was 17.28 per article. The annual number of publications on DprE1 in TB has shown a significantly increasing trend. The European Journal of Medicinal Chemistry is the most published journal, with 19 articles. Lu Yu and Bin Wang contributed the most prolific authors with 18 articles. Stratified by the number of publications, India was the most prolific country that cooperated closely with the USA, UK, Japan, and United Arab Emirates. Burstness analysis of references and keywords showed that the developing research trends in this field mainly woven around "Mtb", "DprE1" and "inhibitors" during the past years. Conclusion A systematic bibliometric study indicates that DprE1 remains a focal point in the anti-TB domain. These results can serve as a data-driven reference for future research and offer precise insights into the development of anti-TB agents associated with DprE1. To the best of our knowledge, this study is the first to comprehensively investigate DprE1 in TB by means of bibliometric analysis.
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Affiliation(s)
- Qingqing Wang
- College of Pharmacy, Guizhou University of Traditional Chinese Medicine/National Engineering Technology Research Center for Miao Medicine/Guizhou Engineering Technology Research Center for Processing and Preparation of Traditional Chinese Medicine and Ethnic Medicine, Guiyang, People’s Republic of China
| | - Huixiao Fu
- Department of Science and Education, The First People’s Hospital of Guiyang, Guiyang, People’s Republic of China
| | - Yining Zhang
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, People’s Republic of China
| | - Man Zhang
- College of Pharmacy, Guizhou University of Traditional Chinese Medicine/National Engineering Technology Research Center for Miao Medicine/Guizhou Engineering Technology Research Center for Processing and Preparation of Traditional Chinese Medicine and Ethnic Medicine, Guiyang, People’s Republic of China
| | - Jian Xu
- College of Pharmacy, Guizhou University of Traditional Chinese Medicine/National Engineering Technology Research Center for Miao Medicine/Guizhou Engineering Technology Research Center for Processing and Preparation of Traditional Chinese Medicine and Ethnic Medicine, Guiyang, People’s Republic of China
| | - Jian Fu
- College of Pharmacy, Guizhou University of Traditional Chinese Medicine/National Engineering Technology Research Center for Miao Medicine/Guizhou Engineering Technology Research Center for Processing and Preparation of Traditional Chinese Medicine and Ethnic Medicine, Guiyang, People’s Republic of China
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, People’s Republic of China
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Bohórquez JA, Jagannath C, Xu H, Wang X, Yi G. T Cell Responses during Human Immunodeficiency Virus/ Mycobacterium tuberculosis Coinfection. Vaccines (Basel) 2024; 12:901. [PMID: 39204027 PMCID: PMC11358969 DOI: 10.3390/vaccines12080901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 08/05/2024] [Accepted: 08/07/2024] [Indexed: 09/03/2024] Open
Abstract
Coinfection with Mycobacterium tuberculosis (Mtb) and the human immunodeficiency virus (HIV) is a significant public health concern. Individuals infected with Mtb who acquire HIV are approximately 16 times more likely to develop active tuberculosis. T cells play an important role as both targets for HIV infection and mediators of the immune response against both pathogens. This review aims to synthesize the current literature and provide insights into the effects of HIV/Mtb coinfection on T cell populations and their contributions to immunity. Evidence from multiple in vitro and in vivo studies demonstrates that T helper responses are severely compromised during coinfection, leading to impaired cytotoxic responses. Moreover, HIV's targeting of Mtb-specific cells, including those within granulomas, offers an explanation for the severe progression of the disease. Herein, we discuss the patterns of differentiation, exhaustion, and transcriptomic changes in T cells during coinfection, as well as the metabolic adaptations that are necessary for T cell maintenance and functionality. This review highlights the interconnectedness of the immune response and the pathogenesis of HIV/Mtb coinfection.
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Affiliation(s)
- José Alejandro Bohórquez
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX 75708, USA;
- Center for Biomedical Research, The University of Texas Health Science Center at Tyler, Tyler, TX 75708, USA
- Department of Medicine, The University of Texas at Tyler School of Medicine, Tyler, TX 75708, USA
| | - Chinnaswamy Jagannath
- Department of Pathology and Genomic Medicine, Center for Infectious Diseases and Translational Medicine, Houston Methodist Research Institute, Houston, TX 77030, USA;
| | - Huanbin Xu
- Tulane National Primate Research Center, Tulane University School of Medicine, Tulane University, Covington, LA 70112, USA; (H.X.); (X.W.)
| | - Xiaolei Wang
- Tulane National Primate Research Center, Tulane University School of Medicine, Tulane University, Covington, LA 70112, USA; (H.X.); (X.W.)
| | - Guohua Yi
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX 75708, USA;
- Center for Biomedical Research, The University of Texas Health Science Center at Tyler, Tyler, TX 75708, USA
- Department of Medicine, The University of Texas at Tyler School of Medicine, Tyler, TX 75708, USA
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Lema YL, Prodjinotho UF, Makasi C, Nanyaro MWA, Kilale AM, Mfinanga S, Stelzle D, Schmidt V, Carabin H, Winkler AS, Lyamuya EF, Ngowi BJ, Chachage M, Prazeres da Costa C. Evaluating the modulation of peripheral immune profile in people living with HIV and (Neuro)cysticercosis. PLoS Negl Trop Dis 2024; 18:e0012345. [PMID: 39093864 PMCID: PMC11324146 DOI: 10.1371/journal.pntd.0012345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Revised: 08/14/2024] [Accepted: 07/05/2024] [Indexed: 08/04/2024] Open
Abstract
BACKGROUND The parasitic infection caused by Taenia solium represents a significant public health concern in developing countries. Larval invasion of body tissues leads to cysticercosis (CC), while central nervous system (CNS) involvement results in neurocysticercosis (NCC). Both conditions exhibit diverse clinical manifestations, and the potential impact of concomitant HIV infection especially prevalent in sub-Saharan Africa on peripheral and CNS immune responses remains poorly understood. This study aimed to identify the potential impact of HIV coinfection in CC and NCC patients. METHODOLOGY A nested study within a cross-sectional analysis in two Tanzanian regions was performed and 234 participants (110 HIV+ and 124 HIV-) were tested for cysticercosis antibodies, antigens, CD4 counts and serum Th1 and Th2 cytokines via multiplex bead-based immunoassay. 127 cysticercosis seropositive individuals underwent cranial computed tomography (CCT) and clinical symptoms were assessed. Multiple regression analyses were performed to identify factors associated with cytokine modulation due to HIV in CC and NCC patients. RESULTS Serologically, 18.8% tested positive for cysticercosis antibodies, with no significant difference HIV+ and HIV+. A significantly higher rate of cysticercosis antigen positivity was found in HIV+ individuals (43.6%) compared to HIV- (28.2%) (p = 0.016). CCT scans revealed that overall 10.3% had active brain cysts (NCC+). Our study found no significant changes in the overall cytokine profiles between HIV+ and HIV- participants coinfected CC and NCC, except for IL-5 which was elevated in HIV+ individuals with cysticercosis. Furthermore, HIV infection in general was associated with increased levels of pro-and some anti-inflammatory cytokines e.g. TNF-α, IL-8, and IFN-γ. However, based on the interaction analyses, no cytokine changes were observed due to HIV in CC or NCC patients. CONCLUSIONS In conclusion, while HIV infection itself significantly modulates levels of key cytokines such as TNF-α, IL-8, and IFN-γ, it does not modulate any cytokine changes due to CC or NCC. This underscores the dominant influence of HIV on the immune system and highlights the importance of effective antiretroviral therapy in managing immune responses in individuals coinfected with HIV and CC/NCC.
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Affiliation(s)
- Yakobo Leonard Lema
- Muhimbili Medical Research Center, National Institute for Medical Research (NIMR), Dar es Salaam, Tanzania
| | - Ulrich Fabien Prodjinotho
- Institute for Medical Microbiology, Immunology, and Hygiene, Technical University of Munich (TUM), Munich, Germany
- Center for Global Health, Technical University of Munich, Munich, Germany
| | - Charles Makasi
- Muhimbili Medical Research Center, National Institute for Medical Research (NIMR), Dar es Salaam, Tanzania
- Kilimanjaro Christian Medical University College, Moshi, Tanzania
| | - Mary-Winnie A. Nanyaro
- Muhimbili Medical Research Center, National Institute for Medical Research (NIMR), Dar es Salaam, Tanzania
| | - Andrew Martin Kilale
- Muhimbili Medical Research Center, National Institute for Medical Research (NIMR), Dar es Salaam, Tanzania
| | - Sayoki Mfinanga
- Muhimbili Medical Research Center, National Institute for Medical Research (NIMR), Dar es Salaam, Tanzania
- Kampala International University, Kampala, Tanzania
- School of Public Health, Muhimbili University of Health & Allied Sciences (MUHAS), Dar Es Salaam, Tanzania
| | - Dominik Stelzle
- Center for Global Health, Technical University of Munich, Munich, Germany
- Department of Neurology, School of Medicine and Health, Technical University Munich (TUM), Munich, Germany
| | - Veronika Schmidt
- Center for Global Health, Technical University of Munich, Munich, Germany
- Department of Neurology, School of Medicine and Health, Technical University Munich (TUM), Munich, Germany
| | - Hélène Carabin
- Faculty of Veterinary Medicine, University of Montreal, Saint-Hyacinthe, Quebec, Canada
- School of Public Health, University of Montreal, Montreal, Quebec, Canada
- Research Group on Epidemiology of Zoonoses and Public Health (GREZOSP), Saint-Hyacinthe, Quebec, Canada
- Public Health Research Center of the University of Montreal and the CIUSSS of Center-Sud-de-l’île-de-Montréal (CReSP), Montreal, Quebec, Canada
| | - Andrea Sylvia Winkler
- Center for Global Health, Technical University of Munich, Munich, Germany
- Department of Neurology, School of Medicine and Health, Technical University Munich (TUM), Munich, Germany
- Department of Community Medicine and Global Health, Institute of Health and Society, University of Oslo, Oslo, Norway
- Department of Global Health and Social Medicine, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Eligius F. Lyamuya
- Department of Microbiology & Immunology, Muhimbili University of Health & Allied Sciences (MUHAS), Dar Es Salaam, Tanzania
| | - Bernard J. Ngowi
- Muhimbili Medical Research Center, National Institute for Medical Research (NIMR), Dar es Salaam, Tanzania
- Mbeya College of Health & Allied Sciences, University of Dar Es Salaam, Mbeya Tanzania
| | - Mkunde Chachage
- Mbeya College of Health & Allied Sciences, University of Dar Es Salaam, Mbeya Tanzania
- Mbeya Medical Research Center, National Institute for Medical Research (NIMR), Mbeya, Tanzania
| | - Clarissa Prazeres da Costa
- Institute for Medical Microbiology, Immunology, and Hygiene, Technical University of Munich (TUM), Munich, Germany
- Center for Global Health, Technical University of Munich, Munich, Germany
- German Center for Infection Research (DZIF), partner site Munich, Germany
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Oyageshio OP, Myrick JW, Saayman J, van der Westhuizen L, Al-Hindi DR, Reynolds AW, Zaitlen N, Hoal EG, Uren C, Möller M, Henn BM. Strong effect of demographic changes on Tuberculosis susceptibility in South Africa. PLOS GLOBAL PUBLIC HEALTH 2024; 4:e0002643. [PMID: 39042651 PMCID: PMC11265723 DOI: 10.1371/journal.pgph.0002643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Accepted: 06/12/2024] [Indexed: 07/25/2024]
Abstract
South Africa is among the world's top eight tuberculosis (TB) burden countries, and despite a focus on HIV-TB co-infection, most of the population living with TB are not HIV co-infected. The disease is endemic across the country, with 80-90% exposure by adulthood. We investigated epidemiological risk factors for (TB) in the Northern Cape Province, South Africa: an understudied TB endemic region with extreme TB incidence (926/100,000). We leveraged the population's high TB incidence and community transmission to design a case-control study with similar mechanisms of exposure between the groups. We recruited 1,126 participants with suspected TB from 12 community health clinics and generated a cohort of 774 individuals (cases = 374, controls = 400) after implementing our enrollment criteria. All participants were GeneXpert Ultra tested for active TB by a local clinic. We assessed important risk factors for active TB using logistic regression and random forest modeling. We find that factors commonly identified in other global populations tend to replicate in our study, e.g. male gender and residence in a town had significant effects on TB risk (OR: 3.02 [95% CI: 2.30-4.71]; OR: 3.20 [95% CI: 2.26-4.55]). We also tested for demographic factors that may uniquely reflect historical changes in health conditions in South Africa. We find that socioeconomic status (SES) significantly interacts with an individual's age (p = 0.0005) indicating that protective effect of higher SES changed across age cohorts. We further find that being born in a rural area and moving to a town strongly increases TB risk, while town birthplace and current rural residence is protective. These interaction effects reflect rapid demographic changes, specifically SES over recent generations and mobility, in South Africa. Our models show that such risk factors combined explain 19-21% of the variance (r2) in TB case/control status.
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Affiliation(s)
- Oshiomah P. Oyageshio
- Center for Population Biology, University of California, Davis, Davis, California, United States of America
| | - Justin W. Myrick
- UC Davis Genome Center, University of California, Davis, Davis, California, United States of America
| | - Jamie Saayman
- DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Lena van der Westhuizen
- DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Dana R. Al-Hindi
- Department of Anthropology, University of California, Davis, Davis, California, United States of America
| | - Austin W. Reynolds
- Department of Microbiology, Immunology, and Genetics, School of Biomedical Sciences, University of North Texas Health Science Center, Fort Worth, Texas, United States of America
| | - Noah Zaitlen
- Department of Computational Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States of America
| | - Eileen G. Hoal
- DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Caitlin Uren
- DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
- Centre for Bioinformatics and Computational Biology, Stellenbosch University, Stellenbosch, South Africa
| | - Marlo Möller
- DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
- Centre for Bioinformatics and Computational Biology, Stellenbosch University, Stellenbosch, South Africa
| | - Brenna M. Henn
- Center for Population Biology, University of California, Davis, Davis, California, United States of America
- UC Davis Genome Center, University of California, Davis, Davis, California, United States of America
- Department of Anthropology, University of California, Davis, Davis, California, United States of America
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Cronin S, de Vries-Egan A, Vahlas Z, Czernikier A, Melucci C, Pereyra Gerber P, O’Neil T, Gloss B, Sharabas M, Turk G, Verollet C, Balboa L, Palmer S, Duette G. The immunosuppressive tuberculosis-associated microenvironment inhibits viral replication and promotes HIV-1 latency in CD4 + T cells. iScience 2024; 27:110324. [PMID: 39055929 PMCID: PMC11269811 DOI: 10.1016/j.isci.2024.110324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 04/15/2024] [Accepted: 06/18/2024] [Indexed: 07/28/2024] Open
Abstract
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is the most common coinfection among people living with HIV-1. This coinfection is associated with accelerated HIV-1 disease progression and reduced survival. However, the impact of the HIV-1/TB coinfection on HIV-1 replication and latency in CD4+ T cells remains poorly studied. Using the acellular fraction of tuberculous pleural effusion (TB-PE), we investigated whether viral replication and HIV-1 latency in CD4+ T cells are affected by a TB-associated microenvironment. Our results revealed that TB-PE impaired T cell receptor-dependent cell activation and decreased HIV-1 replication in CD4+ T cells. Moreover, this immunosuppressive TB microenvironment promoted viral latency and inhibited HIV-1 reactivation. This study indicates that the TB-induced immune response may contribute to the persistence of the viral reservoir by silencing HIV-1 expression, allowing the virus to persist undetected by the immune system, and increasing the size of the latent HIV-1 reservoir.
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Affiliation(s)
- Samantha Cronin
- The Westmead Institute for Medical Research, Centre for Virus Research, Westmead, NSW 2145, Australia
- University of Sydney, Faculty of Medicine and Health, Sydney, NSW 2050, Australia
| | - Anneke de Vries-Egan
- The Westmead Institute for Medical Research, Centre for Virus Research, Westmead, NSW 2145, Australia
| | - Zoï Vahlas
- Institut de Pharmacologie et Biologie Structurale (IPBS), Université de Toulouse, Centre National de La Recherche Scientifique, Université Toulouse III - Paul Sabatier (UPS), 31077 Toulouse, France
- International Research Project CNRS “MAC-TB/HIV”, Toulouse, France and Buenos Aires, Argentina
| | - Alejandro Czernikier
- Instituto de Investigaciones Biomédicas en Retrovirus y SIDA, Universidad de Buenos Aires-CONICET, Buenos Aires C1121ABG, Argentina
| | - Claudia Melucci
- Instituto de Investigaciones Biomédicas en Retrovirus y SIDA, Universidad de Buenos Aires-CONICET, Buenos Aires C1121ABG, Argentina
| | - Pehuén Pereyra Gerber
- Cambridge Institute for Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge CB2 0AW, UK
| | - Thomas O’Neil
- The Westmead Institute for Medical Research, Centre for Virus Research, Westmead, NSW 2145, Australia
- University of Sydney, Faculty of Medicine and Health, Sydney, NSW 2050, Australia
| | - Brian Gloss
- The Westmead Institute for Medical Research, Centre for Virus Research, Westmead, NSW 2145, Australia
| | - Mayssa Sharabas
- The Westmead Institute for Medical Research, Centre for Virus Research, Westmead, NSW 2145, Australia
| | - Gabriela Turk
- Instituto de Investigaciones Biomédicas en Retrovirus y SIDA, Universidad de Buenos Aires-CONICET, Buenos Aires C1121ABG, Argentina
| | - Christel Verollet
- Institut de Pharmacologie et Biologie Structurale (IPBS), Université de Toulouse, Centre National de La Recherche Scientifique, Université Toulouse III - Paul Sabatier (UPS), 31077 Toulouse, France
- International Research Project CNRS “MAC-TB/HIV”, Toulouse, France and Buenos Aires, Argentina
| | - Luciana Balboa
- International Research Project CNRS “MAC-TB/HIV”, Toulouse, France and Buenos Aires, Argentina
- Instituto de Investigaciones Biomédicas en Retrovirus y SIDA, Universidad de Buenos Aires-CONICET, Buenos Aires C1121ABG, Argentina
- Instituto de Medicina Experimental-CONICET, Academia Nacional de Medicina, Buenos Aires C1425ASU, Argentina
| | - Sarah Palmer
- The Westmead Institute for Medical Research, Centre for Virus Research, Westmead, NSW 2145, Australia
- University of Sydney, Faculty of Medicine and Health, Sydney, NSW 2050, Australia
| | - Gabriel Duette
- The Westmead Institute for Medical Research, Centre for Virus Research, Westmead, NSW 2145, Australia
- University of Sydney, Faculty of Medicine and Health, Sydney, NSW 2050, Australia
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Reid VA, Ramos EI, Veerapandian R, Carmona A, Gadad SS, Dhandayuthapani S. Differential Expression of lncRNAs in HIV Patients with TB and HIV-TB with Anti-Retroviral Treatment. Noncoding RNA 2024; 10:40. [PMID: 39051374 PMCID: PMC11270221 DOI: 10.3390/ncrna10040040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 06/26/2024] [Accepted: 07/10/2024] [Indexed: 07/27/2024] Open
Abstract
Tuberculosis (TB) is the leading cause of death among people with HIV-1 infection. To improve the diagnosis and treatment of HIV-TB patients, it is important to understand the mechanisms underlying these conditions. Here, we used an integrated genomics approach to analyze and determine the lncRNAs that are dysregulated in HIV-TB patients and HIV-TB patients undergoing anti-retroviral therapy (ART) using a dataset available in the public domain. The analyses focused on the portion of the genome transcribed into non-coding transcripts, which historically have been poorly studied and received less focus. This revealed that Mtb infection in HIV prominently up-regulates the expression of long non-coding RNA (lncRNA) genes DAAM2-AS1, COL4A2-AS1, LINC00599, AC008592.1, and CLRN1-AS1 and down-regulates the expression of lncRNAs AC111000.4, AC100803.3, AC016168.2, AC245100.7, and LINC02073. It also revealed that ART down-regulates the expression of some lncRNA genes (COL4A2-AS1, AC079210.1, MFA-AS1, and LINC01993) that are highly up-regulated in HIV-TB patients. Furthermore, the interrogation of the genomic regions that are associated with regulated lncRNAs showed enrichment for biological processes linked to immune pathways in TB-infected conditions. However, intriguingly, TB patients treated with ART showed completely opposite and non-overlapping pathways. Our findings suggest that lncRNAs could be used to identify critical diagnostic, prognostic, and treatment targets for HIV-TB patients.
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Affiliation(s)
- Victoria A. Reid
- Center of Emphasis in Infectious Diseases, Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA; (V.A.R.); (R.V.); (A.C.)
- Center of Emphasis in Cancer, Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA;
| | - Enrique I. Ramos
- Center of Emphasis in Cancer, Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA;
- Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX 79968, USA
| | - Raja Veerapandian
- Center of Emphasis in Infectious Diseases, Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA; (V.A.R.); (R.V.); (A.C.)
| | - Areanna Carmona
- Center of Emphasis in Infectious Diseases, Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA; (V.A.R.); (R.V.); (A.C.)
| | - Shrikanth S. Gadad
- Center of Emphasis in Infectious Diseases, Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA; (V.A.R.); (R.V.); (A.C.)
- Center of Emphasis in Cancer, Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA;
- Frederick L. Francis Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA
| | - Subramanian Dhandayuthapani
- Center of Emphasis in Infectious Diseases, Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA; (V.A.R.); (R.V.); (A.C.)
- Center of Emphasis in Cancer, Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA;
- Frederick L. Francis Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX 79905, USA
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7
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Singh M, Patel B, Seo M, Ahn P, Wais N, Shen H, Nakka S, Kishore P, Venketaraman V. TB and HIV induced immunosenescence: where do vaccines play a role? FRONTIERS IN AGING 2024; 5:1385963. [PMID: 38903242 PMCID: PMC11188299 DOI: 10.3389/fragi.2024.1385963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 05/13/2024] [Indexed: 06/22/2024]
Abstract
This paper tackles the complex interplay between Human Immunodeficiency virus (HIV-1) and Mycobacterium tuberculosis (M. tuberculosis) infections, particularly their contribution to immunosenescence, the age-related decline in immune function. Using the current literature, we discuss the immunological mechanisms behind TB and HIV-induced immunosenescence and critically evaluate the BCG (Bacillus Calmette-Guérin) vaccine's role. Both HIV-1 and M. tuberculosis demonstrably accelerate immunosenescence: M. tuberculosis through DNA modification and heightened inflammation, and HIV-1 through chronic immune activation and T cell production compromise. HIV-1 and M. tuberculosis co-infection further hastens immunosenescence by affecting T cell differentiation, underscoring the need for prevention and treatment. Furthermore, the use of the BCG tuberculosis vaccine is contraindicated in patients who are HIV positive and there is a lack of investigation regarding the use of this vaccine in patients who develop HIV co-infection with possible immunosenescence. As HIV does not currently have a vaccine, we focus our review more so on the BCG vaccine response as a result of immunosenescence. We found that there are overall limitations with the BCG vaccine, one of which is that it cannot necessarily prevent re-occurrence of infection due to effects of immunosenescence or protect the elderly due to this reason. Overall, there is conflicting evidence to show the vaccine's usage due to factors involving its production and administration. Further research into developing a vaccine for HIV and improving the BCG vaccine is warranted to expand scientific understanding for public health and beyond.
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Affiliation(s)
- Mona Singh
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, United States
| | - Bhumika Patel
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, United States
| | - Michael Seo
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, United States
| | - Phillip Ahn
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, United States
| | - Nejma Wais
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, United States
| | - Haley Shen
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, United States
| | - SriHarsha Nakka
- Kempegowda Institute of Medical Sciences, Bengaluru, Karnataka, India
- Masters of Public Health, Chamberlain University, Addison, IL, United States
| | - Priya Kishore
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, United States
| | - Vishwanath Venketaraman
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, United States
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Windels EM, Wampande EM, Joloba ML, Boom WH, Goig GA, Cox H, Hella J, Borrell S, Gagneux S, Brites D, Stadler T. HIV co-infection is associated with reduced Mycobacterium tuberculosis transmissibility in sub-Saharan Africa. PLoS Pathog 2024; 20:e1011675. [PMID: 38696531 DOI: 10.1371/journal.ppat.1011675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 05/14/2024] [Accepted: 04/10/2024] [Indexed: 05/04/2024] Open
Abstract
Persons living with HIV are known to be at increased risk of developing tuberculosis (TB) disease upon infection with Mycobacterium tuberculosis (Mtb). However, it has remained unclear how HIV co-infection affects subsequent Mtb transmission from these patients. Here, we customized a Bayesian phylodynamic framework to estimate the effects of HIV co-infection on the Mtb transmission dynamics from sequence data. We applied our model to four Mtb genomic datasets collected in sub-Saharan African countries with a generalized HIV epidemic. Our results confirm that HIV co-infection is a strong risk factor for developing active TB. Additionally, we demonstrate that HIV co-infection is associated with a reduced effective reproductive number for TB. Stratifying the population by CD4+ T-cell count yielded similar results, suggesting that, in this context, CD4+ T-cell count is not a better predictor of Mtb transmissibility than HIV infection status alone. Together, our genome-based analyses complement observational household contact studies, and more firmly establish the negative association between HIV co-infection and Mtb transmissibility.
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Affiliation(s)
- Etthel M Windels
- Department of Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland
- Swiss Tropical and Public Health Institute, Allschwil, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | | | | | - W Henry Boom
- Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, Ohio, United States of America
| | - Galo A Goig
- Swiss Tropical and Public Health Institute, Allschwil, Switzerland
- University of Basel, Basel, Switzerland
| | - Helen Cox
- University of Cape Town, Cape Town, South Africa
| | - Jerry Hella
- Ifakara Health Institute, Dar es Salaam, Tanzania
| | - Sonia Borrell
- Swiss Tropical and Public Health Institute, Allschwil, Switzerland
- University of Basel, Basel, Switzerland
| | - Sebastien Gagneux
- Swiss Tropical and Public Health Institute, Allschwil, Switzerland
- University of Basel, Basel, Switzerland
| | - Daniela Brites
- Swiss Tropical and Public Health Institute, Allschwil, Switzerland
- University of Basel, Basel, Switzerland
| | - Tanja Stadler
- Department of Biosystems Science and Engineering, ETH Zürich, Basel, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
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9
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Nosik M, Ryzhov K, Kudryavtseva AV, Kuimova U, Kravtchenko A, Sobkin A, Zverev V, Svitich O. Decreased IL-1 β Secretion as a Potential Predictor of Tuberculosis Recurrence in Individuals Diagnosed with HIV. Biomedicines 2024; 12:954. [PMID: 38790916 PMCID: PMC11117744 DOI: 10.3390/biomedicines12050954] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 04/14/2024] [Accepted: 04/22/2024] [Indexed: 05/26/2024] Open
Abstract
Background: The mechanisms of the formation of immunological competence against tuberculosis (TB), and especially those associated with HIV co-infection, remain poorly understood. However, there is an urgent need for risk recurrence predictive biomarkers, as well as for predictors of successful treatment outcomes. The goal of the study was to identify possible immunological markers of TB recurrence in individuals with HIV/TB co-infection. Methods: The plasma levels of IFN-γ, TNF-α, IL-10, and IL-1β (cytokines which play important roles in the immune activation and protection against Mycobacterium tuberculosis) were measured using ELISA EIA-BEST kits. The cytokine concentrations were determined using a standard curve obtained with the standards provided by the manufacturer of each kit. Results: A total of 211 individuals were enrolled in the study as follows: 62 patients with HIV/TB co-infection, 52 with HIV monoinfection, 52 with TB monoinfection, and 45 healthy donors. Out of the 62 patients with HIV/TB, 75.8% (47) of patients were newly diagnosed with HIV and TB, and 24.2% (15) displayed recurrent TB and were newly diagnosed with HIV. Decreased levels of IFN-γ, TNF-α, and IL-10 were observed in patients with HIV/TB when compared with HIV and TB patients. However, there was no difference in IFN-γ, TNF-α, or IL-10 secretion between both HIV/TB groups. At the same time, an almost 4-fold decrease in Il-1β levels was detected in the HIV/TB group with TB recurrence when compared with the HIV/TB group (p = 0.0001); a 2.8-fold decrease when compared with HIV patients (p = 0.001); and a 2.2-fold decrease with newly diagnosed TB patients (p = 0.001). Conclusions: Significantly decreased Il-1β levels in HIV/TB patients' cohort with secondary TB indicate that this cytokine can be a potential biomarker of TB recurrence.
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Affiliation(s)
- Marina Nosik
- I.I. Mechnikov Institute of Vaccines and Sera, 105064 Moscow, Russia; (K.R.); (V.Z.); (O.S.)
| | - Konstantin Ryzhov
- I.I. Mechnikov Institute of Vaccines and Sera, 105064 Moscow, Russia; (K.R.); (V.Z.); (O.S.)
| | - Asya V. Kudryavtseva
- La Facultad de Ciencias Médicas, Universidad Bernardo O’Higgings-Escuela de Medicina, Santiago 8370993, Chile;
| | - Ulyana Kuimova
- Central Research Institute of Epidemiology, Rospotrebnadzor, 111123 Moscow, Russia; (U.K.); (A.K.)
| | - Alexey Kravtchenko
- Central Research Institute of Epidemiology, Rospotrebnadzor, 111123 Moscow, Russia; (U.K.); (A.K.)
| | - Alexandr Sobkin
- G.A. Zaharyan Moscow Tuberculosis Clinic, Department for Treatment of TB Patients with HIV, 125466 Moscow, Russia;
| | - Vitaly Zverev
- I.I. Mechnikov Institute of Vaccines and Sera, 105064 Moscow, Russia; (K.R.); (V.Z.); (O.S.)
| | - Oxana Svitich
- I.I. Mechnikov Institute of Vaccines and Sera, 105064 Moscow, Russia; (K.R.); (V.Z.); (O.S.)
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10
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Marangi M, Boughattas S, Valzano F, La Bella G, De Nittis R, Margaglione M, Arena F. Prevalence of Blastocystis sp. and other gastrointestinal pathogens among diarrheic COVID-19 patients in Italy. New Microbes New Infect 2024; 58:101228. [PMID: 38406386 PMCID: PMC10884970 DOI: 10.1016/j.nmni.2024.101228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Revised: 02/05/2024] [Accepted: 02/05/2024] [Indexed: 02/27/2024] Open
Abstract
Background Gastrointestinal pathogens (GPs) contribute significantly to the burden of illness worldwide with diarrhoea being the most common among gastrointestinal symptoms (GSs). In the COVID-19 disease, diarrhoea, could be one of the initial presenting symptoms. However, no data on the potential correlation between diarrhoea-causing pathogens and SARS-CoV-2 infection are available. Therefore, we carried out a 2-years retrospective study aimed to evaluate the prevalence of "classic" GPs among SARS-CoV-2 infected and non-infected patients with diarrhoea in Italy. Methods Results of SARS-CoV-2 research from nasopharyngeal and detection of GPs from stool swab samples by Allplex™ SARS-CoV-2 and GI Virus, Bacteria and Parasite Assay were analysed for all patients with diarrhoea referring to Policlinico Ospedaliero Universitario, Foggia, (Italy) from February 2022 to October 2023. Results Out of the 833 involved patients, 81 (3.9%) were COVID-19 positive, while 752 (90.3%) were COVID-19 negative. Among COVID-19-positive patients, 37% (n = 30/81) were found positive for one or more GPs with a higher prevalence of protozoan parasites (18.5%) (Blastocystis ST1-ST4 subtypes, Dientamoeba fragilis genotype I), followed by bacteria (7.4%) (Campylobacter sp., Salmonella sp.). Viral pathogens were more frequent among COVID-19 negative patients (Adenovirus, Norovirus). Among GPs, Blastocystis ST3 subtype was the most prevalent registered in the 16% of patients (p = 0.0001). Conclusions Based on obtained results, a likely interaction between the classic GPs and SARS-CoV-2 infection can be speculated, driven by protozoan parasites. Moreover, these results also provide baseline data to understand more deeply Blastocystis sp. role in this scenario of dysbiosis, particularly in those cases of SARS-CoV-2 co-infection.
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Affiliation(s)
- Marianna Marangi
- Department of Clinical and Experimental Medicine, University of Foggia, Viale Luigi Pinto, 71122, Foggia, Italy
| | | | - Felice Valzano
- Department of Clinical and Experimental Medicine, University of Foggia, Viale Luigi Pinto, 71122, Foggia, Italy
| | - Gianfranco La Bella
- Department of Clinical and Experimental Medicine, University of Foggia, Viale Luigi Pinto, 71122, Foggia, Italy
- Istituto Zooprofilattico Sperimentale della Puglia e della Basilicata, Via Manfredonia 20, 71121, Foggia, Italy
| | - Rosella De Nittis
- Microbiology and Virology Unit, Ospedali Riuniti, Viale Luigi Pinto, 71122, Foggia, Italy
| | - Maurizio Margaglione
- Department of Clinical and Experimental Medicine, University of Foggia, Viale Luigi Pinto, 71122, Foggia, Italy
| | - Fabio Arena
- Department of Clinical and Experimental Medicine, University of Foggia, Viale Luigi Pinto, 71122, Foggia, Italy
- Microbiology and Virology Unit, Ospedali Riuniti, Viale Luigi Pinto, 71122, Foggia, Italy
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11
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Zhang L, Cai M, Su B, Ma Y, Zhang Y. Mitochondrial Metabolism in Alveolar Macrophages of Patients Infected with HIV, Tuberculosis, and HIV/Tuberculosis. AIDS Res Hum Retroviruses 2024; 40:148-157. [PMID: 37885217 DOI: 10.1089/aid.2023.0064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2023] Open
Abstract
Tuberculosis (TB) is one of the most common opportunistic infections and is a leading cause of mortality in patients with HIV and AIDS. HIV infection causes serious defects in the host immune system and increases the risk of active TB. TB infection promotes HIV replication and aggravates host damage in patients with HIV/AIDS. Alveolar macrophages (AMs) are essential immune cells during TB and HIV infections. AMs undergo a shift in mitochondrial metabolism during TB or HIV infection, that is, metabolic reprogramming, allowing them to act in the form of classical activated macrophages (M1) and alternative activated macrophages (M2) at different stages of infection. We reviewed the alterations in the mitochondrial energy metabolism of AMs in patients with HIV, TB, and HIV/TB to provide ideas for further research on the role of metabolic reprogramming by AMs in the pathogeneses of HIV, TB, and HIV/TB coinfection.
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Affiliation(s)
- Ling Zhang
- Department of Respiratory and Critical Care Medicine, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Miaotian Cai
- Department of Respiratory and Critical Care Medicine, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Bin Su
- Beijing Key Laboratory for HIV/AIDS Research, Clinical and Research Center for Infectious Diseases, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Yingmin Ma
- Department of Respiratory and Critical Care Medicine, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
| | - Yulin Zhang
- Department of Respiratory and Critical Care Medicine, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, China
- Laboratory for Clinical Medicine, Capital Medical University, Beijing, China
- Beijing Research Center for Respiratory Infectious Diseases, Beijing, China
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12
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Kalyan M, Sharma S, Kaur P, Sharma A, Verma I. Antibody response to mycobacterial Rpf B protein and its immunodominant peptides in HIV-TB co-infected individuals. Tuberculosis (Edinb) 2024; 144:102464. [PMID: 38141523 DOI: 10.1016/j.tube.2023.102464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Revised: 12/10/2023] [Accepted: 12/11/2023] [Indexed: 12/25/2023]
Abstract
Diagnosis of TB at early stages of HIV infection may lead to timely intervention for improving patient outcome. Antibodies to Mycobacterium tuberculosis recombinant RpfB protein and two immunodominant peptides of Rpf B protein were evaluated in the sera of HIV +TB+, HIV+ and HIV- pulmonary TB patients by ELISA. Serum antibodies from 90 % and 65 % of HIV+TB+ patients reacted to recombinant RpfB protein and synthetic peptide RpfP1 respectively. Overall, this study shows that resuscitation promoting factor B elicits humoral antibody response in HIV+TB+ co-infected individuals and be proposed as a potential biomarker for diagnosis of HIV+TB+ patients, however further longitudinal follow up studies are warranted.
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Affiliation(s)
- Madhur Kalyan
- Department of Biochemistry, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India.
| | - Sumedha Sharma
- Department of Biochemistry, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India.
| | - Prabhdeep Kaur
- Department of Biochemistry, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India.
| | - Aman Sharma
- Department of Internal Medicine, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India.
| | - Indu Verma
- Department of Biochemistry, Post Graduate Institute of Medical Education and Research, Chandigarh, 160012, India.
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13
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Oyanedel D, Lagorce A, Bruto M, Haffner P, Morot A, Labreuche Y, Dorant Y, de La Forest Divonne S, Delavat F, Inguimbert N, Montagnani C, Morga B, Toulza E, Chaparro C, Escoubas JM, Gueguen Y, Vidal-Dupiol J, de Lorgeril J, Petton B, Degremont L, Tourbiez D, Pimparé LL, Leroy M, Romatif O, Pouzadoux J, Mitta G, Le Roux F, Charrière GM, Travers MA, Destoumieux-Garzón D. Cooperation and cheating orchestrate Vibrio assemblages and polymicrobial synergy in oysters infected with OsHV-1 virus. Proc Natl Acad Sci U S A 2023; 120:e2305195120. [PMID: 37751557 PMCID: PMC10556616 DOI: 10.1073/pnas.2305195120] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 08/10/2023] [Indexed: 09/28/2023] Open
Abstract
Polymicrobial infections threaten the health of humans and animals but remain understudied in natural systems. We recently described the Pacific Oyster Mortality Syndrome (POMS), a polymicrobial disease affecting oyster production worldwide. In the French Atlantic coast, the disease involves coinfection with ostreid herpesvirus 1 (OsHV-1) and virulent Vibrio. However, it is unknown whether consistent Vibrio populations are associated with POMS in different regions, how Vibrio contribute to POMS, and how they interact with OsHV-1 during pathogenesis. By connecting field-based approaches in a Mediterranean ecosystem, laboratory infection assays and functional genomics, we uncovered a web of interdependencies that shape the structure and function of the POMS pathobiota. We show that Vibrio harveyi and Vibrio rotiferianus are predominant in OsHV-1-diseased oysters and that OsHV-1 drives the partition of the Vibrio community observed in the field. However only V. harveyi synergizes with OsHV-1 by promoting mutual growth and accelerating oyster death. V. harveyi shows high-virulence potential and dampens oyster cellular defenses through a type 3 secretion system, making oysters a more favorable niche for microbe colonization. In addition, V. harveyi produces a key siderophore called vibrioferrin. This important resource promotes the growth of V. rotiferianus, which cooccurs with V. harveyi in diseased oysters, and behaves as a cheater by benefiting from V. harveyi metabolite sharing. Our data show that cooperative behaviors contribute to synergy between bacterial and viral coinfecting partners. Additional cheating behaviors further shape the polymicrobial consortium. Controlling cooperative behaviors or countering their effects opens avenues for mitigating polymicrobial diseases.
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Affiliation(s)
- Daniel Oyanedel
- Interactions Hôtes Pathogènes Environnements (IHPE), Université de Montpellier, CNRS, Ifremer, Université de Perpignan Via Domitia, MontpellierF-34090, France
| | - Arnaud Lagorce
- Interactions Hôtes Pathogènes Environnements (IHPE), Université de Montpellier, CNRS, Ifremer, Université de Perpignan Via Domitia, MontpellierF-34090, France
| | - Maxime Bruto
- Ifremer, Unité Physiologie Fonctionnelle des Organismes Marins, ZI de la Pointe du Diable, PlouzanéF-29280, France
- Sorbonne Université, Université Pierre et Marie Curie Paris 06, CNRS, UMR8227, Integrative Biology of Marine Models, Station Biologique de Roscoff, RoscoffF-29680, France
| | - Philippe Haffner
- Interactions Hôtes Pathogènes Environnements (IHPE), Université de Montpellier, CNRS, Ifremer, Université de Perpignan Via Domitia, MontpellierF-34090, France
| | - Amandine Morot
- Université de Bretagne Occidentale, CNRS, Institut de recherche pour le développement (IRD), Ifremer, Laboratoire des sciences de l'environnement marin (LEMAR), Plouzané,F-29280, France
- Laboratoire de Biotechnologie et Chimie Marines, Université Bretagne Sud, EMR CNRS 6076, Institut Universitaire Européen de la Mer, LorientF-56100, France
| | - Yannick Labreuche
- Ifremer, Unité Physiologie Fonctionnelle des Organismes Marins, ZI de la Pointe du Diable, PlouzanéF-29280, France
- Sorbonne Université, Université Pierre et Marie Curie Paris 06, CNRS, UMR8227, Integrative Biology of Marine Models, Station Biologique de Roscoff, RoscoffF-29680, France
| | - Yann Dorant
- Interactions Hôtes Pathogènes Environnements (IHPE), Université de Montpellier, CNRS, Ifremer, Université de Perpignan Via Domitia, MontpellierF-34090, France
| | - Sébastien de La Forest Divonne
- Interactions Hôtes Pathogènes Environnements (IHPE), Université de Montpellier, CNRS, Ifremer, Université de Perpignan Via Domitia, MontpellierF-34090, France
| | - François Delavat
- Nantes Université, CNRS, Unité en Sciences Biologiques et Biotechnologies (US2B), UMR6286, Nantes,F-44000, France
| | - Nicolas Inguimbert
- Centre de Recherches Insulaires et OBservatoire de l’Environnement (CRIOBE), UAR3278, Ecole Pratique des Hautes Etudes (EPHE), Université de Perpignan Via Domitia, CNRS, PerpignanF-66860, France
| | - Caroline Montagnani
- Interactions Hôtes Pathogènes Environnements (IHPE), Université de Montpellier, CNRS, Ifremer, Université de Perpignan Via Domitia, MontpellierF-34090, France
| | - Benjamin Morga
- Ifremer, Adaptation Santé des invertébrés Marins (ASIM), La TrembladeF-17390, France
| | - Eve Toulza
- Interactions Hôtes Pathogènes Environnements (IHPE), Université de Montpellier, CNRS, Ifremer, Université de Perpignan Via Domitia, MontpellierF-34090, France
| | - Cristian Chaparro
- Interactions Hôtes Pathogènes Environnements (IHPE), Université de Montpellier, CNRS, Ifremer, Université de Perpignan Via Domitia, MontpellierF-34090, France
| | - Jean-Michel Escoubas
- Interactions Hôtes Pathogènes Environnements (IHPE), Université de Montpellier, CNRS, Ifremer, Université de Perpignan Via Domitia, MontpellierF-34090, France
| | - Yannick Gueguen
- Interactions Hôtes Pathogènes Environnements (IHPE), Université de Montpellier, CNRS, Ifremer, Université de Perpignan Via Domitia, MontpellierF-34090, France
- MARine Biodiversity, Exploitation and Conservation (MARBEC) Univ Montpellier, CNRS, Ifremer, IRD, SèteF-34200, France
| | - Jeremie Vidal-Dupiol
- Interactions Hôtes Pathogènes Environnements (IHPE), Université de Montpellier, CNRS, Ifremer, Université de Perpignan Via Domitia, MontpellierF-34090, France
| | - Julien de Lorgeril
- Interactions Hôtes Pathogènes Environnements (IHPE), Université de Montpellier, CNRS, Ifremer, Université de Perpignan Via Domitia, MontpellierF-34090, France
- Ifremer, IRD, Univ Nouvelle-Calédonie, Univ La Réunion, ENTROPIE, Nouméa, Nouvelle-Calédonie,F-98800, France
| | - Bruno Petton
- Ifremer, Unité Physiologie Fonctionnelle des Organismes Marins, ZI de la Pointe du Diable, PlouzanéF-29280, France
- Université de Bretagne Occidentale, CNRS, Institut de recherche pour le développement (IRD), Ifremer, Laboratoire des sciences de l'environnement marin (LEMAR), Plouzané,F-29280, France
| | - Lionel Degremont
- Ifremer, Adaptation Santé des invertébrés Marins (ASIM), La TrembladeF-17390, France
| | - Delphine Tourbiez
- Ifremer, Adaptation Santé des invertébrés Marins (ASIM), La TrembladeF-17390, France
| | - Léa-Lou Pimparé
- Interactions Hôtes Pathogènes Environnements (IHPE), Université de Montpellier, CNRS, Ifremer, Université de Perpignan Via Domitia, MontpellierF-34090, France
| | - Marc Leroy
- Interactions Hôtes Pathogènes Environnements (IHPE), Université de Montpellier, CNRS, Ifremer, Université de Perpignan Via Domitia, MontpellierF-34090, France
| | - Océane Romatif
- Interactions Hôtes Pathogènes Environnements (IHPE), Université de Montpellier, CNRS, Ifremer, Université de Perpignan Via Domitia, MontpellierF-34090, France
| | - Juliette Pouzadoux
- Interactions Hôtes Pathogènes Environnements (IHPE), Université de Montpellier, CNRS, Ifremer, Université de Perpignan Via Domitia, MontpellierF-34090, France
| | - Guillaume Mitta
- Interactions Hôtes Pathogènes Environnements (IHPE), Université de Montpellier, CNRS, Ifremer, Université de Perpignan Via Domitia, MontpellierF-34090, France
- Ifremer, Université de Polynésie Française, IRD, Institut Louis Malardé (ILM), Ecosystèmes Insulaires Océaniens (EIO), VairaoF-98719, Polynésie Française
| | - Frédérique Le Roux
- Ifremer, Unité Physiologie Fonctionnelle des Organismes Marins, ZI de la Pointe du Diable, PlouzanéF-29280, France
- Sorbonne Université, Université Pierre et Marie Curie Paris 06, CNRS, UMR8227, Integrative Biology of Marine Models, Station Biologique de Roscoff, RoscoffF-29680, France
| | - Guillaume M. Charrière
- Interactions Hôtes Pathogènes Environnements (IHPE), Université de Montpellier, CNRS, Ifremer, Université de Perpignan Via Domitia, MontpellierF-34090, France
| | - Marie-Agnès Travers
- Interactions Hôtes Pathogènes Environnements (IHPE), Université de Montpellier, CNRS, Ifremer, Université de Perpignan Via Domitia, MontpellierF-34090, France
| | - Delphine Destoumieux-Garzón
- Interactions Hôtes Pathogènes Environnements (IHPE), Université de Montpellier, CNRS, Ifremer, Université de Perpignan Via Domitia, MontpellierF-34090, France
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14
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Corleis B, Bastian M, Hoffmann D, Beer M, Dorhoi A. Animal models for COVID-19 and tuberculosis. Front Immunol 2023; 14:1223260. [PMID: 37638020 PMCID: PMC10451089 DOI: 10.3389/fimmu.2023.1223260] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 07/21/2023] [Indexed: 08/29/2023] Open
Abstract
Respiratory infections cause tremendous morbidity and mortality worldwide. Amongst these diseases, tuberculosis (TB), a bacterial illness caused by Mycobacterium tuberculosis which often affects the lung, and coronavirus disease 2019 (COVID-19) caused by the Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV-2), stand out as major drivers of epidemics of global concern. Despite their unrelated etiology and distinct pathology, these infections affect the same vital organ and share immunopathogenesis traits and an imperative demand to model the diseases at their various progression stages and localizations. Due to the clinical spectrum and heterogeneity of both diseases experimental infections were pursued in a variety of animal models. We summarize mammalian models employed in TB and COVID-19 experimental investigations, highlighting the diversity of rodent models and species peculiarities for each infection. We discuss the utility of non-human primates for translational research and emphasize on the benefits of non-conventional experimental models such as livestock. We epitomize advances facilitated by animal models with regard to understanding disease pathophysiology and immune responses. Finally, we highlight research areas necessitating optimized models and advocate that research of pulmonary infectious diseases could benefit from cross-fertilization between studies of apparently unrelated diseases, such as TB and COVID-19.
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Affiliation(s)
- Björn Corleis
- Institute of Immunology, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Germany
| | - Max Bastian
- Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Germany
| | - Donata Hoffmann
- Institute of Diagnostic Virology, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Germany
| | - Martin Beer
- Institute of Diagnostic Virology, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Germany
| | - Anca Dorhoi
- Institute of Immunology, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Germany
- Faculty of Mathematics and Natural Sciences, University of Greifswald, Greifswald, Germany
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15
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Torres M, Tubay J, de losReyes A. Quantitative Assessment of a Dual Epidemic Caused by Tuberculosis and HIV in the Philippines. Bull Math Biol 2023; 85:56. [PMID: 37211585 DOI: 10.1007/s11538-023-01156-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 04/05/2023] [Indexed: 05/23/2023]
Abstract
Tuberculosis (TB) and human immunodeficiency virus (HIV) are the two major public health emergencies in the Philippines. The country is ranked fourth worldwide in TB incidence cases despite national efforts and initiatives to mitigate the disease. Concurrently, the Philippines has the fastest-growing HIV epidemic in Asia and the Pacific region. The TB-HIV dual epidemic forms a lethal combination enhancing each other's progress, driving the deterioration of immune responses. In order to understand and describe the transmission dynamics and epidemiological patterns of the co-infection, a compartmental model for TB-HIV is developed. A class of people living with HIV (PLHIV) who did not know their HIV status is incorporated into the model. These unaware PLHIV who do not seek medical treatment are potential sources of new HIV infections that could significantly influence the disease transmission dynamics. Sensitivity analysis using the partial rank correlation coefficient is performed to assess model parameters that are influential to the output of interests. The model is calibrated using available Philippine data on TB, HIV, and TB-HIV. Parameters that are identified include TB and HIV transmission rates, progression rates from exposed to active TB, and from TB-latent with HIV to active infectious TB with HIV in the AIDS stage. Uncertainty analysis is performed to identify the degree of accuracy of the estimates. Simulations predict an alarming increase of 180% and 194% in new HIV and TB-HIV infections in 2025, respectively, relative to 2019 data. These projections underscore an ongoing health crisis in the Philippines that calls for a combined and collective effort by the government and the public to take action against the lethal combination of TB and HIV.
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Affiliation(s)
- Monica Torres
- Institute of Mathematical Sciences and Physics, University of the Philippines Los Baños, Los Baños, 4031, Laguna, Philippines
| | - Jerrold Tubay
- Institute of Mathematical Sciences and Physics, University of the Philippines Los Baños, Los Baños, 4031, Laguna, Philippines.
| | - Aurelio de losReyes
- Institute of Mathematics, University of the Philippines Diliman, Quezon City, 1101, Philippines
- Biomedical Mathematics Group, Pioneer Research Center for Mathematical and Computational Sciences, Institute for Basic Science, Daejeon, 34126, Republic of Korea
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16
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Chiok KR, Dhar N, Banerjee A. Mycobacterium tuberculosis and SARS-CoV-2 co-infections: The knowns and unknowns. iScience 2023; 26:106629. [PMID: 37091987 PMCID: PMC10082467 DOI: 10.1016/j.isci.2023.106629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/25/2023] Open
Abstract
Health impacts of Mycobacterium tuberculosis (Mtb) and SARS-CoV-2 co-infections are not fully understood. Both pathogens modulate host responses and induce immunopathology with extensive lung damage. With a quarter of the world's population harboring latent TB, exploring the relationship between SARS-CoV-2 infection and its effect on the transition of Mtb from latent to active form is paramount to control this pathogen. The effects of active Mtb infection on establishment and severity of COVID-19 are also unknown, despite the ability of TB to orchestrate profound long-lasting immunopathologies in the lungs. Absence of mechanistic studies and co-infection models hinder the development of effective interventions to reduce the health impacts of SARS-CoV-2 and Mtb co-infection. Here, we highlight dysregulated immune responses induced by SARS-CoV-2 and Mtb, their potential interplay, and implications for co-infection in the lungs. As both pathogens master immunomodulation, we discuss relevant converging and diverging immune-related pathways underlying SARS-CoV-2 and Mtb co-infections.
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Affiliation(s)
- Kim R Chiok
- Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, SK S7N 5E3, Canada
| | - Neeraj Dhar
- Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, SK S7N 5E3, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
- Respiratory Research Centre, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
| | - Arinjay Banerjee
- Vaccine and Infectious Disease Organization, University of Saskatchewan, Saskatoon, SK S7N 5E3, Canada
- Respiratory Research Centre, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
- Department of Veterinary Microbiology, University of Saskatchewan, Saskatoon, SK S7N 5B4, Canada
- Department of Biology, University of Waterloo, Waterloo, ON N2L 3G1, Canada
- Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
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17
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Mhmoud NA. Association of Toll-like Receptors 1, 2, 4, 6, 8, 9 and 10 Genes Polymorphisms and Susceptibility to Pulmonary Tuberculosis in Sudanese Patients. Immunotargets Ther 2023; 12:47-75. [PMID: 37051380 PMCID: PMC10085002 DOI: 10.2147/itt.s404915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Accepted: 03/29/2023] [Indexed: 04/08/2023] Open
Abstract
Background Genetic factors are important contributors to the development of a wide range of complex disease. Polymorphisms in genes encoding for toll-like receptors (TLRs) usually influence the efficiency of the immune response to infection and are associated with disease susceptibility and progression. Therefore, we aim to describe the first association between TLR1, TLR2, TLR4 TLR6, TLR8, TLR9 and TLR10 genes polymorphisms and susceptibility to pulmonary tuberculosis (PTB) in Sudanese patients. Methodology Here we performed a case study which included 160 tuberculosis patients and 220 healthy matched controls from Sudan. In the study population, we evaluated the possible association between 86 markers in TLR1, TLR2, TLR4 TLR6, TLR8, TLR9 and TLR10 genes polymorphisms and susceptibility to PTB disease in Sudanese population using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Results From our results it appeared that in the PTB population the TLR1 (rs5743557, rs4833095, rs5743596), TLR2 (rs5743704, rs5743708, rs3804099), TLR4 (rs4986790, rs4986791), TLR6 (rs5743810), TLR8 (rs3764879, rs3764880), TLR9 (rs352165, rs352167, rs187084) and TLR10 (rs4129009) were significantly more often encountered (p<0.0001) than in the control population and were associated with PTB in the Sudanese population. For the other polymorphisms tested, no association with PTB was found in the population tested. Conclusion The work describes novel mutations in TLR1, TLR2, TLR4, TLR6, TLR8, TLR9 and TLR10 genes and their association with PTB infection in Sudanese population. These results will enhance our ability to determine the risk of developing the disease by targeting specific TLR pathways to reduce the severity of the disease. Future studies are needed in a larger sample to replicate our findings and understand the mechanism of association of TLR polymorphism in PTB.
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Affiliation(s)
- Najwa A Mhmoud
- Faculty of Medical Laboratory Sciences, Department of Medical Microbiology and Immunology, University of Khartoum, Khartoum, Sudan
- Correspondence: Najwa A Mhmoud, Faculty of Medical Laboratory Sciences, Department of Medical Microbiology and Immunology University of Khartoum, P.O. Box 102, Khartoum, Sudan, Fax +249-83-383590, Email
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18
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Qin H, Wang Y, Huang L, Huang Y, Ye J, Liang G, Zhou C, Liang D, Liang X, Zhao Y, Lin M. Efficacy and Risk Factors of Interferon-Gamma Release Assays among HIV-Positive Individuals. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2023; 20:4556. [PMID: 36901567 PMCID: PMC10001609 DOI: 10.3390/ijerph20054556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 03/01/2023] [Accepted: 03/02/2023] [Indexed: 06/18/2023]
Abstract
Latent tuberculosis is prevalent in HIV-infected people and has an impact on the progression of AIDS. The aim of this study is to match a more accurate IGRA method for the better detection of latent tuberculosis infection in HIV patients. All 2394 patients enrolled were tested using three IGRA methods. The positive rate consistency of pairwise comparison and risk factors were analyzed. Receiver operator characteristic (ROC) curve analysis was applied to evaluate the diagnostic value of T-SPOTTB. The positive rates of the three methods were statistically different (p < 0.001). The CD4+ T cell number statistically impacted the QuantiFERON and Wan Tai tests after the analysis with univariate logistic regression, while no statistical difference was observed in T-SPOT.TB. Additionally, there was a better sensitivity and specificity of T-SPOT.TB if the positive cut-off value of ESAT-6 and CFP-10 was 4.5 and 5.5, respectively. This study provides an insight into the IGRA methods and demonstrated that the positive response detected via QuantiFERON declined with decreased CD4+ T cells in the HIV-infected population; T-SPOT.TB functions independently of the CD4+ T cell level and Wan Tai was affected in some cases. This will be useful in the diagnosis of LTBI in the HIV-infected population, which will be a key step toward TB elimination in China.
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Affiliation(s)
- Huifang Qin
- Guangxi Key Laboratory of Major Infectious Disease Prevention and Control and Biosafety Emergency Response, Nanning 530028, China
- Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention, Nanning 530028, China
| | - Yiting Wang
- Institute for Immunization and Prevention, Beijing Center for Disease Prevention and Control, Beijing 100013, China
- National Tuberculosis Reference Laboratory, Chinese Center for Disease Control and Prevention, Beijing 102206, China
| | - Liwen Huang
- Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention, Nanning 530028, China
| | - Yan Huang
- Guangxi Key Laboratory of Major Infectious Disease Prevention and Control and Biosafety Emergency Response, Nanning 530028, China
- Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention, Nanning 530028, China
| | - Jing Ye
- Guangxi Key Laboratory of Major Infectious Disease Prevention and Control and Biosafety Emergency Response, Nanning 530028, China
- Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention, Nanning 530028, China
| | - Guijin Liang
- Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention, Nanning 530028, China
| | - Chongxing Zhou
- Guangxi Key Laboratory of Major Infectious Disease Prevention and Control and Biosafety Emergency Response, Nanning 530028, China
- Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention, Nanning 530028, China
| | - Dabin Liang
- Guangxi Key Laboratory of Major Infectious Disease Prevention and Control and Biosafety Emergency Response, Nanning 530028, China
- Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention, Nanning 530028, China
| | - Xiaoyan Liang
- Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention, Nanning 530028, China
| | - Yanlin Zhao
- National Tuberculosis Reference Laboratory, Chinese Center for Disease Control and Prevention, Beijing 102206, China
| | - Mei Lin
- Guangxi Key Laboratory of Major Infectious Disease Prevention and Control and Biosafety Emergency Response, Nanning 530028, China
- Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention, Nanning 530028, China
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19
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Palma Albornoz SP, Fraga-Silva TF, de Carvalho RV, Rodrigues TS, Gembre AF, de Oliveira RS, de Souza FM, Corrêa GF, Ramalho LN, Carlos D, de Almeida DC, Câmara NO, Zamboni DS, Takahashi VN, Sorgi CA, Faccioli LH, Medeiros AI, Costa DL, Bonato VL. Cell death induced by NLRP3-palmitate axis impairs pulmonary damage tolerance and aggravates immunopathology during obesity-tuberculosis comorbidity. J Pathol 2023; 259:291-303. [PMID: 36441400 DOI: 10.1002/path.6041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 09/27/2022] [Accepted: 11/24/2022] [Indexed: 11/29/2022]
Abstract
A low-grade and persistent inflammation, which is the hallmark of obesity, requires the participation of NLRP3 and cell death. During Mycobacterium tuberculosis infection, NLRP3 signaling is important for bacterial killing by macrophages in vitro but was shown to be dispensable for host protection in vivo. We hypothesized that during obesity-tuberculosis (TB) comorbidity, NLRP3 signaling might play a detrimental role by inducing excessive inflammation. We employed a model of high-fat-diet-induced obesity, followed by M. tuberculosis infection in C57BL/6 mice. Obese mice presented increased susceptibility to infection and pulmonary immunopathology compared to lean mice. Using treatment with NLRP3 antagonist and Nlrp3-/- mice, we showed that NLRP3 signaling promoted cell death, with no effect in bacterial loads. The levels of palmitate were higher in the lungs of obese infected mice compared to lean counterparts, and we observed that this lipid increased M. tuberculosis-induced macrophage death in vitro, which was dependent on NLRP3 and caspase-1. At the chronic phase, although lungs of obese Nlrp3-/- mice showed an indication of granuloma formation compared to obese wild-type mice, there was no difference in the bacterial load. Our findings indicate that NLRP3 may be a potential target for host-directed therapy to reduce initial and severe inflammation-mediated disease and to treat comorbidity-associated TB. © 2022 The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Sandra P Palma Albornoz
- Basic and Applied Immunology Program, Ribeirao Preto Medical School, University of Sao Paulo, São Paulo, Brazil
| | - Thais Fc Fraga-Silva
- Department of Biochemistry and Immunology, Ribeirao Preto Medical School, University of Sao Paulo, São Paulo, Brazil
| | - Renan Vh de Carvalho
- Basic and Applied Immunology Program, Ribeirao Preto Medical School, University of Sao Paulo, São Paulo, Brazil
| | - Tamara S Rodrigues
- Basic and Applied Immunology Program, Ribeirao Preto Medical School, University of Sao Paulo, São Paulo, Brazil
| | - Ana Flávia Gembre
- Department of Biochemistry and Immunology, Ribeirao Preto Medical School, University of Sao Paulo, São Paulo, Brazil
| | - Rômulo Silva de Oliveira
- Basic and Applied Immunology Program, Ribeirao Preto Medical School, University of Sao Paulo, São Paulo, Brazil
| | - Fernanda Mesquita de Souza
- Basic and Applied Immunology Program, Ribeirao Preto Medical School, University of Sao Paulo, São Paulo, Brazil
| | - Giseli Furlan Corrêa
- Basic and Applied Immunology Program, Ribeirao Preto Medical School, University of Sao Paulo, São Paulo, Brazil
| | - Leandra Nz Ramalho
- Department of Pathology and Legal Medicine, Ribeirao Preto Medical School, University of Sao Paulo, São Paulo, Brazil
| | - Daniela Carlos
- Basic and Applied Immunology Program, Ribeirao Preto Medical School, University of Sao Paulo, São Paulo, Brazil.,Department of Biochemistry and Immunology, Ribeirao Preto Medical School, University of Sao Paulo, São Paulo, Brazil
| | - Danilo C de Almeida
- Department of Immunology, Institute of Biomedical Sciences IV, University of Sao Paulo, São Paulo, Brazil
| | - Niels Os Câmara
- Department of Immunology, Institute of Biomedical Sciences IV, University of Sao Paulo, São Paulo, Brazil
| | - Dario S Zamboni
- Basic and Applied Immunology Program, Ribeirao Preto Medical School, University of Sao Paulo, São Paulo, Brazil.,Department of Cell Biology, Ribeirao Preto Medical School, University of Sao Paulo, São Paulo, Brazil
| | - Viviani Nardini Takahashi
- Department of Clinical Analysis, Toxicology and Bromatology, School of Pharmaceutical Sciences of Ribeirão Preto, University of Sao Paulo, São Paulo, Brazil
| | - Carlos A Sorgi
- Department of Clinical Analysis, Toxicology and Bromatology, School of Pharmaceutical Sciences of Ribeirão Preto, University of Sao Paulo, São Paulo, Brazil
| | - Lucia H Faccioli
- Basic and Applied Immunology Program, Ribeirao Preto Medical School, University of Sao Paulo, São Paulo, Brazil.,Department of Clinical Analysis, Toxicology and Bromatology, School of Pharmaceutical Sciences of Ribeirão Preto, University of Sao Paulo, São Paulo, Brazil
| | - Alexandra I Medeiros
- Basic and Applied Immunology Program, Ribeirao Preto Medical School, University of Sao Paulo, São Paulo, Brazil.,Department of Biological Sciences, School of Pharmaceutical Sciences, São Paulo State University, São Paulo, Brazil
| | - Diego Luís Costa
- Basic and Applied Immunology Program, Ribeirao Preto Medical School, University of Sao Paulo, São Paulo, Brazil.,Department of Biochemistry and Immunology, Ribeirao Preto Medical School, University of Sao Paulo, São Paulo, Brazil
| | - Vânia Ld Bonato
- Basic and Applied Immunology Program, Ribeirao Preto Medical School, University of Sao Paulo, São Paulo, Brazil.,Department of Biochemistry and Immunology, Ribeirao Preto Medical School, University of Sao Paulo, São Paulo, Brazil
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20
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Dagostin F, Vanalli C, Boag B, Casagrandi R, Gatto M, Mari L, Cattadori IM. The enemy of my enemy is my friend: Immune-mediated facilitation contributes to fitness of co-infecting helminths. J Anim Ecol 2023; 92:477-491. [PMID: 36478135 DOI: 10.1111/1365-2656.13863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Accepted: 11/28/2022] [Indexed: 12/12/2022]
Abstract
The conceptual understanding of immune-mediated interactions between parasites is rooted in the theory of community ecology. One of the limitations of this approach is that most of the theory and empirical evidence has focused on resource or immune-mediated competition between parasites and yet there is ample evidence of positive interactions that could be generated by immune-mediated facilitation. We developed an immuno-epidemiological model and applied it to long-term data of two gastrointestinal helminths in two rabbit populations to investigate, through model testing, how immune-mediated mechanisms of parasite regulation could explain the higher intensities of both helminths in rabbits with dual than single infections. The model framework was selected and calibrated on rabbit population A and then validated on the nearby rabbit population B to confirm the consistency of the findings and the generality of the mechanisms. Simulations suggested that the higher intensities in rabbits with dual infections could be explained by a weakened or low species-specific IgA response and an asymmetric IgA cross-reaction. Simulations also indicated that rabbits with dual infections shed more free-living stages that survived for longer in the environment, implying greater transmission than stages from hosts with single infections. Temperature and humidity selectively affected the free-living stages of the two helminths. These patterns were comparable in the two rabbit populations and support the hypothesis that immune-mediated facilitation can contribute to greater parasite fitness and local persistence.
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Affiliation(s)
- Francesca Dagostin
- Research and Innovation Centre, Fondazione Edmund Mach, San Michele all'Adige, Italy.,Center for Infectious Disease Dynamics and Department of Biology, The Pennsylvania State University, University Park, Pennsylvania, USA
| | - Chiara Vanalli
- Center for Infectious Disease Dynamics and Department of Biology, The Pennsylvania State University, University Park, Pennsylvania, USA
| | - Brian Boag
- The James Hutton Institute, Invergowrie, UK
| | - Renato Casagrandi
- Dipartimento di Elettronica, Informazione e Bioingegneria, Politecnico di Milano, Milan, Italy
| | - Marino Gatto
- Dipartimento di Elettronica, Informazione e Bioingegneria, Politecnico di Milano, Milan, Italy
| | - Lorenzo Mari
- Dipartimento di Elettronica, Informazione e Bioingegneria, Politecnico di Milano, Milan, Italy
| | - Isabella M Cattadori
- Center for Infectious Disease Dynamics and Department of Biology, The Pennsylvania State University, University Park, Pennsylvania, USA
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21
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Mouse Models for Mycobacterium tuberculosis Pathogenesis: Show and Do Not Tell. Pathogens 2022; 12:pathogens12010049. [PMID: 36678397 PMCID: PMC9865329 DOI: 10.3390/pathogens12010049] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 11/29/2022] [Accepted: 12/25/2022] [Indexed: 12/29/2022] Open
Abstract
Science has been taking profit from animal models since the first translational experiments back in ancient Greece. From there, and across all history, several remarkable findings have been obtained using animal models. One of the most popular models, especially for research in infectious diseases, is the mouse. Regarding research in tuberculosis, the mouse has provided useful information about host and bacterial traits related to susceptibility to the infection. The effect of aging, sexual dimorphisms, the route of infection, genetic differences between mice lineages and unbalanced immunity scenarios upon Mycobacterium tuberculosis infection and tuberculosis development has helped, helps and will help biomedical researchers in the design of new tools for diagnosis, treatment and prevention of tuberculosis, despite various discrepancies and the lack of deep study in some areas of these traits.
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22
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Diriba G, Alemu A, Eshetu K, Yenew B, Gamtesa DF, Tola HH. Bacteriologically confirmed extrapulmonary tuberculosis and the associated risk factors among extrapulmonary tuberculosis suspected patients in Ethiopia: A systematic review and meta-analysis. PLoS One 2022; 17:e0276701. [PMID: 36417408 PMCID: PMC9683558 DOI: 10.1371/journal.pone.0276701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 10/12/2022] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND The actual burden of bacteriologically confirmed extrapulmonary tuberculosis (EPTB) and risk factors in Ethiopia is not well known due to the lack of a strong surveillance system in Ethiopia. Thus, this study was conducted to estimate the pooled prevalence of bacteriologically confirmed EPTB and the associated risk factors among persons suspected to have non-respiratory tuberculosis in Ethiopia. METHODS A systematic review and meta-analysis of published studies reporting the prevalence of EPTB from searched electronic databases; Science Direct, PubMed, and Google Scholar was estimated spread across the research periods, nationally, and in different areas, using a fixed-effects model. We used I2 to analyze heterogeneity in the reported prevalence of bacteriologically confirmed extrapulmonary tuberculosis. RESULTS After reviewing 938 research articles, 20 studies (19 cross-sectional and 1 retrospective) from 2003 to 2021 were included in the final analyses. The pooled prevalence of bacteriologically confirmed EPTB was 43% (95%CI; 0.34-0.52, I2 = 98.45%). The asymmetry of the funnel plot revealed the presence of publication bias. Specifically the pooled prevalence of bacteriologically confirmed EPTB based on smear microscopy, Xpert MTB/RIF assay, and culture were 22% (95%CI; 0.13-0.30, I2 = 98.56%), 39% (95%CI; 0.23-0.54, I2 = 98.73%) and 49% (95%CI; 0.41-0.57, I2 = 96.43%) respectively. In this study, a history of pulmonary tuberculosis (PTB) contact with PTB patients, contact with live animals, consumption of raw milk, HIV-positive, male, and lower monthly income, were found to be independently associated with bacteriologically confirmed EPTB. CONCLUSION Ethiopia has a high rate of bacteriologically confirmed EPTB. A history of previous PTB, being HIV-positive and having contact with PTB patients were the most reported risk factors for EPTB in the majority of studies. Strengthening laboratory services for EPTB diagnosis should be given priority to diagnose EPTB cases as early as possible.
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Affiliation(s)
- Getu Diriba
- Ethiopian Public Health Institute, Addis Ababa, Ethiopia
| | - Ayinalem Alemu
- Ethiopian Public Health Institute, Addis Ababa, Ethiopia
- Aklilu Lemma Institute of Pathobiology, Addis Ababa University, Addis Ababa, Ethiopia
| | - Kirubel Eshetu
- USAID Eliminate TB Project, Management Sciences for Health, Addis Ababa, Ethiopia
| | - Bazezew Yenew
- Ethiopian Public Health Institute, Addis Ababa, Ethiopia
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23
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White HA, Baggaley RF, Okhai H, Patel H, Stephenson I, Bodimeade C, Wiselka MJ, Pareek M. The impact, effectiveness and outcomes of targeted screening thresholds for programmatic latent tuberculosis infection testing in HIV. AIDS 2022; 36:2035-2044. [PMID: 35983827 PMCID: PMC9612707 DOI: 10.1097/qad.0000000000003364] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 06/02/2022] [Accepted: 06/16/2022] [Indexed: 11/26/2022]
Abstract
BACKGROUND Screening and treatment for latent tuberculosis infection (LTBI) are key for TB control. In the UK, the National Institute for Health and Care Excellence (NICE) and the British HIV Association (BHIVA) give conflicting guidance on which groups of people with HIV (PWH) should be screened, and previous national analysis demonstrated heterogeneity in how guidance is applied. There is an urgent need for a firmer clinical effectiveness evidence base on which to build screening policy. METHODS We conducted a systematic, programmatic LTBI-screening intervention for all PWH receiving care in Leicester, UK. We compared yields (percentage IGRA positive) and number of tests required when applying the NICE and BHIVA testing strategies, as well as strategies targeting screening by TB incidence in patients' countries of birth. RESULTS Of 1053 PWH tested, 118 were IGRA-positive (11.2%). Positivity was associated with higher TB incidence in country-of-birth [adjusted odds ratio, 50-149 cases compared with <50 cases/100 000: 11.6; 95% confidence interval (CI) 4.79-28.10)]. There was high testing uptake (1053/1069, 98.5%). Appropriate chemoprophylaxis was commenced in 100 of 117 (85.5%) patients diagnosed with LTBI, of whom 96 of 100 (96.0%) completed treatment. Delivering targeted testing to PWH from countries with TB incidence greater than 150 per 100 000 population or any sub-Saharan African country, would have correctly identified 89.8% of all LTBI cases while cutting tests required by 46.1% compared with NICE guidance, performing as well as BHIVA 2018 guidance. CONCLUSION Targeting screening to higher risk PWH increases yield and reduces the number requiring testing. Our proposed 'PWH-LTBI streamlined guidance' offers a simplified approach, with the potential to improve national LTBI-screening implementation.
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Affiliation(s)
- Helena A. White
- Department of Infection and HIV Medicine, University Hospitals of Leicester NHS Trust, Infirmary Square, Leicester
- Department of Respiratory Sciences, University of Leicester, Leicester
| | | | - Hajra Okhai
- Institute for Global Health, University College London, London
| | - Hemu Patel
- Department of Microbiology, University Hospitals of Leicester NHS Trust, Infirmary Square, Leicester, UK
| | - Iain Stephenson
- Department of Infection and HIV Medicine, University Hospitals of Leicester NHS Trust, Infirmary Square, Leicester
| | - Chris Bodimeade
- Department of Infection and HIV Medicine, University Hospitals of Leicester NHS Trust, Infirmary Square, Leicester
| | - Martin J. Wiselka
- Department of Infection and HIV Medicine, University Hospitals of Leicester NHS Trust, Infirmary Square, Leicester
| | - Manish Pareek
- Department of Infection and HIV Medicine, University Hospitals of Leicester NHS Trust, Infirmary Square, Leicester
- Department of Respiratory Sciences, University of Leicester, Leicester
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24
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Han M, Woottum M, Mascarau R, Vahlas Z, Verollet C, Benichou S. Mechanisms of HIV-1 cell-to-cell transfer to myeloid cells. J Leukoc Biol 2022; 112:1261-1271. [PMID: 35355323 DOI: 10.1002/jlb.4mr0322-737r] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 03/09/2022] [Indexed: 12/24/2022] Open
Abstract
In addition to CD4+ T lymphocytes, cells of the myeloid lineage such as macrophages, dendritic cells (DCs), and osteoclasts (OCs) are emerging as important target cells for HIV-1, as they likely participate in all steps of pathogenesis, including sexual transmission and early virus dissemination in both lymphoid and nonlymphoid tissues where they can constitute persistent virus reservoirs. At least in vitro, these myeloid cells are poorly infected by cell-free viral particles. In contrast, intercellular virus transmission through direct cell-to-cell contacts may be a predominant mode of virus propagation in vivo leading to productive infection of these myeloid target cells. HIV-1 cell-to-cell transfer between CD4+ T cells mainly through the formation of the virologic synapse, or from infected macrophages or dendritic cells to CD4+ T cell targets, have been extensively described in vitro. Recent reports demonstrate that myeloid cells can be also productively infected through virus homotypic or heterotypic cell-to-cell transfer between macrophages or from virus-donor-infected CD4+ T cells, respectively. These modes of infection of myeloid target cells lead to very efficient spreading in these poorly susceptible cell types. Thus, the goal of this review is to give an overview of the different mechanisms reported in the literature for cell-to-cell transfer and spreading of HIV-1 in myeloid cells.
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Affiliation(s)
- Mingyu Han
- Institut Cochin, Inserm U1016, Paris, France.,Centre National de la Recherche Scientifique CNRS UMR8104, Paris, France.,Faculty of Health, University of Paris Cité, Paris, France
| | - Marie Woottum
- Institut Cochin, Inserm U1016, Paris, France.,Centre National de la Recherche Scientifique CNRS UMR8104, Paris, France.,Faculty of Health, University of Paris Cité, Paris, France
| | - Rémi Mascarau
- Institut de Pharmacologie et Biologie Structurale, IPBS, Université de Toulouse, CNRS, Toulouse, France.,International Research Project (IRP) CNRS, Toulouse, France.,International Research Project (IRP), CNRS, Buenos Aires, Argentina
| | - Zoï Vahlas
- Institut de Pharmacologie et Biologie Structurale, IPBS, Université de Toulouse, CNRS, Toulouse, France.,International Research Project (IRP) CNRS, Toulouse, France.,International Research Project (IRP), CNRS, Buenos Aires, Argentina
| | - Christel Verollet
- Institut de Pharmacologie et Biologie Structurale, IPBS, Université de Toulouse, CNRS, Toulouse, France.,International Research Project (IRP) CNRS, Toulouse, France.,International Research Project (IRP), CNRS, Buenos Aires, Argentina
| | - Serge Benichou
- Institut Cochin, Inserm U1016, Paris, France.,Centre National de la Recherche Scientifique CNRS UMR8104, Paris, France.,Faculty of Health, University of Paris Cité, Paris, France
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25
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Hoerter A, Arnett E, Schlesinger LS, Pienaar E. Systems biology approaches to investigate the role of granulomas in TB-HIV coinfection. Front Immunol 2022; 13:1014515. [PMID: 36405707 PMCID: PMC9670175 DOI: 10.3389/fimmu.2022.1014515] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 09/20/2022] [Indexed: 09/29/2023] Open
Abstract
The risk of active tuberculosis disease is 15-21 times higher in those coinfected with human immunodeficiency virus-1 (HIV) compared to tuberculosis alone, and tuberculosis is the leading cause of death in HIV+ individuals. Mechanisms driving synergy between Mycobacterium tuberculosis (Mtb) and HIV during coinfection include: disruption of cytokine balances, impairment of innate and adaptive immune cell functionality, and Mtb-induced increase in HIV viral loads. Tuberculosis granulomas are the interface of host-pathogen interactions. Thus, granuloma-based research elucidating the role and relative impact of coinfection mechanisms within Mtb granulomas could inform cohesive treatments that target both pathogens simultaneously. We review known interactions between Mtb and HIV, and discuss how the structure, function and development of the granuloma microenvironment create a positive feedback loop favoring pathogen expansion and interaction. We also identify key outstanding questions and highlight how coupling computational modeling with in vitro and in vivo efforts could accelerate Mtb-HIV coinfection discoveries.
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Affiliation(s)
- Alexis Hoerter
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, United States
| | - Eusondia Arnett
- Host-Pathogen Interactions Program, Texas Biomedical Research Institute, San Antonio, TX, United States
| | - Larry S. Schlesinger
- Host-Pathogen Interactions Program, Texas Biomedical Research Institute, San Antonio, TX, United States
| | - Elsje Pienaar
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, United States
- Regenstrief Center for Healthcare Engineering, Purdue University, West Lafayette, IN, United States
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26
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Hildebrand RE, Chandrasekar SS, Riel M, Touray BJB, Aschenbroich SA, Talaat AM. Superinfection with SARS-CoV-2 Has Deleterious Effects on Mycobacterium bovis BCG Immunity and Promotes Dissemination of Mycobacterium tuberculosis. Microbiol Spectr 2022; 10:e0307522. [PMID: 36200898 PMCID: PMC9603897 DOI: 10.1128/spectrum.03075-22] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 09/19/2022] [Indexed: 01/04/2023] Open
Abstract
An estimated one-third of the world's population is infected with Mycobacterium tuberculosis, with the majority being vaccinated with Mycobacterium bovis BCG. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains a threat, and we must understand how SARS-CoV-2 can modulate both BCG immunity and tuberculosis pathogenesis. Interestingly, neither BCG vaccination nor tuberculosis infection resulted in differences in clinical outcomes associated with SARS-CoV-2 in transgenic mice. Surprisingly, earlier M. tuberculosis infection resulted in lower SARS-CoV-2 viral loads, mediated by the heightened immune microenvironment of the murine lungs, unlike vaccination with BCG, which had no impact. In contrast, M. tuberculosis-infected tissues had increased bacterial loads and decreased histiocytic inflammation in the lungs following SARS-CoV-2 superinfection. SARS-CoV-2 modulated BCG-induced type 17 responses while decreasing type 1 and increasing type 2 cytokines in M. tuberculosis-infected mice. These findings challenge initial findings of BCG's positive impact on SARS-CoV-2 infection and suggest potential ramifications for M. tuberculosis reactivation upon SARS-CoV-2 superinfection. IMPORTANCE Prior to SARS-CoV-2, M. tuberculosis was the leading infectious disease killer, with an estimated one-third of the world's population infected and 1.7 million deaths a year. Here, we show that SARS-CoV-2 superinfection caused increased bacterial dissemination in M. tuberculosis-infected mice along with immune and pathological changes. SARS-CoV-2 also impacted the immunity of BCG-vaccinated mice, resulting in decreased interleukin-17 (IL-17) levels, while offering no protective effect against SARS-CoV-2. These results demonstrate that SARS-CoV-2 may have a deleterious effect on the ongoing M. tuberculosis pandemic and potentially limit BCG's efficacy.
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Affiliation(s)
- Rachel E. Hildebrand
- Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin—Madison, Madison, Wisconsin, USA
| | - Shaswath Sekar Chandrasekar
- Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin—Madison, Madison, Wisconsin, USA
| | - Mariah Riel
- Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin—Madison, Madison, Wisconsin, USA
| | - Bubacarr J. B. Touray
- Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin—Madison, Madison, Wisconsin, USA
| | - Sophie A. Aschenbroich
- Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin—Madison, Madison, Wisconsin, USA
| | - Adel M. Talaat
- Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin—Madison, Madison, Wisconsin, USA
- Pan Genome Systems, Madison, Wisconsin, USA
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27
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Sitoe N, Ahmed MIM, Enosse M, Bakuli A, Chissumba RM, Held K, Hoelscher M, Nhassengo P, Khosa C, Rachow A, Geldmacher C. Tuberculosis Treatment Response Monitoring by the Phenotypic Characterization of MTB-Specific CD4+ T-Cells in Relation to HIV Infection Status. Pathogens 2022; 11:pathogens11091034. [PMID: 36145465 PMCID: PMC9506022 DOI: 10.3390/pathogens11091034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 09/03/2022] [Accepted: 09/06/2022] [Indexed: 11/16/2022] Open
Abstract
HIV infection causes systemic immune activation, impacts TB disease progression and hence may influence the diagnostic usability of Mycobacterium tuberculosis-specific T cell profiling. We investigated changes of activation and maturation markers on MTB-specific CD4+ T-cells after anti-tuberculosis treatment initiation in relation to HIV status and the severity of lung impairment. Thawed peripheral blood mononuclear cells from TB patients with (n = 27) and without HIV (n = 17) were analyzed using an intracellular IFN-γ assay and flow cytometry 2 and 6 months post-TB treatment initiation. H37Rv antigen was superior to the profile MTB-specific CD4+ T-cells phenotype when compared to PPD and ESAT6/CFP10. Regardless of HIV status and the severity of lung impairment, activation markers (CD38, HLA-DR and Ki67) on MTB-specific CD4+ T-cells declined after TB treatment initiation (p < 0.01), but the expression of the maturation marker CD27 did not change over the course of TB treatment. The MTB-specific T cell phenotype before, during and after treatment completion was similar between people living with and without HIV, as well as between subjects with severe and mild lung impairment. These data suggest that the assessment of activation and maturation markers on MTB-specific CD4+ T-cells can be useful for TB treatment monitoring, regardless of HIV status and the severity of lung disease.
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Affiliation(s)
- Nádia Sitoe
- Instituto Nacional de Saúde, Marracuene 3943, Mozambique
- CIH LMU Center for International Health, Ludwig-Maximilians University, 80802 Munich, Germany
- Correspondence: ; Tel.: +258-840784833
| | - Mohamed I. M. Ahmed
- Division of Infectious Diseases and Tropical Medicine, Klinikum of the University of Munich (LMU), 80802 Munich, Germany
- German Center for Infection Research, Partner Site Munich, 80802 Munich, Germany
| | - Maria Enosse
- Instituto Nacional de Saúde, Marracuene 3943, Mozambique
| | - Abhishek Bakuli
- Division of Infectious Diseases and Tropical Medicine, Klinikum of the University of Munich (LMU), 80802 Munich, Germany
- German Center for Infection Research, Partner Site Munich, 80802 Munich, Germany
| | | | - Kathrin Held
- Division of Infectious Diseases and Tropical Medicine, Klinikum of the University of Munich (LMU), 80802 Munich, Germany
- German Center for Infection Research, Partner Site Munich, 80802 Munich, Germany
| | - Michael Hoelscher
- Division of Infectious Diseases and Tropical Medicine, Klinikum of the University of Munich (LMU), 80802 Munich, Germany
- German Center for Infection Research, Partner Site Munich, 80802 Munich, Germany
| | | | - Celso Khosa
- Instituto Nacional de Saúde, Marracuene 3943, Mozambique
| | - Andrea Rachow
- Division of Infectious Diseases and Tropical Medicine, Klinikum of the University of Munich (LMU), 80802 Munich, Germany
- German Center for Infection Research, Partner Site Munich, 80802 Munich, Germany
| | - Christof Geldmacher
- Division of Infectious Diseases and Tropical Medicine, Klinikum of the University of Munich (LMU), 80802 Munich, Germany
- German Center for Infection Research, Partner Site Munich, 80802 Munich, Germany
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28
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Synthesis and evaluation of inhibitors of Mycobacterium tuberculosis UGM using bioisosteric replacement. Bioorg Med Chem 2022; 69:116896. [DOI: 10.1016/j.bmc.2022.116896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 06/08/2022] [Accepted: 06/20/2022] [Indexed: 11/22/2022]
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29
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Moriarty RV, Rodgers MA, Ellis AL, Balgeman AJ, Larson EC, Hopkins F, Chase MR, Maiello P, Fortune SM, Scanga CA, O’Connor SL. Spontaneous Control of SIV Replication Does Not Prevent T Cell Dysregulation and Bacterial Dissemination in Animals Co-Infected with M. tuberculosis. Microbiol Spectr 2022; 10:e0172421. [PMID: 35467372 PMCID: PMC9241861 DOI: 10.1128/spectrum.01724-21] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 04/08/2022] [Indexed: 12/27/2022] Open
Abstract
Individuals co-infected with HIV and Mycobacterium tuberculosis (Mtb) are more likely to develop severe tuberculosis (TB) disease than HIV-naive individuals. To understand how a chronic pre-existing Simian immunodeficiency virus (SIV) infection impairs the early immune response to Mtb, we used the Mauritian cynomolgus macaque (MCM) model of SIV/Mtb co-infection. We examined the relationship between peripheral viral control and Mtb burden, Mtb dissemination, and T cell function between SIV+ spontaneous controllers, SIV+ non-controllers, and SIV-naive MCM who were challenged with a barcoded Mtb Erdman strain 6 months post-SIV infection and necropsied 6 weeks post-Mtb infection. Mycobacterial burden was highest in the SIV+ non-controllers in all assessed tissues. In lung granulomas, the frequency of TNF-α-producing CD4+ T cells was reduced in all SIV+ MCM, but IFNγ-producing CD4+ T cells were only lower in the SIV+ non-controllers. Further, while all SIV+ MCM had more PD1+ and TIGIT+ T cells in the lung granulomas relative to SIV-naive MCM, SIV+ controllers exhibited the highest frequency of cells expressing these markers. To measure the effect of SIV infection on within-host bacterial dissemination, we sequenced the molecular barcodes of Mtb present in each tissue and characterized the Mtb population complexity. While Mtb population complexity was not associated with SIV infection group, lymph nodes had increased complexity when compared with lung granulomas across all groups. These results provide evidence that SIV+ animals, independent of viral control, exhibit a dysregulated T cell immune response and enhanced dissemination of Mtb, likely contributing to the poor TB disease course across all SIV/Mtb co-infected animals. IMPORTANCE HIV and TB remain significant global health issues, despite the availability of treatments. Individuals with HIV, including those who are virally suppressed, are at an increased risk to develop and succumb to severe TB disease when compared with HIV-naive individuals. Our study aims to understand the relationship between the extent of SIV replication, mycobacterial growth, and T cell function in the tissues of co-infected Mauritian cynomolgus macaques during the first 6 weeks of Mtb infection. Here we demonstrate that increased viral replication is associated with increased bacterial burden in the tissues and impaired T cell responses, and that the immunological damage attributed to virus infection is not fully eliminated when animals spontaneously control virus replication.
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Affiliation(s)
- Ryan V. Moriarty
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Mark A. Rodgers
- Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Amy L. Ellis
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Alexis J. Balgeman
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Erica C. Larson
- Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Forrest Hopkins
- Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Michael R. Chase
- Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Pauline Maiello
- Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Sarah M. Fortune
- Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Charles A. Scanga
- Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Center for Vaccine Research, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Shelby L. O’Connor
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA
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30
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Pires D, Calado M, Velez T, Mandal M, Catalão MJ, Neyrolles O, Lugo-Villarino G, Vérollet C, Azevedo-Pereira JM, Anes E. Modulation of Cystatin C in Human Macrophages Improves Anti-Mycobacterial Immune Responses to Mycobacterium tuberculosis Infection and Coinfection With HIV. Front Immunol 2021; 12:742822. [PMID: 34867965 PMCID: PMC8637326 DOI: 10.3389/fimmu.2021.742822] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 10/21/2021] [Indexed: 11/25/2022] Open
Abstract
Tuberculosis owes its resurgence as a major global health threat mostly to the emergence of drug resistance and coinfection with HIV. The synergy between HIV and Mycobacterium tuberculosis (Mtb) modifies the host immune environment to enhance both viral and bacterial replication and spread. In the lung immune context, both pathogens infect macrophages, establishing favorable intracellular niches. Both manipulate the endocytic pathway in order to avoid destruction. Relevant players of the endocytic pathway to control pathogens include endolysosomal proteases, cathepsins, and their natural inhibitors, cystatins. Here, a mapping of the human macrophage transcriptome for type I and II cystatins during Mtb, HIV, or Mtb-HIV infection displayed different profiles of gene expression, revealing cystatin C as a potential target to control mycobacterial infection as well as HIV coinfection. We found that cystatin C silencing in macrophages significantly improves the intracellular killing of Mtb, which was concomitant with an increased general proteolytic activity of cathepsins. In addition, downmodulation of cystatin C led to an improved expression of the human leukocyte antigen (HLA) class II in macrophages and an increased CD4+ T-lymphocyte proliferation along with enhanced IFN-γ secretion. Overall, our results suggest that the targeting of cystatin C in human macrophages represents a promising approach to improve the control of mycobacterial infections including multidrug-resistant (MDR) TB.
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Affiliation(s)
- David Pires
- Host-Pathogen Interactions, Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Marta Calado
- Host-Pathogen Interactions, Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Tomás Velez
- Host-Pathogen Interactions, Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Manoj Mandal
- Host-Pathogen Interactions, Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Maria João Catalão
- Host-Pathogen Interactions, Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Olivier Neyrolles
- Institut de Pharmacologie et Biologie Structurale, IPBS, Université de Toulouse, Centre National de la Recherche Scientifique (CNRS), Toulouse, France
| | - Geanncarlo Lugo-Villarino
- Institut de Pharmacologie et Biologie Structurale, IPBS, Université de Toulouse, Centre National de la Recherche Scientifique (CNRS), Toulouse, France
| | - Christel Vérollet
- Institut de Pharmacologie et Biologie Structurale, IPBS, Université de Toulouse, Centre National de la Recherche Scientifique (CNRS), Toulouse, France
| | - José Miguel Azevedo-Pereira
- Host-Pathogen Interactions, Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Elsa Anes
- Host-Pathogen Interactions, Research Institute for Medicines, iMed-ULisboa, Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
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31
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Liebenberg C, Luies L, Williams AA. Metabolomics as a Tool to Investigate HIV/TB Co-Infection. Front Mol Biosci 2021; 8:692823. [PMID: 34746228 PMCID: PMC8565463 DOI: 10.3389/fmolb.2021.692823] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 10/04/2021] [Indexed: 12/28/2022] Open
Abstract
The HIV/AIDS (human immunodeficiency virus/acquired immunodeficiency syndrome) and tuberculosis (TB) pandemics are perpetuated by a significant global burden of HIV/TB co-infection. The synergy between HIV and Mycobacterium tuberculosis (Mtb) during co-infection of a host is well established. While this synergy is known to be driven by immunological deterioration, the metabolic mechanisms thereof remain poorly understood. Metabolomics has been applied to study various aspects of HIV and Mtb infection separately, yielding insights into infection- and treatment-induced metabolic adaptations experienced by the host. Despite the contributions that metabolomics has made to the field, this approach has not yet been systematically applied to characterize the HIV/TB co-infected state. Considering that limited HIV/TB co-infection metabolomics studies have been published to date, this review briefly summarizes what is known regarding the HIV/TB co-infection synergism from a conventional and metabolomics perspective. It then explores metabolomics as a tool for the improved characterization of HIV/TB co-infection in the context of previously published human-related HIV infection and TB investigations, respectively as well as for addressing the gaps in existing knowledge based on the similarities and deviating trends reported in these HIV infection and TB studies.
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32
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Zaharie AM, Tigau M. Negative Impact Factors in HIV-Tuberculosis. MÆDICA 2021; 16:179-183. [PMID: 34621336 DOI: 10.26574/maedica.2021.16.2.179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
About one quarter of all tuberculosis (TB) deaths are among people living with HIV. Tuberculosis is a leading infectious cause of death among persons infected with HIV and the outcome of TB treatment is poorer in these patients. Objective: To identify the factors associated with a poor tuberculosis outcome in patients with HIV-TB coinfection. Material and methods: This is a retrospective cohort study using data from the local TB registry for 2009-2016. We performed descriptive statistics as well as univariate and multivariate analysis. Results: During the study period we identified 86 patients (4.76% of all patients registered for TB treatment) with HIV-TB who had a mean age of 35.05±9.10 years and were mostly male (73.25%). More than half of patients were current drug users (51.16%) and 22.10% homeless. The mean CD4 value was 179.11±204.76/mm3 and 69.76% of patients received antiretroviral treatment during TB treatment. Viral hepatitis was present in 61.62% of cases, and 77.9% of patients were new TB cases. Pulmonary TB was noted in 72 cases, with confirmation by culture being obtained in 84.44% of cases. Treatment success was achieved in 63.95% of cases, 22.09% of patients died, 8.13% abandoned treatment, and 5.81% were lost to follow up. Several factors related to poor outcome were identified by univariate analysis, including drug use (OR=3.14, p=0.027), homeless status (OR=3.01, p=0.039) and viral hepatitis (OR=2.93, p=0.045). Multivariate analysis revealed marginal insignificance for homeless status (p=0.06) and drug use (p=0.86). Conclusion: A special attention and dedicated programs should be considered for patients who are intravenous drug users or those without a stable home.
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Affiliation(s)
- Ana-Maria Zaharie
- Marius Nasta Institute of Pneumology, 4th District TB Unit, Bucharest, Romania
| | - Mirela Tigau
- Marius Nasta Institute of Pneumology, 4th District TB Unit, Bucharest, Romania
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33
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Foreman HCC, Frank A, Stedman TT. Determination of variable region sequences from hybridoma immunoglobulins that target Mycobacterium tuberculosis virulence factors. PLoS One 2021; 16:e0256079. [PMID: 34415957 PMCID: PMC8378720 DOI: 10.1371/journal.pone.0256079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 07/29/2021] [Indexed: 11/19/2022] Open
Abstract
Mycobacterium tuberculosis (Mtb) infects one-quarter of the world's population. Mtb and HIV coinfections enhance the comorbidity of tuberculosis (TB) and AIDS, accounting for one-third of all AIDS-associated mortalities. Humoral antibody to Mtb correlates with TB susceptibility, and engineering of Mtb antibodies may lead to new diagnostics and therapeutics. The characterization and validation of functional immunoglobulin (Ig) variable chain (IgV) sequences provide a necessary first step towards developing therapeutic antibodies against pathogens. The virulence-associated Mtb antigens SodA (Superoxide Dismutase), KatG (Catalase), PhoS1/PstS1 (regulatory factor), and GroES (heat shock protein) are potential therapeutic targets but lacked IgV sequence characterization. Putative IgV sequences were identified from the mRNA of hybridomas targeting these antigens and isotype-switched into a common immunoglobulin fragment crystallizable region (Fc region) backbone, subclass IgG2aκ. Antibodies were validated by demonstrating recombinant Ig assembly and secretion, followed by the determination of antigen-binding specificity using ELISA and immunoblot assay.
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Affiliation(s)
- Hui-Chen Chang Foreman
- BEI Resources, ATCC., Manassas, Virginia, United States of America
- * E-mail: (HCCF); (TTS)
| | - Andrew Frank
- BEI Resources, ATCC., Manassas, Virginia, United States of America
| | - Timothy T. Stedman
- BEI Resources, ATCC., Manassas, Virginia, United States of America
- * E-mail: (HCCF); (TTS)
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34
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Devi P, Khan A, Chattopadhyay P, Mehta P, Sahni S, Sharma S, Pandey R. Co-infections as Modulators of Disease Outcome: Minor Players or Major Players? Front Microbiol 2021; 12:664386. [PMID: 34295314 PMCID: PMC8290219 DOI: 10.3389/fmicb.2021.664386] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 06/16/2021] [Indexed: 12/12/2022] Open
Abstract
Human host and pathogen interaction is dynamic in nature and often modulated by co-pathogens with a functional role in delineating the physiological outcome of infection. Co-infection may present either as a pre-existing pathogen which is accentuated by the introduction of a new pathogen or may appear in the form of new infection acquired secondarily due to a compromised immune system. Using diverse examples of co-infecting pathogens such as Human Immunodeficiency Virus, Mycobacterium tuberculosis and Hepatitis C Virus, we have highlighted the role of co-infections in modulating disease severity and clinical outcome. This interaction happens at multiple hierarchies, which are inclusive of stress and immunological responses and together modulate the disease severity. Already published literature provides much evidence in favor of the occurrence of co-infections during SARS-CoV-2 infection, which eventually impacts the Coronavirus disease-19 outcome. The availability of biological models like 3D organoids, mice, cell lines and mathematical models provide us with an opportunity to understand the role and mechanism of specific co-infections. Exploration of multi-omics-based interactions across co-infecting pathogens may provide deeper insights into their role in disease modulation.
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Affiliation(s)
- Priti Devi
- INtegrative GENomics of HOst-PathogEn Laboratory, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Azka Khan
- INtegrative GENomics of HOst-PathogEn Laboratory, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
| | - Partha Chattopadhyay
- INtegrative GENomics of HOst-PathogEn Laboratory, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Priyanka Mehta
- INtegrative GENomics of HOst-PathogEn Laboratory, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
| | - Shweta Sahni
- INtegrative GENomics of HOst-PathogEn Laboratory, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
| | - Sachin Sharma
- INtegrative GENomics of HOst-PathogEn Laboratory, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
| | - Rajesh Pandey
- INtegrative GENomics of HOst-PathogEn Laboratory, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India.,Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
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35
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Larson EC, Ellis-Connell A, Rodgers MA, Balgeman AJ, Moriarty RV, Ameel CL, Baranowski TM, Tomko JA, Causgrove CM, Maiello P, O'Connor SL, Scanga CA. Pre-existing Simian Immunodeficiency Virus Infection Increases Expression of T Cell Markers Associated with Activation during Early Mycobacterium tuberculosis Coinfection and Impairs TNF Responses in Granulomas. THE JOURNAL OF IMMUNOLOGY 2021; 207:175-188. [PMID: 34145063 DOI: 10.4049/jimmunol.2100073] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 04/19/2021] [Indexed: 01/01/2023]
Abstract
Tuberculosis (TB) is the leading infectious cause of death among people living with HIV. People living with HIV are more susceptible to contracting Mycobacterium tuberculosis and often have worsened TB disease. Understanding the immunologic defects caused by HIV and the consequences it has on M. tuberculosis coinfection is critical in combating this global health epidemic. We previously showed in a model of SIV and M. tuberculosis coinfection in Mauritian cynomolgus macaques (MCM) that SIV/M. tuberculosis-coinfected MCM had rapidly progressive TB. We hypothesized that pre-existing SIV infection impairs early T cell responses to M. tuberculosis infection. We infected MCM with SIVmac239, followed by coinfection with M. tuberculosis Erdman 6 mo later. Although similar, TB progression was observed in both SIV+ and SIV-naive animals at 6 wk post-M. tuberculosis infection; longitudinal sampling of the blood (PBMC) and airways (bronchoalveolar lavage) revealed a significant reduction in circulating CD4+ T cells and an influx of CD8+ T cells in airways of SIV+ animals. At sites of M. tuberculosis infection (i.e., granulomas), SIV/M. tuberculosis-coinfected animals had a higher proportion of CD4+ and CD8+ T cells expressing PD-1 and TIGIT. In addition, there were fewer TNF-producing CD4+ T cells in granulomas of SIV/M. tuberculosis-coinfected animals. Taken together, we show that concurrent SIV infection alters T cell phenotypes in granulomas during the early stages of TB disease. As it is critical to establish control of M. tuberculosis replication soon postinfection, these phenotypic changes may distinguish the immune dysfunction that arises from pre-existing SIV infection, which promotes TB progression.
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Affiliation(s)
- Erica C Larson
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA;
| | - Amy Ellis-Connell
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, WI
| | - Mark A Rodgers
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Alexis J Balgeman
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, WI
| | - Ryan V Moriarty
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, WI
| | - Cassaundra L Ameel
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Tonilynn M Baranowski
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Jaime A Tomko
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Chelsea M Causgrove
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Pauline Maiello
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Shelby L O'Connor
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, WI.,Wisconsin National Primate Research Center, University of Wisconsin-Madison, WI; and
| | - Charles A Scanga
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA; .,Center for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh, PA
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Endsley JJ, Huante MB, Naqvi KF, Gelman BB, Endsley MA. Advancing our understanding of HIV co-infections and neurological disease using the humanized mouse. Retrovirology 2021; 18:14. [PMID: 34134725 PMCID: PMC8206883 DOI: 10.1186/s12977-021-00559-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 06/09/2021] [Indexed: 11/15/2022] Open
Abstract
Humanized mice have become an important workhorse model for HIV research. Advances that enabled development of a human immune system in immune deficient mouse strains have aided new basic research in HIV pathogenesis and immune dysfunction. The small animal features facilitate development of clinical interventions that are difficult to study in clinical cohorts, and avoid the high cost and regulatory burdens of using non-human primates. The model also overcomes the host restriction of HIV for human immune cells which limits discovery and translational research related to important co-infections of people living with HIV. In this review we emphasize recent advances in modeling bacterial and viral co-infections in the setting of HIV in humanized mice, especially neurological disease, and Mycobacterium tuberculosis and HIV co-infections. Applications of current and future co-infection models to address important clinical and research questions are further discussed.
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Affiliation(s)
- Janice J Endsley
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, 77555, USA.
| | - Matthew B Huante
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, 77555, USA
| | - Kubra F Naqvi
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, 77555, USA
| | - Benjamin B Gelman
- Department of Pathology, University of Texas Medical Branch, Galveston, TX, 77555, USA
| | - Mark A Endsley
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, 77555, USA.
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Zenebe Y, Adem Y, Tulu B, Mekonnen D, Derbie A, Mekonnen Z, Biadglegne F. Tuberculosis Lymphadenitis and Human Immunodeficiency Virus Co-infections among Lymphadenitis Patients in Northwest Ethiopia. Ethiop J Health Sci 2021; 31:653-662. [PMID: 34483623 PMCID: PMC8365488 DOI: 10.4314/ejhs.v31i3.23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 10/07/2020] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Tuberculosis and human immunodeficiency virus (HIV) are among the major health problems in Ethiopia. This study assessed the proportion of tuberculosis lymphadenitis (TBLN), HIV infection and their co-infection among TBLN presumptive individuals at the selected hospitals in Northwest Ethiopia. METHODS Institution based cross sectional study was carried out. Data on demographic and clinical variables were collected with standardized questionnaire. Microbiological culture was done on specimen obtained by fine needle aspirates. The HIV status was determined by rapid anti-HIV antibody test. Data was entered and scrutinized using SPSS version 20 statistical packages. A stepwise logistic regression model was used. The result was considered as statistically significant at P<0. 05. RESULTS A total of 381 lymphadenitis patients were included in the study. The overall prevalence of TBLN and HIV were at 250(65.6%) and 9(2.4%), respectively and their co-infection was at 6(2.4%). Based on the cytological examination, 301(79.0%) of them were diagnosed as TBLN. The age group, (P=0.01) and residency, (P=0.01) were found significantly associated with TBLN. Similarly, unsafe sex was also statistically significant for HIV infection (P=0.007). CONCLUSION Tuberculosis lymphadenitis is the leading cause of TB and lymphadenitis in the region. However, TBLN-HIV coinfection was promisingly low. High rate of discrepancy was noticed between cytological and culture results. Hence, the TBLN diagnostic criteria shall pursue revision.
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Affiliation(s)
- Yohannes Zenebe
- Department of Medical Laboratory Sciences, College of Medicine and Health Sciences, Bahir Dar University, Bahir Dar, Ethiopia
- Biotechnology Research Institute, Bahir Dar University, Bahir Dar, Ethiopia
| | - Yesuf Adem
- Department of Medical Laboratory Sciences, College of Medicine and Health Sciences, Bahir Dar University, Bahir Dar, Ethiopia
| | - Begna Tulu
- Department of Medical Laboratory Sciences, College of Medicine and Health Sciences, Bahir Dar University, Bahir Dar, Ethiopia
| | - Daniel Mekonnen
- Department of Medical Laboratory Sciences, College of Medicine and Health Sciences, Bahir Dar University, Bahir Dar, Ethiopia
- Biotechnology Research Institute, Bahir Dar University, Bahir Dar, Ethiopia
| | - Awoke Derbie
- Department of Medical Laboratory Sciences, College of Medicine and Health Sciences, Bahir Dar University, Bahir Dar, Ethiopia
- Biotechnology Research Institute, Bahir Dar University, Bahir Dar, Ethiopia
| | - Zewdie Mekonnen
- Biotechnology Research Institute, Bahir Dar University, Bahir Dar, Ethiopia
- Biochemistry Department, College of Medicine and Health Sciences, Bahir Dar University, Bahir Dar, Ethiopia
| | - Fantahun Biadglegne
- Department of Medical Laboratory Sciences, College of Medicine and Health Sciences, Bahir Dar University, Bahir Dar, Ethiopia
- Leipzig university, Institute of Clinical Immunology, Germany
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38
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Wadee R, Wadee AA. The Pathology of Lymphocytes, Histiocytes, and Immune Mechanisms in Mycobacterium tuberculosis Granulomas. Am J Trop Med Hyg 2021; 104:1796-1802. [PMID: 33720848 PMCID: PMC8103466 DOI: 10.4269/ajtmh.20-1372] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Accepted: 01/24/2021] [Indexed: 12/20/2022] Open
Abstract
Granuloma formation is the pathologic hallmark of tuberculosis (TB). Few studies have detailed the exact production of cytokines in human granulomatous inflammation and little is known about accessory molecule expressions in tuberculous granulomas. We aimed to identify some of the components of the immune response in granulomas in HIV-positive and -negative lymph nodes. We investigated the immunohistochemical profiles of CD4+, CD8+, CD68+, Th-17, Forkhead box P3 (FOXP3) cells, accessory molecule expression (human leukocyte antigen [HLA] classes I and II), and selected cytokines (interleukins 2, 4, and 6 and interferon-γ) of various cells, in granulomas within lymph nodes from 10 HIV-negative (-) and 10 HIV-positive (+) cases. CD4+ lymphocyte numbers were retained in HIV- granulomas, whereas CD4+:CD8 + cell were reversed in HIV+ TB granulomas. CD68 stained all histiocytes. Granulomas from the HIV+ group demonstrated a significant increase in FOXP3 cells. Interleukin-2 cytoplasmic expression was similar in both groups. Interferon-gamma (IFN-γ) expression was moderately increased, IL-6 was statistically increased and IL-4 expression was marginally lower in cells from HIV- than HIV+ TB granulomas. Greater numbers of cells expressed IFN-γ and IL-6 than IL-2 and IL-4 in HIV- TB granulomas. This study highlights the varied cytokine production in HIV-positive and -negative TB granulomas and indicates the need to identify localized tissue factors that play a role in mounting an adequate immune response required to halt infection. Although TB mono-infection causes variation in cell marker expression and cytokines in granulomas, alterations in TB and HIV coinfection are greater, pointing toward evolution of microorganism synergism.
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Affiliation(s)
- Reubina Wadee
- Department of Anatomical Pathology, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, and National Health Laboratory Service (NHLS), Johannesburg, South Africa;,Address correspondence to Reubina Wadee, University of the Witwatersrand/National Health Laboratory Service (NHLS), Rm. 3L30, University of the Witwatersrand, School of Pathology, 7 York Rd., Parktown, Johannesburg 2193, Republic of South Africa. E-mail:
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Massavirov S, Akopyan K, Abdugapparov F, Ciobanu A, Hovhanessyan A, Khodjaeva M, Gadoev J, Parpieva N. Risk Factors for Unfavorable Treatment Outcomes among the Human Immunodeficiency Virus-Associated Tuberculosis Population in Tashkent City, Uzbekistan: 2013-2017. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph18094623. [PMID: 33925377 PMCID: PMC8123775 DOI: 10.3390/ijerph18094623] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 03/18/2021] [Accepted: 03/19/2021] [Indexed: 01/13/2023]
Abstract
Tuberculosis (TB) and human immunodeficiency virus (HIV) co-infection poses a growing clinical challenge. People living with HIV have a higher chance of developing TB, and once the disease has progressed, are at greater risk of having unfavorable TB treatment outcomes. Data on TB treatment outcomes among the HIV-associated TB population in Uzbekistan are limited. Thus, we conducted a cohort study among 808 adult patients with HIV-associated TB registered at the Tashkent TB referral hospital from 2013–2017 to document baseline characteristics and evaluate risk factors for unfavorable TB treatment outcomes. The data were collected from medical records and ambulatory cards. About 79.8% of the study population had favorable treatment outcomes. Antiretroviral therapy (ART) coverage at the admission was 26.9%. Information on CD4-cell counts and viral loads were largely missing. Having extrapulmonary TB (aOR 2.21, 95% CI: 1.38–3.53, p = 0.001), positive sputum smear laboratory results on admission (aOR 1.62, 95% CI: 1.07–2.40), diabetes (aOR 5.16, 95% CI: 1.77–14.98), and hepatitis C (aOR 1.68, 95% CI: 1.14–2.46) were independent risk factors for developing unfavorable TB treatment outcomes. The study findings provide evidence for targeted clinical management in co-infected patients with risk factors. Strengthening the integration of TB/HIV services may improve availability of key data to improve co-infection management.
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Affiliation(s)
- Sherali Massavirov
- Department of Phthisiology and Pulmonology of the Tashkent Medical Academy, Tashkent 100109, Uzbekistan; (F.A.); (M.K.); (N.P.)
- Correspondence: ; Tel.: +99-8781-507-832 & +99-8909-872-324
| | - Kristina Akopyan
- WHO Regional Office for Europe, DK-2100 Copenhagen, Denmark; (K.A.); (A.C.); (A.H.)
- Tuberculosis Research and Prevention Center NGO, Yerevan 0070, Armenia
| | - Fazlkhan Abdugapparov
- Department of Phthisiology and Pulmonology of the Tashkent Medical Academy, Tashkent 100109, Uzbekistan; (F.A.); (M.K.); (N.P.)
| | - Ana Ciobanu
- WHO Regional Office for Europe, DK-2100 Copenhagen, Denmark; (K.A.); (A.C.); (A.H.)
| | - Arax Hovhanessyan
- WHO Regional Office for Europe, DK-2100 Copenhagen, Denmark; (K.A.); (A.C.); (A.H.)
| | - Mavluda Khodjaeva
- Department of Phthisiology and Pulmonology of the Tashkent Medical Academy, Tashkent 100109, Uzbekistan; (F.A.); (M.K.); (N.P.)
| | - Jamshid Gadoev
- World Health Organization Country Office in Uzbekistan, 16, Tarobiy Street, Tashkent 100100, Uzbekistan;
| | - Nargiza Parpieva
- Department of Phthisiology and Pulmonology of the Tashkent Medical Academy, Tashkent 100109, Uzbekistan; (F.A.); (M.K.); (N.P.)
- The Republican Specialized Scientific-Practical Medical Center of Phthisiology and Pulmonology, Tashkent 100086, Uzbekistan
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40
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Bortell N, Aguilera ER, Lenz LL. Pulmonary insults exacerbate susceptibility to oral Listeria monocytogenes infection through the production of IL-10 by NK cells. PLoS Pathog 2021; 17:e1009531. [PMID: 33878120 PMCID: PMC8087096 DOI: 10.1371/journal.ppat.1009531] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 04/30/2021] [Accepted: 04/05/2021] [Indexed: 12/18/2022] Open
Abstract
Most individuals who consume foods contaminated with the bacterial pathogen Listeria monocytogenes (Lm) develop mild symptoms, while others are susceptible to life-threatening systemic infections (listeriosis). Although it is known that the risk of severe disease is increased in certain human populations, including the elderly, it remains unclear why others who consume contaminated food develop listeriosis. Here, we used a murine model to discover that pulmonary coinfections can impair the host's ability to adequately control and eradicate systemic Lm that cross from the intestines to the bloodstream. We found that the resistance of mice to oral Lm infection was dramatically reduced by coinfection with Streptococcus pneumoniae (Spn), a bacterium that colonizes the respiratory tract and can also cause severe infections in the elderly. Exposure to Spn or microbial products, including a recombinant Lm protein (L1S) and lipopolysaccharide (LPS), rendered otherwise resistant hosts susceptible to severe systemic Lm infection. In addition, we show that this increase in susceptibility was dependent on an increase in the production of interleukin-10 (IL-10) from Ncr1+ cells, including natural killer (NK) cells. Lastly, the ability of Ncr1+ cell derived IL-10 to increase disease susceptibility correlated with a dampening of both myeloid cell accumulation and myeloid cell phagocytic capacity in infected tissues. These data suggest that efforts to minimize inflammation in response to an insult at the respiratory mucosa render the host more susceptible to infections by Lm and possibly other pathogens that access the oral mucosa.
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Affiliation(s)
- Nikki Bortell
- Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States of America
| | - Elizabeth R. Aguilera
- Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States of America
| | - Laurel L. Lenz
- Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States of America
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Balfour A, Schutz C, Goliath R, Wilkinson KA, Sayed S, Sossen B, Kanyik JP, Ward A, Ndzhukule R, Gela A, Lewinsohn DM, Lewinsohn DA, Meintjes G, Shey M. Functional and Activation Profiles of Mucosal-Associated Invariant T Cells in Patients With Tuberculosis and HIV in a High Endemic Setting. Front Immunol 2021; 12:648216. [PMID: 33828558 PMCID: PMC8019701 DOI: 10.3389/fimmu.2021.648216] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 02/24/2021] [Indexed: 11/13/2022] Open
Abstract
Background: MAIT cells are non-classically restricted T lymphocytes that recognize and rapidly respond to microbial metabolites or cytokines and have the capacity to kill bacteria-infected cells. Circulating MAIT cell numbers generally decrease in patients with active TB and HIV infection, but findings regarding functional changes differ. Methods: We conducted a cross-sectional study on the effect of HIV, TB, and HIV-associated TB (HIV-TB) on MAIT cell frequencies, activation and functional profile in a high TB endemic setting in South Africa. Blood was collected from (i) healthy controls (HC, n = 26), 24 of whom had LTBI, (ii) individuals with active TB (aTB, n = 36), (iii) individuals with HIV infection (HIV, n = 50), 37 of whom had LTBI, and (iv) individuals with HIV-associated TB (HIV-TB, n = 26). All TB participants were newly diagnosed and sampled before treatment, additional samples were also collected from 18 participants in the aTB group after 10 weeks of TB treatment. Peripheral blood mononuclear cells (PBMC) stimulated with BCG-expressing GFP (BCG-GFP) and heat-killed (HK) Mycobacterium tuberculosis (M.tb) were analyzed using flow cytometry. MAIT cells were defined as CD3+ CD161+ Vα7.2+ T cells. Results: Circulating MAIT cell frequencies were depleted in individuals with HIV infection (p = 0.009). MAIT cells showed reduced CD107a expression in aTB (p = 0.006), and reduced IFNγ expression in aTB (p < 0.001) and in HIV-TB (p < 0.001) in response to BCG-GFP stimulation. This functional impairment was coupled with a significant increase in activation (defined by HLA-DR expression) in resting MAIT cells from HIV (p < 0.001), aTB (p = 0.019), and HIV-TB (p = 0.005) patients, and higher HLA-DR expression in MAIT cells expressing IFNγ in aTB (p = 0.009) and HIV-TB (p = 0.002) after stimulation with BCG-GFP and HK-M.tb. After 10 weeks of TB treatment, there was reversion in the observed functional impairment in total MAIT cells, with increases in CD107a (p = 0.020) and IFNγ (p = 0.010) expression. Conclusions: Frequencies and functional profile of MAIT cells in response to mycobacterial stimulation are significantly decreased in HIV infected persons, active TB and HIV-associated TB, with a concomitant increase in MAIT cell activation. These alterations may reduce the capacity of MAIT cells to play a protective role in the immune response to these two pathogens.
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Affiliation(s)
- Avuyonke Balfour
- Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.,Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa
| | - Charlotte Schutz
- Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.,Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa
| | - Rene Goliath
- Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa
| | - Katalin A Wilkinson
- Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa.,The Francis Crick Institute, London, United Kingdom
| | - Sumaya Sayed
- Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa
| | - Bianca Sossen
- Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.,Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa
| | - Jean-Paul Kanyik
- Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa
| | - Amy Ward
- Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa
| | - Rhandzu Ndzhukule
- Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa
| | - Anele Gela
- South African Tuberculosis Vaccine Initiative, Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa
| | - David M Lewinsohn
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Oregon Health and Science University, Portland, OR, United States
| | - Deborah A Lewinsohn
- Division of Infectious Diseases, Department of Paediatrics, Oregon Health and Science University, Portland, OR, United States
| | - Graeme Meintjes
- Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.,Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa
| | - Muki Shey
- Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.,Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa), Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine (IDM), University of Cape Town, Cape Town, South Africa
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Sharma V, Makhdoomi M, Singh L, Kumar P, Khan N, Singh S, Verma HN, Luthra K, Sarkar S, Kumar D. Trehalose limits opportunistic mycobacterial survival during HIV co-infection by reversing HIV-mediated autophagy block. Autophagy 2021; 17:476-495. [PMID: 32079455 PMCID: PMC7610453 DOI: 10.1080/15548627.2020.1725374] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Revised: 01/27/2020] [Accepted: 01/29/2020] [Indexed: 02/07/2023] Open
Abstract
Opportunistic bacterial infections amongst HIV-infected individuals contribute significantly to HIV-associated mortality. The role of HIV-mediated modulation of innate mechanisms like autophagy in promoting opportunistic infections, however, remains obscure. Here we show, HIV reactivation in or infection of macrophages inhibits autophagy and helps the survival of pathogenic Mycobacterium tuberculosis (Mtb) and nonpathogenic non-tuberculous mycobacterial strains (NTMs). The HIV-mediated impairment of xenophagy flux facilitated bacterial survival. Activation of autophagy by trehalose could induce xenophagy flux and kill intracellular Mtb or NTMs either during single or co-infections. Trehalose, we delineate, activates PIKFYVE leading to TFEB nuclear translocation in MCOLN1-dependent manner to induce autophagy. Remarkably, trehalose significantly reduced HIV-p24 levels in ex-vivo-infected PBMCs or PBMCs from treatment-naive HIV patients and also controlled mycobacterial survival within Mtb-infected animals. To conclude, we report leveraging of HIV-mediated perturbed host innate-immunity by opportunistic bacterial pathogens and show an attractive therapeutic strategy for HIV and associated co-morbidities.Abbreviations: AIDS: acquired immune deficiency syndrome; AMPK: AMP-activated protein kinase; ATG5: autophagy related 5; BafA1: bafilomycin A1; CFU: colony forming unit; CTSD: cathepsin D; CD63: CD63 molecule; EGFP: enhanced green fluorescent protein; FRET: Förster resonance energy transfer; GABARAP: gamma-aminobutyric acid receptor-associated protein; GAPDH: glyceraldehyde 3-phosphate dehydrogenase; GLUT: glucose transporter; HIV: human immunodeficiency virus; hMDMs: human monocyte derived macrophages; IL2: interleukin 2; LAMP1: lysosomal-associated membrane protein 1; LC3B-II: lipidated microtubule-associated proteins 1A/1B light chain 3B; Mtb: Mycobacterium tuberculosis; MTOR: mechanistic target of rapamycin; mRFP: monomeric red fluorescent protein; M6PR: mannose-6-phosphate receptor; NAC: N- acetyl- L -cysteine; NTM's: non-tuberculous mycobacteria; PBMC: Peripheral Blood Mononuclear cells; PIKFYVE: phosphoinositide kinase; FYVE-Type Zinc Finger; PHA: phytohemagglutinin; PMA: phorbol 12-myristate 13-acetate; PtdIns(3,5)P2: Phosphatidylinositol 3,5-bisphosphate; ptfLC3: pEGFP-mRFP-LC3; ROS: reactive oxygen species; SQSTM1: sequestosome1; TFEB: transcription factor EB; MCOLN1/TRPML1: mucolipin 1; PIP4P1/TMEM55B: Human trans-membrane Protein 55B; UVRAG: UV Radiation Resistance Associate; VPS35: vacuolar protein sorting associated protein 35; WDR45: WD repeat domain 45; YCAM: Yellow Chameleon.
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Affiliation(s)
- Vartika Sharma
- Cellular Immunology Group, International Center for Genetic Engineering and Biotechnology, New Delhi, India
| | - Muzamil Makhdoomi
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Lakshyaveer Singh
- Cellular Immunology Group, International Center for Genetic Engineering and Biotechnology, New Delhi, India
| | - Purnima Kumar
- Cellular Immunology Group, International Center for Genetic Engineering and Biotechnology, New Delhi, India
| | - Nabab Khan
- Cellular Immunology Group, International Center for Genetic Engineering and Biotechnology, New Delhi, India
| | - Sarman Singh
- Division of Clinical Microbiology & Molecular Medicine, Department of Laboratory Medicine, All India Institute of Medical Sciences, New Delhi, India
| | - H N Verma
- School of Life Sciences, Jaipur National University, Jaipur, India
| | - Kalpana Luthra
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Sovan Sarkar
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Dhiraj Kumar
- Cellular Immunology Group, International Center for Genetic Engineering and Biotechnology, New Delhi, India
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Santos-Pereira A, Magalhães C, Araújo PMM, Osório NS. Evolutionary Genetics of Mycobacterium tuberculosis and HIV-1: "The Tortoise and the Hare". Microorganisms 2021; 9:147. [PMID: 33440808 PMCID: PMC7827287 DOI: 10.3390/microorganisms9010147] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 12/24/2020] [Accepted: 01/06/2021] [Indexed: 12/16/2022] Open
Abstract
The already enormous burden caused by Mycobacterium tuberculosis and Human Immunodeficiency Virus type 1 (HIV-1) alone is aggravated by co-infection. Despite obvious differences in the rate of evolution comparing these two human pathogens, genetic diversity plays an important role in the success of both. The extreme evolutionary dynamics of HIV-1 is in the basis of a robust capacity to evade immune responses, to generate drug-resistance and to diversify the population-level reservoir of M group viral subtypes. Compared to HIV-1 and other retroviruses, M. tuberculosis generates minute levels of genetic diversity within the host. However, emerging whole-genome sequencing data show that the M. tuberculosis complex contains at least nine human-adapted phylogenetic lineages. This level of genetic diversity results in differences in M. tuberculosis interactions with the host immune system, virulence and drug resistance propensity. In co-infected individuals, HIV-1 and M. tuberculosis are likely to co-colonize host cells. However, the evolutionary impact of the interaction between the host, the slowly evolving M. tuberculosis bacteria and the HIV-1 viral "mutant cloud" is poorly understood. These evolutionary dynamics, at the cellular niche of monocytes/macrophages, are also discussed and proposed as a relevant future research topic in the context of single-cell sequencing.
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Affiliation(s)
- Ana Santos-Pereira
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; (A.S.-P.); (C.M.); (P.M.M.A.)
- ICVS/3B’s-T Government Associate Laboratory, 4710-057 Braga/Guimarães, Portugal
| | - Carlos Magalhães
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; (A.S.-P.); (C.M.); (P.M.M.A.)
- ICVS/3B’s-T Government Associate Laboratory, 4710-057 Braga/Guimarães, Portugal
| | - Pedro M. M. Araújo
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; (A.S.-P.); (C.M.); (P.M.M.A.)
- ICVS/3B’s-T Government Associate Laboratory, 4710-057 Braga/Guimarães, Portugal
| | - Nuno S. Osório
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal; (A.S.-P.); (C.M.); (P.M.M.A.)
- ICVS/3B’s-T Government Associate Laboratory, 4710-057 Braga/Guimarães, Portugal
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Analysis of Antimicrobial Activity of Monocytic Myeloid-Derived Suppressor Cells in Infection with Mycobacterium tuberculosis and Human Immunodeficiency Virus. Methods Mol Biol 2021; 2236:115-127. [PMID: 33237545 DOI: 10.1007/978-1-0716-1060-2_11] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Myeloid-derived suppressor cells (MDSC) encompass a subset of myeloid cells, which suppress both innate and adaptive immune functions. Since Mycobacterium tuberculosis (M. tuberculosis) can infect these cells, interest has emerged to study the antimicrobial response of MDSC to mycobacteria causing tuberculosis. Reactive oxygen species (ROS) are critical mediators to control intracellular replication of M. tuberculosis and MDSC express high levels of these effector molecules. Here we describe the flow cytometric assessment of total cellular ROS produced by MDSC in response to infection with M. tuberculosis and compare it with the ROS activity of non-MDSC myeloid cells. To further understand the dynamics of host-pathogen interactions, we provide details on methods for measurement of the intracellular replication of M. tuberculosis within MDSC. Of note, these procedures were adopted for primary MDSC and non-MDSC subsets isolated from human immunodeficiency virus (HIV)-uninfected or HIV-infected individuals, in vitro infected with M. tuberculosis to mimic M. tuberculosis mono- or HIV-M. tuberculosis coinfection, respectively.
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Singer M, Rylko-Bauer B. The Syndemics and Structural Violence of the COVID Pandemic: Anthropological Insights on a Crisis. ACTA ACUST UNITED AC 2020. [DOI: 10.1515/opan-2020-0100] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Abstract
This paper examines the COVID-19 pandemic in light of two key concepts in medical anthropology: syndemics and structural violence. Following a discussion of the nature of these two concepts, the paper addresses the direct and associated literatures on the syndemic and structural violence features of the COVID pandemic, with a specific focus on: 1) the importance of local socioenvironmental conditions/demographics and disease configurations in creating varying local syndemic expressions; 2) the ways that the pandemic has exposed the grave weaknesses in global health care investment; and 3) how the syndemic nature of the pandemic reveals the rising rate of noncommunicable diseases and their potential for interaction with current and future infectious disease. The paper concludes with a discussion on the role of anthropology in responding to COVID-19 from a syndemics perspective.
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Affiliation(s)
- Merrill Singer
- University of Connecticut , Department of Anthropology , 354 Mansfield Road, Unit 1176, Storrs, CT 06269-1176, United States
| | - Barbara Rylko-Bauer
- Michigan State University , Department of Anthropology , 655 Auditorium Drive – East Lansing, MI 48824, United States
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Arega B, Mersha A, Minda A, Getachew Y, Sitotaw A, Gebeyehu T, Agunie A. Epidemiology and the diagnostic challenge of extra-pulmonary tuberculosis in a teaching hospital in Ethiopia. PLoS One 2020; 15:e0243945. [PMID: 33320897 PMCID: PMC7737896 DOI: 10.1371/journal.pone.0243945] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 11/30/2020] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Ethiopia reported a high rate of extra-pulmonary tuberculosis (EPTB) and the cases are increasing since the last three decades. However, diagnostic evidence to initiate TB treatment among EPTB cases is not well known. Therefore, we described the epidemiology and assessed how EPTB is diagnosed in a teaching hospital in Ethiopia. METHODS We conducted a retrospective review among all adult EPTB cases diagnosed in Yekatit 12 Hospital Medical College from 2015 to 2019. Using a standardized data abstraction sheet, we collected data from patients' medical records on sociodemographic, sites, and laboratory diagnosis of EPTB cases. RESULTS Of the 965 total TB cases, 49.8%(481) had a recorded diagnosis of EPTB during the study period. The mean age of EPTB patients was 32.9 years (SD±13.9) and 50.7% were males. Tubercular lymphadenitis (40.3%), abdominal (23.4%), and pleural TB(13.5%) were the most common sites of EPTB involvement, followed in descending order by the genitourinary, skeletal, central nervous system, abscess, breast, and laryngeal TB. We found a histopathology finding consistent with EPTB in 59.1% of cases, Acid-fast bacilli positive in 1.5%, and the rest diagnosed on radiological grounds. In the majority of cases, more than one diagnostic method was used to diagnose EPTB cases. CONCLUSIONS Nearly half of TB patients had a recorded diagnosis of EPTB that comprise heterogeneous anatomical sites. All EPTB patients were started anti-TB therapy without definitive microbiology results. This indicates the diagnostic challenge of EPTB faced in our setting and proves to be significant for TB control in Ethiopia.
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MESH Headings
- Adolescent
- Adult
- Antitubercular Agents/therapeutic use
- Ethiopia/epidemiology
- Female
- Hospitals, Teaching
- Humans
- Male
- Risk Factors
- Tuberculosis, Lymph Node/drug therapy
- Tuberculosis, Lymph Node/epidemiology
- Tuberculosis, Lymph Node/microbiology
- Tuberculosis, Lymph Node/pathology
- Tuberculosis, Pleural/drug therapy
- Tuberculosis, Pleural/epidemiology
- Tuberculosis, Pleural/microbiology
- Tuberculosis, Pleural/pathology
- Tuberculosis, Pulmonary/drug therapy
- Tuberculosis, Pulmonary/epidemiology
- Tuberculosis, Pulmonary/microbiology
- Tuberculosis, Pulmonary/pathology
- Young Adult
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Affiliation(s)
- Balew Arega
- Yekatit 12 Hospital Medical College, Addis Ababa, Ethiopia
| | | | - Abraham Minda
- Yekatit 12 Hospital Medical College, Addis Ababa, Ethiopia
| | | | - Alazar Sitotaw
- Yekatit 12 Hospital Medical College, Addis Ababa, Ethiopia
| | | | - Asnake Agunie
- Yekatit 12 Hospital Medical College, Addis Ababa, Ethiopia
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Rakshit S, Hingankar N, Alampalli SV, Adiga V, Sundararaj BK, Sahoo PN, Finak G, Uday Kumar J AJ, Dhar C, D'Souza G, Virkar RG, Ghate M, Thakar MR, Paranjape RS, De Rosa SC, Ottenhoff THM, Vyakarnam A. HIV Skews a Balanced Mtb-Specific Th17 Response in Latent Tuberculosis Subjects to a Pro-inflammatory Profile Independent of Viral Load. Cell Rep 2020; 33:108451. [PMID: 33264614 DOI: 10.1016/j.celrep.2020.108451] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 09/15/2020] [Accepted: 11/09/2020] [Indexed: 02/08/2023] Open
Abstract
HIV infection predisposes latent tuberculosis-infected (LTBI) subjects to active TB. This study is designed to determine whether HIV infection of LTBI subjects compromises the balanced Mycobacterium tuberculosis (Mtb)-specific T helper 17 (Th17) response of recognized importance in anti-TB immunity. Comparative analysis of Mtb- and cytomegalovirus (CMV)-specific CD4+ T cell responses demonstrates a marked dampening of the Mtb-specific CD4+ T cell effectors and polyfunctional cells while preserving CMV-specific response. Additionally, HIV skews the Mtb-specific Th17 response in chronic HIV-infected LTBI progressors, but not long-term non-progressors (LTNPs), with preservation of pro-inflammatory interferon (IFN)-γ+/interleukin-17+ (IL-17+) and significant loss of anti-inflammatory IL-10+/IL-17+ effectors that is restored by anti-retroviral therapy (ART). HIV-driven impairment of Mtb-specific response cannot be attributed to preferential infection as cell-associated HIV DNA and HIV RNA reveal equivalent viral burden in CD4+ T cells from different antigen specificities. We therefore propose that beyond HIV-induced loss of Mtb-specific CD4+ T cells, the associated dysregulation of Mtb-specific T cell homeostasis can potentially enhance the onset of TB in LTBI subjects.
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Affiliation(s)
- Srabanti Rakshit
- Laboratory of Immunology of HIV-TB Co-infection, Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, India
| | - Nitin Hingankar
- Laboratory of Immunology of HIV-TB Co-infection, Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, India
| | - Shuba Varshini Alampalli
- Laboratory of Immunology of HIV-TB Co-infection, Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, India
| | - Vasista Adiga
- Laboratory of Immunology of HIV-TB Co-infection, Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, India
| | - Bharath K Sundararaj
- Laboratory of Immunology of HIV-TB Co-infection, Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, India
| | - Pravat Nalini Sahoo
- Laboratory of Immunology of HIV-TB Co-infection, Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, India
| | - Greg Finak
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Anto Jesuraj Uday Kumar J
- Departments of Infectious Diseases & Pulmonary Medicine, St. John's Research Institute, Bangalore, India
| | - Chirag Dhar
- Departments of Infectious Diseases & Pulmonary Medicine, St. John's Research Institute, Bangalore, India
| | - George D'Souza
- Departments of Infectious Diseases & Pulmonary Medicine, St. John's Research Institute, Bangalore, India
| | | | - Manisha Ghate
- National Aids Research Institute, Bhosari, Pune, Maharashtra, India
| | - Madhuri R Thakar
- National Aids Research Institute, Bhosari, Pune, Maharashtra, India
| | | | - Stephen C De Rosa
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Tom H M Ottenhoff
- Department of Infectious Diseases, Leiden University Medical Center, Leiden, the Netherlands
| | - Annapurna Vyakarnam
- Laboratory of Immunology of HIV-TB Co-infection, Centre for Infectious Disease Research, Indian Institute of Science, Bangalore, India; Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, Faculty of Life Sciences & Medicine, Guy's Hospital, King's College London, London SE1 9RT, UK.
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The Association of Tuberculosis Mono-infection and Tuberculosis-Human Immunodeficiency Virus (TB-HIV) Co-infection in the Pathogenesis of Hypertensive Disorders of Pregnancy. Curr Hypertens Rep 2020; 22:104. [PMID: 33159613 DOI: 10.1007/s11906-020-01114-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/10/2020] [Indexed: 10/23/2022]
Abstract
PURPOSE OF REVIEW This review highlights the impact of TB mono-infection and TB-HIV co-infection on the pathogenesis of adverse maternal outcomes such as hypertensive disorders of pregnancy (HDP) and adverse fetal outcomes such as recurrent spontaneous abortion (RSA), fetal growth restriction (FGR), and low birth weight. RECENT FINDINGS Research has shown that HDP, such as severe pre-eclampsia (PE) and eclampsia, as well as adverse fetal outcomes such as recurrent spontaneous abortion, fetal growth restriction, and low birth weight, are higher in women diagnosed with TB mono-infection and even higher in TB-HIV co-infection compared to those without TB. This is speculated to occur due to exaggerated activation of both angiogenic factors such as vascular endothelial growth factor (VEGF), nitric oxide (NO), angiotensin 2, (Ang 2), intracellular adhesion molecules (ICAMs), and inflammatory cytokines such as interleukin 2 (IL-2), (IL-17), and interferon-gamma (INF-γ). There is a lack of information with regard to the pathogenesis of adverse maternal and fetal outcomes upon TB mono-infection and TB-HIV co-infection; therefore, further investigations on the impact of TB mono-infection and TB-HIV co-infection on adverse maternal and fetal outcomes are urgently needed. This will assist in improving diagnostic procedures in pregnant women affected with TB as wells as TB-HIV co-infection.
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Quinn CM, Poplin V, Kasibante J, Yuquimpo K, Gakuru J, Cresswell FV, Bahr NC. Tuberculosis IRIS: Pathogenesis, Presentation, and Management across the Spectrum of Disease. Life (Basel) 2020; 10:E262. [PMID: 33138069 PMCID: PMC7693460 DOI: 10.3390/life10110262] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 10/13/2020] [Accepted: 10/21/2020] [Indexed: 12/14/2022] Open
Abstract
Antiretroviral therapy (ART), while essential in combatting tuberculosis (TB) and HIV coinfection, is often complicated by the TB-associated immune reconstitution inflammatory syndrome (TB-IRIS). Depending on the TB disease site and treatment status at ART initiation, this immune-mediated worsening of TB pathology can take the form of paradoxical TB-IRIS, unmasking TB-IRIS, or CNS TB-IRIS. Each form of TB-IRIS has unique implications for diagnosis and treatment. Recently published studies have emphasized the importance of neutrophils and T cell subtypes in TB-IRIS pathogenesis, alongside the recognized role of CD4 T cells and macrophages. Research has also refined our prognostic understanding, revealing how the disease can impact lung function. While corticosteroids remain the only trial-supported therapy for prevention and management of TB-IRIS, increasing interest has been given to biologic therapies directly targeting the immune pathology. TB-IRIS, especially its unmasking form, remains incompletely described and more data is needed to validate biomarkers for diagnosis. Management strategies remain suboptimal, especially in the highly morbid central nervous system (CNS) form of the disease, and further trials are necessary to refine treatment. In this review we will summarize the current understanding of the immunopathogenesis, the presentation of TB-IRIS and the evidence for management recommendations.
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Affiliation(s)
- Carson M. Quinn
- School of Medicine, University of California, San Francisco, CA 94143, USA
- Infectious Diseases Institute, College of Health Sciences, Makerere University, Kampala, Uganda; (J.K.); (J.G.); (F.V.C.)
| | - Victoria Poplin
- Division of Infectious Diseases, Department of Medicine, University of Kansas, Kansas City, KS 66045, USA; (V.P.); (N.C.B.)
| | - John Kasibante
- Infectious Diseases Institute, College of Health Sciences, Makerere University, Kampala, Uganda; (J.K.); (J.G.); (F.V.C.)
| | - Kyle Yuquimpo
- Department of Medicine, University of Kansas, Kansas City, KS 66045, USA;
| | - Jane Gakuru
- Infectious Diseases Institute, College of Health Sciences, Makerere University, Kampala, Uganda; (J.K.); (J.G.); (F.V.C.)
| | - Fiona V. Cresswell
- Infectious Diseases Institute, College of Health Sciences, Makerere University, Kampala, Uganda; (J.K.); (J.G.); (F.V.C.)
- Clinical Research Department, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK
- Medical Research Council, Uganda Virus Research Unit, London School of Hygiene and Tropical Medicine Uganda Research Unit, Entebbe, Uganda
| | - Nathan C. Bahr
- Division of Infectious Diseases, Department of Medicine, University of Kansas, Kansas City, KS 66045, USA; (V.P.); (N.C.B.)
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50
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Birku M, Desalegn G, Kassa G, Tsegaye A, Abebe M. Effect of pregnancy and HIV infection on detection of latent TB infection by Tuberculin Skin Test and QuantiFERON-TB Gold In-Tube assay among women living in a high TB and HIV burden setting. Int J Infect Dis 2020; 101:235-242. [PMID: 33039610 DOI: 10.1016/j.ijid.2020.09.1452] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Revised: 09/18/2020] [Accepted: 09/22/2020] [Indexed: 11/29/2022] Open
Abstract
OBJECTIVE To investigate the effect of pregnancy and Human immunodeficiency virus (HIV) infection on detection performances of tuberculin skin test (TST) and QuantiFERON-TB Gold In-Tube (QFTGIT) for the diagnosis of latent tuberculosis infection (LTBI) among women living in high TB and HIV endemic setting. METHOD A cross-sectional study was conducted among women with and without pregnancy and HIV infection. Three-hundred twenty women were enrolled in this study and were diagnosed using TST and QFTGIT for the detection of LTBI. RESULTS Overall prevalence of LTBI among the enrolled women was 55.6%, 46.3% and 51.1% as determined by TST, QFTGIT and concordant TST/QFTGIT results, respectively. Our study revealed that pregnancy or HIV infection reduced the rate of detection of LTBI by TST and QFTGIT tests, with the utmost effect observed in HIV-positive pregnant women. Additionally, we observed that the concordance between TST and QFTGIT among women increased with the presence of pregnancy and/or HIV infection. A history of contact with TB patients was significantly associated with positivity of TST and QFTGIT. CONCLUSION This study demonstrated that both pregnancy and HIV infection profoundly affected the detection performance of TST and QFTGIT, which may be associated with immunosuppression of anti-mycobacterial immunity in women with pregnancy and/or HIV infection.
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Affiliation(s)
- Mahlet Birku
- Armauer Hansen Research Institute (AHRI), Addis Ababa, Ethiopia; Department of Medical Laboratory Sciences, Addis Ababa University, Addis Ababa, Ethiopia
| | - Girmay Desalegn
- Department of Medical Microbiology and Immunology, Mekelle University, Mekelle, Ethiopia.
| | - Getachew Kassa
- Ethiopian Public Health Institute, Addis Ababa, Ethiopia
| | - Aster Tsegaye
- Department of Medical Laboratory Sciences, Addis Ababa University, Addis Ababa, Ethiopia
| | - Markos Abebe
- Armauer Hansen Research Institute (AHRI), Addis Ababa, Ethiopia
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