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Pérez AR, Bottasso OA, Santucci NE. Immune-endocrine crossroads: the impact of nuclear receptors in Tuberculosis and Chagas disease. Front Endocrinol (Lausanne) 2025; 16:1538376. [PMID: 39991733 PMCID: PMC11842248 DOI: 10.3389/fendo.2025.1538376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Accepted: 01/13/2025] [Indexed: 02/25/2025] Open
Abstract
Nuclear Receptors (NRs) comprise a superfamily of proteins with essential roles in cell signaling, survival, proliferation, and metabolism. They act as transcription factors and are subclassified into families based on their ligands, DNA-binding sequences, tissue specificity, and functions. Evidence indicates that in infectious diseases, cancer, and autoimmunity, NRs modulate immune and endocrine responses, altering the transcriptional profile of cells and organs and influencing disease progression. Chronic infectious diseases, characterized by pathogen persistence, are particularly notable for an exaggerated inflammatory process. Unlike acute inflammation, which helps the host respond to pathogens, chronic inflammation leads to metabolic disorders and a dysregulated neuro-immuno-endocrine response. Over time, disturbances in cytokine, hormone, and other compound production foster an unbalanced, detrimental defensive response. This complexity underscores the significant role of ligand-dependent NRs. Tuberculosis and Chagas Disease are two critical chronic infections. The causative agents, Mycobacterium tuberculosis and Trypanosoma cruzi, have developed evasion strategies to establish chronic infections. Their clinical manifestations are associated with disrupted immuno-endocrine responses, pointing to a potential involvement of NRs. This review explores the current understanding of NRs in regulating immune-endocrine interactions within the context Tuberculosis and Chagas Disease. These diseases remain significant global health concerns, particularly in developing countries, highlighting the importance of understanding the molecular mechanisms underlying host-pathogen interactions mediated by NRs.
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Affiliation(s)
- Ana R. Pérez
- Laboratorio de Estudios en Enfermedad de Chagas, Instituto de Inmunología Clínica y Experimental de Rosario (IDICER)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Universidad Nacional de Rosario (UNR), Rosario, Argentina
- Facultad de Ciencias Médicas, Universidad Nacional de Rosario (UNR), Rosario, Argentina
| | - Oscar A. Bottasso
- Laboratorio de Estudios en Enfermedad de Chagas, Instituto de Inmunología Clínica y Experimental de Rosario (IDICER)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Universidad Nacional de Rosario (UNR), Rosario, Argentina
- Facultad de Ciencias Médicas, Universidad Nacional de Rosario (UNR), Rosario, Argentina
- Laboratorio de Estudios en Tuberculosis, Instituto de Inmunología Clínica y Experimental de Rosario (IDICER)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Universidad Nacional de Rosario (UNR), Rosario, Argentina
| | - Natalia E. Santucci
- Facultad de Ciencias Médicas, Universidad Nacional de Rosario (UNR), Rosario, Argentina
- Laboratorio de Estudios en Tuberculosis, Instituto de Inmunología Clínica y Experimental de Rosario (IDICER)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Universidad Nacional de Rosario (UNR), Rosario, Argentina
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Oliveira KKDS, Torres DJL, Barros MDS, Rafael Moreira L, Junior CDDS, Soares AKDA, de Albuquerque MDPCR, Cavalcante MDGAM, Junior WADO, Rabello MCDS, de Lorena VMB. Vitamin D treatment distinctly modulates cytokine production by peripheral blood mononuclear cells among patients with chronic cardiac and indeterminate clinical forms of Chagas disease. Immun Inflamm Dis 2024; 12:e1330. [PMID: 39267468 PMCID: PMC11393450 DOI: 10.1002/iid3.1330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 06/17/2024] [Accepted: 06/18/2024] [Indexed: 09/17/2024] Open
Abstract
INTRODUCTION Chagas disease is caused by the protozoan Trypanosoma cruzi and is clinically divided into acute and chronic phases. Chronic Chagas cardiomyopathy is the most studied manifestation of the disease. Vitamin D deficiency has been suggested as a risk factor for cardiovascular disease. No studies demonstrate the action of this hormone in the cells of patients with chronic Chagas heart disease. OBJECTIVE To evaluate the in vitro immunomodulatory effect of vitamin D on peripheral blood mononuclear cells of patients with the different chronic clinical forms of Chagas disease. Evaluating vitamin D's in vitro effect on blood cells by producing cytokines. METHODS Thirteen patients of the undetermined form (IND), 13 of the mild cardiac form (CARD1) and 14 of the severe cardiac form (CARD2) of Chagas disease, and 12 with idiopathic heart disease (CARDid) were included. The cells obtained from peripheral blood were treated in vitro with vitamin D (1 × 10-7 M) for 24 h and cytokines were dosed in the culture supernatant. RESULTS Although it was not possible to demonstrate statistically significant differences between the groups studied, our data showed that the cells treated with vitamin D modify (p < .05) the production of interferon-γ (IFN-γ) (decrease in IND), tumor necrosis factor-α (TNF-α) (decreased in CARD1 and CARDid), interleukin (IL)-6 (increased in all groups), and IL-10 (decreased in CARD1, CARD2, and CARDid) when compared to untreated cells. CONCLUSION In vitro treatment with vitamin D distinctly modulated the production of cytokines by mononuclear cells of peripheral blood among patients with chronic and indeterminate cardiac clinical forms of Chagas disease.
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Affiliation(s)
| | - Diego José Lira Torres
- Institute Aggeu Magalhães, Laboratory of ImmunoparasitologyOswaldo Cruz Foundation‐FIOCRUZRecifePernambucoBrazil
- Tropical Medicine DepartmentFederal University of Pernambuco (UFPE)RecifePernambucoBrazil
| | - Michelle da Silva Barros
- Institute Aggeu Magalhães, Laboratory of ImmunoparasitologyOswaldo Cruz Foundation‐FIOCRUZRecifePernambucoBrazil
| | - Leyllane Rafael Moreira
- Institute Aggeu Magalhães, Laboratory of ImmunoparasitologyOswaldo Cruz Foundation‐FIOCRUZRecifePernambucoBrazil
- Tropical Medicine DepartmentFederal University of Pernambuco (UFPE)RecifePernambucoBrazil
| | - Claudeir Dias da Silva Junior
- Institute Aggeu Magalhães, Laboratory of ImmunoparasitologyOswaldo Cruz Foundation‐FIOCRUZRecifePernambucoBrazil
- Tropical Medicine DepartmentFederal University of Pernambuco (UFPE)RecifePernambucoBrazil
| | | | | | | | - Wilson Alves de Oliveira Junior
- Chagas disease and Heart Failure Outpatient Clinic of the Pronto Socorro Cardiológico de PernambucoUniversity of Pernambuco (UPE)RecifePernambucoBrazil
| | | | - Virginia Maria Barros de Lorena
- Institute Aggeu Magalhães, Laboratory of ImmunoparasitologyOswaldo Cruz Foundation‐FIOCRUZRecifePernambucoBrazil
- Tropical Medicine DepartmentFederal University of Pernambuco (UFPE)RecifePernambucoBrazil
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Liao S, Huang Y, Zhang J, Xiong Q, Chi M, Yang L, Zhang J, Li L, Fan Y. Vitamin D promotes epithelial tissue repair and host defense responses against influenza H1N1 virus and Staphylococcus aureus infections. Respir Res 2023; 24:175. [PMID: 37407993 DOI: 10.1186/s12931-023-02477-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 06/13/2023] [Indexed: 07/07/2023] Open
Abstract
BACKGROUND Early studies indicated that vitamin D (VD) exerted pleiotropic extra-skeletal effects in the airway, but the definite linkage between VD deficiency and airway host responses remains unclear. METHODS 142 cases of clinical data from Department of Otolaryngology, the Seventh Affiliated Hospital of Sun Yat-sen University, were collected to characterize the relationship between VD deficiency and chronic rhinosinusitis (CRS). Based on the clinical observations, 2.5-D airway epithelial organoids cultured at the air-liquid interface (ALI) were used to simulate the effects of VD treatment in the development of airway epithelium and the modulation of the host responses against influenza H1N1 virus (representing viral infections) and Staphylococcus aureus (representing bacterial infections) infections in the airway. The intrinsic mechanisms of VD deficiency underlying epithelial remodeling were mapped by transcriptomic as well as proteomic analyses. RESULTS In this study we observed prevailing VD deficiency among inpatients suffering from CRS, a common disease predominantly characterized by epithelial impairment and remodeling. Relative to control organoids cultured without VD, long-term incubation with VD accelerated basal cell proliferation during nasal epithelial development. Under infectious conditions, VD treatment protected the organoids against influenza H1N1 virus and Staphylococcus aureus invasions by reinforcing the respiratory host defenses, including upregulation of LL37, suppression (or inhibition) of proinflammatory cytokines, strengthening of epithelial integrity, and mucociliary clearance. In silico analysis of transcriptomics and proteomics suggested that VD modulated the epithelial development and remodeling, involving epithelial cell proliferation/differentiation, epithelial-mesenchymal transition (EMT), and cytokine signaling in the immune system, as well as responses to microbe, cell junction organization, and extracellular matrix organization via PTEN signaling, independent of TGF-β signaling. CONCLUSIONS Our findings emphasize the importance of managing VD deficiency in clinical settings for the sake of alleviating pathological epithelial remodeling. Vitamin D promotes epithelial tissue repair and host defense responses against influenza H1N1 and Staphylococcus aureus infections.
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Affiliation(s)
- Shumin Liao
- Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, China
- Department of Otolaryngology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
- Department of Thoracic Surgery, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
- Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Yanhong Huang
- Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, China
- Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Jinxiu Zhang
- Department of Otolaryngology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Qinglan Xiong
- Department of Otolaryngology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Mengshi Chi
- Department of Otolaryngology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China
| | - Liang Yang
- Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, China
| | - Junhang Zhang
- Department of Thoracic Surgery, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China.
| | - Liang Li
- Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, China.
- Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
| | - Yunping Fan
- Department of Otolaryngology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China.
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Alberca GGF, Alberca RW. Role of vitamin D deficiency and comorbidities in COVID-19. World J Virol 2022; 11:85-89. [PMID: 35117974 PMCID: PMC8788214 DOI: 10.5501/wjv.v11.i1.85] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 08/01/2021] [Accepted: 11/25/2021] [Indexed: 02/06/2023] Open
Abstract
Recent manuscripts described the incidence of vitamin D hypovitaminosis in coronavirus disease 2019 (COVID-19) patients. Vitamin D deficiency is also common in patients with comorbidities that are associated with a poor COVID-19 prognosis. In this letter, we review the literature regarding the association of comorbidities, vitamin D deficiency, and COVID-19.
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Affiliation(s)
- Gabriela Gama Freire Alberca
- Department of Microbiology, Institute of Biomedical Sciences-University of São Paulo, São Paulo 04307-100, Brazil
| | - Ricardo Wesley Alberca
- Laboratorio de Dermatologia e Imunodeficiencias (LIM-56), Departamento de Dermatologia, Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo 04307-100, Brazil
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Sakamoto Y, Oono F, Iida K, Wang PL, Tachi Y. Relationship between vitamin D receptor gene polymorphisms (BsmI, TaqI, ApaI, and FokI) and calcium intake on bone mass in young Japanese women. BMC WOMENS HEALTH 2021; 21:76. [PMID: 33607983 PMCID: PMC7893901 DOI: 10.1186/s12905-021-01222-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Accepted: 02/11/2021] [Indexed: 12/20/2022]
Abstract
Background The high prevalence of low bone mass in young women in Japan has emerged as a serious health issue in recent years. Therefore, the aim of the present study was to reevaluate the relationship between genetic and dietary factors, as well as its influence on bone mass in young Japanese women, with particular emphasis on vitamin D receptor (VDR) gene polymorphisms and calcium intake. Methods A total of 499 Japanese women aged 20–24 years were enrolled in the study. The bone mass of the calcaneus was assessed using the quantitative ultrasound method and expressed as the osteo sono-assessment index (OSI). VDR gene polymorphisms (BsmI, TaqI, ApaI, and FokI) were analyzed using DNA extracted from saliva. Calcium intake was assessed using the Food Frequency Questionnaire based on food groups (FFQg) and adjusted with the energy intake. Participants were divided into two groups based on the median calcium intake (250 mg/1000 kcal). Results Consequently, bone mass was significantly different among the BsmI and TaqI genotypes after adjusting for body mass index (BMI) (p = 0.030 and 0.019, respectively). In addition, the BsmI AA and ApaI GT genotypes showed significant differences in bone mass between the calcium-intake groups, with low OSI in the low-calcium intake group and high OSI in the high-calcium intake group, respectively, even after adjusting for BMI (p = 0.020 and 0.038, respectively). Conclusions These findings may prove instrumental in developing a logical approach towards preventing bone loss in young Japanese women.
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Affiliation(s)
- Yuri Sakamoto
- Department of Clinical Dietetics and Human Nutrition, Faculty of Pharmacy and Pharmaceutical Sciences, Josai University, Saitama, Japan.
| | - Fumi Oono
- Department of Nutrition and Food Science, Graduate School of Humanities and Sciences, Ochanomizu University, Tokyo, Japan
| | - Kaoruko Iida
- Department of Nutrition and Food Science, Graduate School of Humanities and Sciences, Ochanomizu University, Tokyo, Japan.,Institute for Human Life Innovation, Ochanomizu University, Tokyo, Japan
| | - Pao-Li Wang
- Department of Innovation in Dental Education, Osaka Dental University, Osaka, Japan
| | - Yoichi Tachi
- Laboratory of Nutrition Physiology, Tokyo Kasei University, Tokyo, Japan
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de Souza-Basqueira M, Ribeiro RM, de Oliveira LC, Moreira CHV, Martins RCR, Franco DC, Amado PPP, Mayer MPA, Sabino EC. Gut Dysbiosis in Chagas Disease. A Possible Link to the Pathogenesis. Front Cell Infect Microbiol 2020; 10:402. [PMID: 32974213 PMCID: PMC7466656 DOI: 10.3389/fcimb.2020.00402] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Accepted: 06/30/2020] [Indexed: 01/20/2023] Open
Abstract
Chagas disease is caused by the flagellate protozoan Trypanosoma cruzi. Cardiomyopathy and damage to gastrointestinal tissue are the main disease manifestations. There are data suggesting that the immune response to T. cruzi depends on the intestinal microbiota. We hypothesized that Chagas disease is associated with an altered gut microbiome and that these changes are related to the disease phenotype. The stool microbiome from 104 individuals, 73 with Chagas disease (30 with the cardiac, 11 with the digestive, and 32 with the indeterminate form), and 31 healthy controls was characterized using 16S rRNA amplification and sequencing. The QIIME (Quantitative Insights Into Microbial Ecology) platform was used to analyze the data. Alpha and beta diversity indexes did not indicate differences between the groups. However, the relative abundance of Verrucomicrobia, represented primarily by the genus Akkermansia, was significantly lower in the Chagas disease groups, especially the cardiac group, compared to the controls. Furthermore, differences in the relative abundances of Alistipes, Bilophila, and Dialister were observed between the groups. We conclude that T. cruzi infection results in changes in the gut microbiome that may play a role in the myocardial and intestinal inflammation seen in Chagas disease.
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Affiliation(s)
- Marcela de Souza-Basqueira
- Departamento de Doenças Infecciosas e Parasitárias, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.,Instituto de Medicina Tropical da Universidade de São Paulo, São Paulo, Brazil
| | - Roberto Marques Ribeiro
- Departamento de Doenças Infecciosas e Parasitárias, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.,Instituto de Medicina Tropical da Universidade de São Paulo, São Paulo, Brazil
| | - Léa Campos de Oliveira
- Laboratório de Investigação Médica (LIM03), Hospital das Clinicas de São Paulo, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Carlos Henrique Valente Moreira
- Instituto de Medicina Tropical da Universidade de São Paulo, São Paulo, Brazil.,Instituto de Infectologia "Emílio Ribas", São Paulo, Brazil
| | - Roberta Cristina Ruedas Martins
- Departamento de Doenças Infecciosas e Parasitárias, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.,Instituto de Medicina Tropical da Universidade de São Paulo, São Paulo, Brazil
| | | | - Pâmela Pontes Penas Amado
- Departamento de Microbiologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil
| | - Marcia Pinto Alves Mayer
- Departamento de Microbiologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil
| | - Ester Cerdeira Sabino
- Departamento de Doenças Infecciosas e Parasitárias, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.,Instituto de Medicina Tropical da Universidade de São Paulo, São Paulo, Brazil.,Fundação Faculdade de Medicina, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
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Placental gene expression and antibody levels of mother-neonate pairs reveal an enhanced risk for inflammation in a helminth endemic country. Sci Rep 2019; 9:15776. [PMID: 31673046 PMCID: PMC6823435 DOI: 10.1038/s41598-019-52074-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Accepted: 10/11/2019] [Indexed: 02/06/2023] Open
Abstract
In utero exposure to environmental factors can modify the development of allergies later in life whereby the mechanisms of the feto-maternal crosstalk still remain largely unknown. Murine studies revealed that inflammatory maternal signals elicited by chronic helminth infection within the placenta imprint a distinct gene expression profile related to the Vitamin-D-receptor (VDR)-inflammation-axis. We thus investigated whether pro- or anti- inflammatory immune responses as well as VDR and related gene expression within the placenta differ between women from helminth-endemic and non-endemic areas. A prospective pilot study was conducted in Munich, Germany (helminth non-endemic) and Lambaréné, Gabon (helminth-endemic). At delivery, clinical information alongside placenta tissue samples and maternal and cord blood were obtained for further laboratory analysis. Schistosoma haematobium infection was detected in 13/54 (23%) Gabonese women. RT PCR revealed significantly lower gene expression of VDR, Cyp27b1, Foxp3 and IL10 in Gabonese compared to German placentae as well as significantly lower levels of plasma IgG4 in newborns resulting in a significantly higher IgE/IgG4 ratio. These findings demonstrate that exposure in utero to different environments alters placental gene expression and thus possibly plays a role in the development and modulation of the immune system of the offspring.
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