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Goosen C, Proost S, Baumgartner J, Mallick K, Tito RY, Barnabas SL, Cotton MF, Zimmermann MB, Raes J, Blaauw R. Associations of HIV and iron status with gut microbiota composition, gut inflammation and gut integrity in South African school-age children: a two-way factorial case-control study. J Hum Nutr Diet 2023; 36:819-832. [PMID: 36992541 PMCID: PMC10946596 DOI: 10.1111/jhn.13171] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Accepted: 03/19/2023] [Indexed: 03/31/2023]
Abstract
BACKGROUND Human immunodeficiency virus (HIV) and iron deficiency (ID) affect many African children. Both HIV and iron status interact with gut microbiota composition and related biomarkers. The study's aim was to determine the associations of HIV and iron status with gut microbiota composition, gut inflammation and gut integrity in South African school-age children. METHODS In this two-way factorial case-control study, 8- to 13-year-old children were enrolled into four groups based on their HIV and iron status: (1) With HIV (HIV+) and ID (n = 43), (2) HIV+ and iron-sufficient nonanaemic (n = 41), (3) without HIV (HIV-) and ID (n = 44) and (4) HIV- and iron-sufficient nonanaemic (n = 38). HIV+ children were virally suppressed (<50 HIV RNA copies/ml) on antiretroviral therapy (ART). Microbial composition of faecal samples (16S rRNA sequencing) and markers of gut inflammation (faecal calprotectin) and gut integrity (plasma intestinal fatty acid-binding protein [I-FABP]) were assessed. RESULTS Faecal calprotectin was higher in ID versus iron-sufficient nonanaemic children (p = 0.007). I-FABP did not significantly differ by HIV or iron status. ART-treated HIV (redundancy analysis [RDA] R2 = 0.009, p = 0.029) and age (RDA R2 = 0.013 p = 0.004) explained the variance in the gut microbiota across the four groups. Probabilistic models showed that the relative abundance of the butyrate-producing genera Anaerostipes and Anaerotruncus was lower in ID versus iron-sufficient children. Fusicatenibacter was lower in HIV+ and in ID children versus their respective counterparts. The prevalence of the inflammation-associated genus Megamonas was 42% higher in children with both HIV and ID versus HIV- and iron-sufficient nonanaemic counterparts. CONCLUSIONS In our sample of 8- to 13-year-old virally suppressed HIV+ and HIV- children with or without ID, ID was associated with increased gut inflammation and changes in the relative abundance of specific microbiota. Moreover, in HIV+ children, ID had a cumulative effect that further shifted the gut microbiota to an unfavourable composition.
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Affiliation(s)
- Charlene Goosen
- Division of Human Nutrition, Department of Global Health, Faculty of Medicine and Health SciencesStellenbosch UniversityCape TownSouth Africa
| | - Sebastian Proost
- Laboratory of Molecular Bacteriology, Department of Microbiology and ImmunologyRega Institute, KU LeuvenLeuvenBelgium
- Center for Microbiology, VIBLeuvenBelgium
| | - Jeannine Baumgartner
- Laboratory of Human Nutrition, Department of Health Sciences and TechnologyETH ZurichZurichSwitzerland
- Department of Nutritional SciencesKing's College LondonLondonUK
| | - Kashish Mallick
- Laboratory of Human Nutrition, Department of Health Sciences and TechnologyETH ZurichZurichSwitzerland
| | - Raul Y. Tito
- Laboratory of Molecular Bacteriology, Department of Microbiology and ImmunologyRega Institute, KU LeuvenLeuvenBelgium
- Center for Microbiology, VIBLeuvenBelgium
| | - Shaun L. Barnabas
- Department of Paediatrics and Child Health, Family Centre for Research with UbuntuStellenbosch UniversityCape TownSouth Africa
| | - Mark F. Cotton
- Department of Paediatrics and Child Health, Family Centre for Research with UbuntuStellenbosch UniversityCape TownSouth Africa
| | - Michael B. Zimmermann
- Laboratory of Human Nutrition, Department of Health Sciences and TechnologyETH ZurichZurichSwitzerland
| | - Jeroen Raes
- Laboratory of Molecular Bacteriology, Department of Microbiology and ImmunologyRega Institute, KU LeuvenLeuvenBelgium
- Center for Microbiology, VIBLeuvenBelgium
| | - Renée Blaauw
- Division of Human Nutrition, Department of Global Health, Faculty of Medicine and Health SciencesStellenbosch UniversityCape TownSouth Africa
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Church JA, Rukobo S, Govha M, Gough EK, Chasekwa B, Lee B, Carmolli MP, Panic G, Giallourou N, Ntozini R, Mutasa K, McNeal MM, Majo FD, Tavengwa NV, Swann JR, Moulton LH, Kirkpatrick BD, Humphrey JH, Prendergast AJ. Associations between biomarkers of environmental enteric dysfunction and oral rotavirus vaccine immunogenicity in rural Zimbabwean infants. EClinicalMedicine 2021; 41:101173. [PMID: 34825149 PMCID: PMC8605235 DOI: 10.1016/j.eclinm.2021.101173] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Revised: 10/01/2021] [Accepted: 10/11/2021] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Oral rotavirus vaccines (RVV) are poorly immunogenic in low-income countries. Environmental enteric dysfunction (EED) resulting from poor water, sanitation and hygiene (WASH) may contribute. We therefore tested associations between EED and RVV immunogenicity, and evaluated the effect of improved WASH on EED. METHODS We measured nine biomarkers of EED among Zimbabwean infants born to mothers enrolled in a cluster-randomised 2 × 2 factorial trial of improved WASH and improved feeding between November 2012 and March 2015 (NCT01824940). We used multivariable regression to determine associations between EED biomarkers and RVV seroconversion, seropositivity and geometric mean titer. Log-binomial regression was used to evaluate the effect of improved WASH on EED. FINDINGS Among 303 infants with EED biomarkers and immunogenicity data, plasma intestinal fatty-acid binding protein and stool myeloperoxidase were positively associated with RVV seroconversion; adjusted RR 1.63 (95%CI 1.04, 2.57) and 1.29 (95%CI 1.01, 1.65), respectively. There were no other associations between RVV immunogenicity and either individual biomarkers or EED domains (intestinal permeability, intestinal damage, intestinal inflammation and microbial translocation). EED biomarkers did not differ between randomised WASH and non-WASH groups. INTERPRETATION We found no evidence that EED was associated with poor RVV immunogenicity. Contrary to our hypothesis, there was weak evidence that EED was associated with increased seroconversion. EED biomarkers were not affected by a package of household-level WASH interventions.
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Affiliation(s)
- James A Church
- Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe
- Centre for Genomics and Child Health, Blizard Institute, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK
- Corresponding authors at: Centre for Genomics and Child Health, Blizard Institute, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK.
| | - Sandra Rukobo
- Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe
| | - Margaret Govha
- Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe
| | - Ethan K Gough
- Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe
- Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Bernard Chasekwa
- Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe
| | - Benjamin Lee
- Departments of Pediatrics, Vaccine Testing Center, Larner College of Medicine, University of Vermont, Burlington, VT, USA
| | - Marya P Carmolli
- Departments of Microbiology and Molecular Genetics, Vaccine Testing Center, Larner College of Medicine, University of Vermont, Burlington, VT, USA
| | - Gordana Panic
- Faculty of Medicine, Imperial College London, South Kensington Campus, London SW7 2AZ, UK
| | - Natasa Giallourou
- Faculty of Medicine, Imperial College London, South Kensington Campus, London SW7 2AZ, UK
| | - Robert Ntozini
- Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe
| | - Kuda Mutasa
- Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe
| | - Monica M McNeal
- Department of Pediatrics, University of Cincinnati College of Medicine, Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Florence D. Majo
- Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe
| | - Naume V. Tavengwa
- Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe
| | - Jonathan R. Swann
- Faculty of Medicine, Imperial College London, South Kensington Campus, London SW7 2AZ, UK
| | - Lawrence H Moulton
- Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Beth D Kirkpatrick
- Departments of Microbiology and Molecular Genetics, Vaccine Testing Center, Larner College of Medicine, University of Vermont, Burlington, VT, USA
| | - Jean H Humphrey
- Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe
- Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Andrew J Prendergast
- Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe
- Centre for Genomics and Child Health, Blizard Institute, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK
- Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
- Corresponding authors at: Centre for Genomics and Child Health, Blizard Institute, Queen Mary University of London, 4 Newark Street, London E1 2AT, UK.
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Olwenyi OA, Johnson SD, Pandey K, Thurman M, Acharya A, Buch SJ, Fox HS, Podany AT, Fletcher CV, Byrareddy SN. Diminished Peripheral CD29hi Cytotoxic CD4+ T Cells Are Associated With Deleterious Effects During SIV Infection. Front Immunol 2021; 12:734871. [PMID: 34721397 PMCID: PMC8548621 DOI: 10.3389/fimmu.2021.734871] [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: 07/01/2021] [Accepted: 09/22/2021] [Indexed: 11/13/2022] Open
Abstract
Cytotoxic CD4+ T cells (CD4+ CTLs) limit HIV pathogenesis, as evidenced in elite controllers (a subset of individuals who suppress the virus without the need for therapy). CD4+ CTLs have also been shown to kill HIV-infected macrophages. However, little is known about their contribution towards HIV persistence, how they are affected following exposure to immune modulators like morphine, and what factors maintain their frequencies and function. Further, the lack of robust markers to identify CD4+ CTLs in various animal models limits understanding of their role in HIV pathogenesis. We utilized various PBMC samples obtained from SIV infected and cART treated rhesus macaques exposed to morphine or saline and subjected to flow cytometry evaluations. Thereafter, we compared and correlated the expression of CD4+ CTL-specific markers to viral load and viral reservoir estimations in total CD4+ T cells. We found that CD29 could be reliably used as a marker to identify CD4+ CTLs in rhesus macaques since CD29hi CD4+ T cells secrete higher cytotoxic and proinflammatory cytokines following PMA/ionomycin or gag stimulation. In addition, this immune cell subset was depleted during untreated SIV infection. Strikingly, we also observed that early initiation of cART reconstitutes depleted CD29hi CD4+ T cells and restores their function. Furthermore, we noted that morphine exposure reduced the secretion of proinflammatory cytokines/cytotoxic molecules in CD29hi CD4+ T cells. Lastly, increased functionality of CD29hi CD4+ T cells as depicted by elevated levels of either IL-21 or granzyme B hi T Bet+ gag specific responses were linked to limiting the size of the replication-competent reservoir during cART treatment. Collectively, our data suggest that CD4+ CTLs are crucial in limiting SIV pathogenesis and persistence.
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Affiliation(s)
- Omalla A. Olwenyi
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, United States
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Samuel D. Johnson
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, United States
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Kabita Pandey
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, United States
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Michellie Thurman
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, United States
| | - Arpan Acharya
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, United States
| | - Shilpa J. Buch
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, United States
| | - Howard S. Fox
- Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, NE, United States
| | - Anthony T. Podany
- Antiviral Pharmacology Laboratory, Center for Drug Discovery, University of Nebraska Medical Center (UNMC), Omaha, NE, United States
| | - Courtney V. Fletcher
- Antiviral Pharmacology Laboratory, Center for Drug Discovery, University of Nebraska Medical Center (UNMC), Omaha, NE, United States
| | - Siddappa N. Byrareddy
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, United States
- Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, NE, United States
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, United States
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
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Johnson SD, Olwenyi OA, Bhyravbhatla N, Thurman M, Pandey K, Klug EA, Johnston M, Dyavar SR, Acharya A, Podany AT, Fletcher CV, Mohan M, Singh K, Byrareddy SN. Therapeutic implications of SARS-CoV-2 dysregulation of the gut-brain-lung axis. World J Gastroenterol 2021; 27:4763-4783. [PMID: 34447225 PMCID: PMC8371510 DOI: 10.3748/wjg.v27.i29.4763] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 05/10/2021] [Accepted: 07/20/2021] [Indexed: 02/06/2023] Open
Abstract
The emergence and rapid spread of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused over 180 million confirmed cases resulting in over 4 million deaths worldwide with no clear end in sight for the coronavirus disease 19 (COVID-19) pandemic. Most SARS-CoV-2 exposed individuals experience mild to moderate symptoms, including fever, cough, fatigue, and loss of smell and taste. However, many individuals develop pneumonia, acute respiratory distress syndrome, septic shock, and multiorgan dysfunction. In addition to these primarily respiratory symptoms, SARS-CoV-2 can also infiltrate the central nervous system, which may damage the blood-brain barrier and the neuron's synapses. Resultant inflammation and neurodegeneration in the brain stem can further prevent efferent signaling to cranial nerves, leading to the loss of anti-inflammatory signaling and normal respiratory and gastrointestinal functions. Additionally, SARS-CoV-2 can infect enterocytes resulting in gut damage followed by microbial dysbiosis and translocation of bacteria and their byproducts across the damaged epithelial barrier. As a result, this exacerbates pro-inflammatory responses both locally and systemically, resulting in impaired clinical outcomes. Recent evidence has highlighted the complex interactions that mutually modulate respiratory, neurological, and gastrointestinal function. In this review, we discuss the ways SARS-CoV-2 potentially disrupts the gut-brain-lung axis. We further highlight targeting specific responses to SARS-CoV-2 for the development of novel, urgently needed therapeutic interventions. Finally, we propose a prospective related to the individuals from Low- and Middle-Income countries. Here, the underlying propensity for heightened gut damage/microbial translocation is likely to result in worse clinical outcomes during this COVID-19 pandemic.
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Affiliation(s)
- Samuel D Johnson
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, United States
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Omalla A Olwenyi
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, United States
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Namita Bhyravbhatla
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Michellie Thurman
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Kabita Pandey
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, United States
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Elizabeth A Klug
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, United States
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Morgan Johnston
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Shetty Ravi Dyavar
- Antiviral Pharmacology Laboratory, University of Nebraska Medical Center (UNMC) Center for Drug Discovery, Omaha, NE 68198, United States
| | - Arpan Acharya
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Anthony T Podany
- Antiviral Pharmacology Laboratory, University of Nebraska Medical Center (UNMC) Center for Drug Discovery, Omaha, NE 68198, United States
| | - Courtney V Fletcher
- Antiviral Pharmacology Laboratory, University of Nebraska Medical Center (UNMC) Center for Drug Discovery, Omaha, NE 68198, United States
| | - Mahesh Mohan
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, TX 78227, United States
| | - Kamal Singh
- Department of Molecular Microbiology and Immunology and Bond Life Sciences Center, University of Missouri, Columbia, MO 65212, United States
| | - Siddappa N Byrareddy
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, United States
- Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, United States
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, United States
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Olwenyi OA, Asingura B, Naluyima P, Anywar GU, Nalunga J, Nakabuye M, Semwogerere M, Bagaya B, Cham F, Tindikahwa A, Kiweewa F, Lichter EZ, Podany AT, Fletcher CV, Byrareddy SN, Kibuuka H. In-vitro Immunomodulatory activity of Azadirachta indica A.Juss. Ethanol: water mixture against HIV associated chronic CD4 + T-cell activation/ exhaustion. BMC Complement Med Ther 2021; 21:114. [PMID: 33836748 PMCID: PMC8034071 DOI: 10.1186/s12906-021-03288-0] [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] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Accepted: 03/25/2021] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND In Sub-Saharan Africa, herbal therapy continues to be utilized for HIV-1 disease management. However, the therapeutic benefits of these substances remain ambiguous. To date, little is known about the effects of these plant extracts on chronic CD4 + T-cell activation and exhaustion which is partly driven by HIV-1 associated microbial translocation. METHODS Effects of Azadirachta indica, Momordica foetida and Moringa oleifera ethanol: water mixtures on cell viability were evaluated using the Guava PCA system. Then, an in-vitro cell culture model was developed to mimic CD4+ T cell exposures to antigens following HIV-1 microbial translocation. In this, peripheral blood mononuclear cells (PBMCs) isolated from HIV negative (n = 13), viral load < 1000 copies per mL (n = 10) and viral load > 1000 copies per mL (n = 6) study participants from rural Uganda were treated with Staphylococcus enterotoxin B (SEB). Then, the candidate plant extract (A. indica) was added to test the potential to inhibit corresponding CD4+ T cell activation. Following BD Facs Canto II event acquisition, variations in %CD38, %CD69, Human Leukocyte Antigen -DR (HLA-DR), Programmed cell death protein 1 (PD-1), T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3), interferon gamma (IFN γ) and interleukin 2 (IL-2) CD4 + T cell expression were evaluated. RESULTS Following exposure to SEB, only A. indica demonstrated a concentration-dependent ability to downregulate the levels of CD4 + T cell activation. At the final concentration of 0.500 μg/mL of A. indica, a significant downregulation of CD4 + CD38 + HLA-DR+ expression was observed in HIV negative (p < 0.0001) and both HIV infected groups (P = 0.0313). This plant extract also significantly lowered SEB induced % CD4+ T cell HLADR, PD-1 and Tim-3 levels. PD-1 and CD69 markers were only significantly downmodulated in only the HIV negative ((p = 0.0001 and p = 0.0078 respectively) and viral load< 1000 copies per ml (p = 0.0078) groups. CONCLUSION A. indica exhibited the in-vitro immunomodulatory potential to inhibit the continuum of SEB induced CD4+ T-cell activation/ exhaustion without impacting general T-cell specific functions such as cytokine secretion. Additional studies are needed to confirm A. indica as a source of natural products for targeting persistent immune activation and inflammation during ART.
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Affiliation(s)
- Omalla A Olwenyi
- Makerere University, Walter Reed Project, P.O Box 16524, Kampala, Uganda.
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.
| | - Bannet Asingura
- Makerere University, Walter Reed Project, P.O Box 16524, Kampala, Uganda
- Department of Immunology and Molecular Biology, College of Health Sciences, Makerere University, Kampala, Uganda
| | - Prossy Naluyima
- Makerere University, Walter Reed Project, P.O Box 16524, Kampala, Uganda
| | - Godwin Upoki Anywar
- Department of Plant Sciences, Microbiology & Biotechnology, College of Natural Sciences, Makerere University, Kampala, Uganda
| | - Justine Nalunga
- Makerere University, Walter Reed Project, P.O Box 16524, Kampala, Uganda
| | - Mariam Nakabuye
- Makerere University, Walter Reed Project, P.O Box 16524, Kampala, Uganda
| | | | - Bernard Bagaya
- Department of Immunology and Molecular Biology, College of Health Sciences, Makerere University, Kampala, Uganda
| | - Fatim Cham
- Makerere University, Walter Reed Project, P.O Box 16524, Kampala, Uganda
| | - Allan Tindikahwa
- Makerere University, Walter Reed Project, P.O Box 16524, Kampala, Uganda
| | - Francis Kiweewa
- Makerere University, Walter Reed Project, P.O Box 16524, Kampala, Uganda
| | - Eliezer Z Lichter
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Anthony T Podany
- Antiviral Pharmacology Laboratory, University of Nebraska Medical Center (UNMC) Center for Drug Discovery, Omaha, NE, USA
| | - Courtney V Fletcher
- Antiviral Pharmacology Laboratory, University of Nebraska Medical Center (UNMC) Center for Drug Discovery, Omaha, NE, USA
| | - Siddappa N Byrareddy
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA
| | - Hannah Kibuuka
- Makerere University, Walter Reed Project, P.O Box 16524, Kampala, Uganda
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Baroncelli S, Galluzzo CM, Liotta G, Andreotti M, Mancinelli S, Mphwere R, Bokola E, Amici R, Marazzi MC, Palombi L, Palmisano L, Giuliano M. Immune Activation and Microbial Translocation Markers in HIV-Exposed Uninfected Malawian Infants in the First Year of Life. J Trop Pediatr 2019; 65:617-625. [PMID: 31006009 DOI: 10.1093/tropej/fmz022] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND HIV-exposed uninfected (HEU) infants show a high rate of morbidity. We aimed to investigate on biomarkers of immune activation/microbial translocation in HEU infants, evaluating the impact that infections/malnutrition can have on biomarker levels during the first year of life. METHODS Clinical data of 72 Malawian infants were recorded monthly and correlated with levels of soluble CD14 (sCD14), lipopolysaccharide-binding protein (LBP) and intestinal fatty acid-binding protein (I-FABP), analyzed longitudinally. RESULTS Levels of sCD14 and LBP showed a significant age-related increase. Higher levels of LBP (19.4 vs. 15.2 μg/ml) were associated with stunting, affecting 30% of the infants. The association remained statistically significant after adjusting for cytomegalovirus acquisition, malaria and respiratory infections (p = 0.031). I-FABP levels were significantly increased in infants experiencing gastrointestinal infections (1442.8 vs. 860.0 pg/ml, p = 0.018). CONCLUSION We provide evidence that stunting is associated with an enhanced inflammatory response to microbial products in HEU children, suggesting that malnutrition status should be taken into consideration to better understand the alteration of the immune profile of HEU infants living in poor socioeconomic settings.
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Affiliation(s)
- Silvia Baroncelli
- National Center for Global Health, Istituto Superiore di Sanità, Rome, Italy
| | | | - Giuseppe Liotta
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Mauro Andreotti
- National Center for Global Health, Istituto Superiore di Sanità, Rome, Italy
| | - Sandro Mancinelli
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | | | - Enok Bokola
- DREAM Program, Community of S. Egidio, Blantyre, Malawi
| | - Roberta Amici
- National Center for Global Health, Istituto Superiore di Sanità, Rome, Italy
| | | | - Leonardo Palombi
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
| | - Lucia Palmisano
- National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy
| | - Marina Giuliano
- National Center for Global Health, Istituto Superiore di Sanità, Rome, Italy
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7
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Monocyte activation, HIV, and cognitive performance in East Africa. J Neurovirol 2019; 26:52-59. [PMID: 31468471 DOI: 10.1007/s13365-019-00794-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Revised: 08/02/2019] [Accepted: 08/14/2019] [Indexed: 02/06/2023]
Abstract
Chronic inflammation associated with monocyte activation has been linked to HIV-related cognitive outcomes in resource-rich settings. Few studies have investigated this relationship in the African context where endemic non-HIV infections may modulate effects. We characterized immune activation biomarkers in Kenyan and Ugandan participants in relation to neuropsychological testing performance (NTP) from the African Cohort Study (AFRICOS). We focused on activation markers associated with monocytes (sCD14, sCD163, neopterin), T cells (HLA-DR+CD38+ on CD4+ and CD8+ T lymphocytes), and microbial translocation (intestinal fatty acid-binding protein, I-FABP). The HIV-infected (n = 290) vs. HIV-uninfected (n = 104) groups were similar in age with mean (SD) of 41 (9.5) vs. 39 (9.9) years, respectively (p = 0.072). Among HIV-infected participants, the mean (SD) current CD4+ count was 402 (232); 217 (75%) were on combination antiretroviral therapy (cART) and 199 (69%) had suppressed plasma HIV RNA. sCD14 was inversely correlated to NTP (r = - 0.14, p = 0.037) in models that included both HIV-infected and uninfected individuals, adjusted for HIV status and research site, whereas sCD163 was not (r = 0.041, p = 0.938). Neither of the T cell activation markers correlated with NTP. In the HIV-infected group, I-FABP was inversely associated with NTP (r = - 0.147, p = 0.049), even among those with suppressed plasma virus (r = - 0.0004, p = 0.025). Among the full group, HIV status did not appear to modulate the effects observed. In this cohort from East Africa, sCD14, but not sCD163, is associated with cognitive performance regardless of HIV status. Findings among both HIV-infected and HIV-uninfected groups is supportive that HIV and non-HIV-related inflammatory sources contribute to cognitive performance in this setting.
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Toll-Like Receptor-3 Mediates HIV-1-Induced Interleukin-6 Expression in the Human Brain Endothelium via TAK1 and JNK Pathways: Implications for Viral Neuropathogenesis. Mol Neurobiol 2017; 55:5976-5992. [PMID: 29128906 DOI: 10.1007/s12035-017-0816-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Accepted: 10/27/2017] [Indexed: 12/22/2022]
Abstract
HIV-1-associated neurocognitive disorders (HAND) is associated with blood-brain-barrier (BBB) inflammation, and inflammation involves toll-like receptors (TLRs) signaling. It is not known whether primary human brain microvascular endothelial cells (HBMEC), the major BBB component, express TLRs or whether TLRs are involved in BBB dysfunction and HAND. We demonstrate that HBMEC express TLR3, 4, 5, 7, 9, and 10, and TLR3 was the most abundant. HIV-1 and TLR3 activation increased endothelial TLR3 transcription and expression. HIV-1-positive human subjects showed significantly higher TLR3 expression in brain tissues and blood vessels, with higher TLR3 levels in subjects with HAND. HIV-1 and TLR3 activation increased endothelial IL6 expression by 6-to-127-fold (P < 0.001), activated c-jun(serine-63) and SAPK/JNK(Thr183/Tyr185). HIV-1 upregulated IL6 through interleukin-1 receptor-associated-kinase (IRAK)-1/4/TAK1/JNK pathways, via ATP-dependent JNK activation. TLR3 activation upregulated IL6 through TAK1/JNK pathways, via ATP-dependent or -independent JNK activation. HIV-1 and TLR3 activation also upregulated transcription factors associated with IL6 and TAK1/JNK pathways (Jun, CEBPA, STAT1). Blocking TLR3 activation prevented HIV-1- and TLR3 ligands-induced upregulation of these transcription factors, prevented IL6 transcription and expression, c-jun and JNK activation. HIV-1 and TLR3 ligands significantly increased monocytes adhesion and migration through the BBB, and decreased endothelial claudin-5 expression. Blocking TLR3 and JNK activation prevented HIV-1- and TLR3 ligands-induced claudin-5 downregulation, monocytes adhesion and transendothelial migration. These data suggest that viral immune recognition via endothelial TLR3 is involved in endothelial inflammation and BBB dysfunction in HIV/AIDS and HAND. Our data provides novel insights into the molecular basis of these HIV-1- and TLR3-mediated effects.
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Prendergast AJ, Chasekwa B, Rukobo S, Govha M, Mutasa K, Ntozini R, Humphrey JH. Intestinal Damage and Inflammatory Biomarkers in Human Immunodeficiency Virus (HIV)-Exposed and HIV-Infected Zimbabwean Infants. J Infect Dis 2017; 216:651-661. [PMID: 28934432 PMCID: PMC5853317 DOI: 10.1093/infdis/jix367] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Accepted: 07/27/2017] [Indexed: 12/14/2022] Open
Abstract
Background Disease progression is rapid in human immunodeficiency virus (HIV)–infected infants. Whether intestinal damage and inflammation underlie mortality is unknown. Methods We measured plasma intestinal fatty acid binding protein (I-FABP), soluble CD14 (sCD14), interleukin 6 (IL-6), and C-reactive protein (CRP) at 6 weeks and 6 months of age in 272 HIV-infected infants who either died (cases) or survived (controls), and in 194 HIV-exposed uninfected (HEU) and 197 HIV-unexposed infants. We estimated multivariable odds ratios for mortality and postnatal HIV transmission for each biomarker using logistic regression. Results At 6 weeks, HIV-infected infants had higher sCD14 and IL-6 but lower I-FABP than HIV-exposed and HIV-unexposed infants (P < .001). CRP was higher in HIV-exposed than HIV-unexposed infants (P = .02). At 6 months, HIV-infected infants had highest sCD14, IL-6, and CRP concentrations (P < .001) and marginally higher I-FABP than other groups (P = .07). CRP remained higher in HIV-exposed vs HIV-unexposed infants (P = .04). No biomarker was associated with mortality in HIV-infected infants, or with odds of breast-milk HIV transmission in HIV-exposed infants. Conclusions HIV-infected infants have elevated inflammatory markers by 6 weeks of age, which increase over time. In contrast to adults and older children, inflammatory biomarkers were not associated with mortality. HEU infants have higher inflammation than HIV-unexposed infants until at least 6 months, which may contribute to poor health outcomes.
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Affiliation(s)
- Andrew J Prendergast
- Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe.,Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.,Blizard Institute, Queen Mary University of London, United Kingdom
| | - Bernard Chasekwa
- Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe
| | - Sandra Rukobo
- Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe
| | - Margaret Govha
- Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe
| | - Kuda Mutasa
- Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe
| | - Robert Ntozini
- Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe
| | - Jean H Humphrey
- Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe.,Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
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Siedner MJ. Aging, Health, and Quality of Life for Older People Living With HIV in Sub-Saharan Africa: A Review and Proposed Conceptual Framework. J Aging Health 2017; 31:109-138. [PMID: 28831864 DOI: 10.1177/0898264317724549] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE The number of people living with HIV (PLWH) over 50 years old in sub-Saharan Africa is predicted to triple in the coming decades, to 6-10 million. Yet, there is a paucity of data on the determinants of health and quality of life for older PLWH in the region. METHODS A review was undertaken to describe the impact of HIV infection on aging for PLWH in sub-Saharan Africa. RESULTS We (a) summarize the pathophysiology and epidemiology of aging with HIV in resource-rich settings, and (b) describe how these relationships might differ in sub-Saharan Africa, (c) propose a conceptual framework to describe determinants of quality of life for older PLWH, and (d) suggest priority research areas needed to ensure long-term gains in quality of life for PLWH in the region. CONCLUSIONS Differences in traditional, lifestyle, and envirnomental risk factors, as well as unique features of HIV epidemiology and care delivery appear to substantially alter the contribution of HIV to aging in sub-Saharan Africa. Meanwhile, unique preferences and conceptualizations of quality of life will require novel measurement and intervention tools. An expanded research and public health infrastructure is needed to ensure that gains made in HIV prevention and treamtent are translated into long-term benefits in this region.
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Affiliation(s)
- Mark J Siedner
- 1 Harvard Medical School, Boston, MA, USA.,2 Massachusetts General Hospital, Boston, MA, USA.,3 Mbarara University of Science and Technology, Mbarara, Uganda
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Bhargavan B, Kanmogne GD. Differential Mechanisms of Inflammation and Endothelial Dysfunction by HIV-1 Subtype-B and Recombinant CRF02_AG Tat Proteins on Human Brain Microvascular Endothelial Cells: Implications for Viral Neuropathogenesis. Mol Neurobiol 2017; 55:1352-1363. [PMID: 28127697 DOI: 10.1007/s12035-017-0382-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Accepted: 01/03/2017] [Indexed: 12/22/2022]
Abstract
The recombinant HIV-1 CRF02_AG is prevalent in West-Central Africa but its effects on the blood-brain barrier (BBB) and HIV-associated neurocognitive disorders (HAND) are not known. We analyzed the effects of Tat from HIV-1 subtype-B (Tat.B) and CRF02_AG (Tat.AG) on primary human brain microvascular endothelial cells (HBMEC), the major BBB component. Exposure of HBMEC to Tat.B increased IL-6 expression and transcription by 9- (P < 0.001) and 113-fold (P < 0.001), respectively, whereas Tat.AG increased IL-6 expression and transcription by 2.7-3.8-fold and 35.7-fold (P < 0.001), respectively. Tat.B induced IL-6 through the interleukin-1 receptor-associated kinase (IRAK)-1/4/mitogen-activated protein kinase kinase(MKK)/C-jun N-terminal kinase(JNK) pathways, in an activator protein-1(AP1)- and nuclear factor-kappaB (NFκB)-independent manner, whereas Tat.AG effects occurred via MKK/JNK/AP1/NFκB pathways. Tat-induced effects were associated with activation of c-jun (serine-63) and SAPK/JNK (Thr183/Tyr185). We demonstrated increased expression of transcription factors associated with these pathways (Jun, RELB, CEBPA), with higher levels in Tat.B-treated cells compared to Tat.AG. Functional studies showed that Tat.B and Tat.AG decreased the expression of tight junction proteins claudin-5 and ZO-1 and decreased the trans-endothelial electric resistance (TEER); Tat.B induced greater reduction in TEER, claudin-5, and ZO-1, compared to Tat.AG. Overall, our data showed increased inflammation and BBB dysfunction with Tat.B, compared to Tat.AG. This suggests these two HIV-1 subtypes differentially affect the BBB and central nervous system; our data provides novel insights into the molecular basis of these differential Tat-mediated effects.
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Affiliation(s)
- Biju Bhargavan
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5800, USA
| | - Georgette D Kanmogne
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5800, USA.
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