The synergy between Mycobacterium tuberculosis (Mtb) and HIV in coinfected patients has profoundly impacted global mortality because of tuberculosis (TB) and AIDS. HIV significantly increases rates of reactivation of latent TB infection... more
The synergy between Mycobacterium tuberculosis (Mtb) and HIV in coinfected patients has profoundly impacted global mortality because of tuberculosis (TB) and AIDS. HIV significantly increases rates of reactivation of latent TB infection (LTBI) to active disease, with the decline in CD4(+) T cells believed to be the major causality. In this study, nonhuman primates were coinfected with Mtb and simian immunodeficiency virus (SIV), recapitulating human coinfection. A majority of animals exhibited rapid reactivation of Mtb replication, progressing to disseminated TB and increased SIV-associated pathology. Although a severe loss of pulmonary CD4(+) T cells was observed in all coinfected macaques, a subpopulation of the animals was still able to prevent reactivation and maintain LTBI. Investigation of pulmonary immune responses and pathology in this cohort demonstrated that increased CD8(+) memory T-cell proliferation, higher granzyme B production, and expanded B-cell follicles correlated...
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Mycobacterium tuberculosis infects one third of the world's population. Due to variable efficacy of the Bacille Calmette Guerin (BCG) vaccine, development of novel TB vaccines remains a priority. Here, we demonstrate the protective... more
Mycobacterium tuberculosis infects one third of the world's population. Due to variable efficacy of the Bacille Calmette Guerin (BCG) vaccine, development of novel TB vaccines remains a priority. Here, we demonstrate the protective efficacy of a novel multivalent DNA vaccine, which contains 15 synthetic antigens targeting the Mtb ESX secretion system.
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Research Interests: Physiology, Immunology, Primary Health Care, Biology, Health, and 15 moreTuberculosis, Humans, Mycobacterium tuberculosis, Chronic Disease, Vaccination, Cytokine, Developed Countries, Immune system, Cellular Immunity, Clients, Bacterial growth, Chronic Inflammation, Interleukin, BCG vaccine, and Inflammatory response
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Tuberculosis (TB) is a global pandaemic, partially due to the failure of vaccination approaches. Novel anti-TB vaccines are therefore urgently required. Here we show that aerosol immunization of macaques with the Mtb mutant in SigH... more
Tuberculosis (TB) is a global pandaemic, partially due to the failure of vaccination approaches. Novel anti-TB vaccines are therefore urgently required. Here we show that aerosol immunization of macaques with the Mtb mutant in SigH (MtbΔsigH) results in significant recruitment of inducible bronchus-associated lymphoid tissue (iBALT) as well as CD4(+) and CD8(+) T cells expressing activation and proliferation markers to the lungs. Further, the findings indicate that pulmonary vaccination with MtbΔsigH elicited strong central memory CD4(+) and CD8(+) T-cell responses in the lung. Vaccination with MtbΔsigH results in significant protection against a lethal TB challenge, as evidenced by an approximately three log reduction in bacterial burdens, significantly diminished clinical manifestations and granulomatous pathology and characterized by the presence of profound iBALT. This highly protective response is virtually absent in unvaccinated and BCG-vaccinated animals after challenge. These results suggest that future TB vaccine candidates can be developed on the basis of MtbΔsigH.
Research Interests: Immune response, Flow Cytometry, Tuberculosis and Infectious Disease, Multidisciplinary, Aerosols, and 18 moreTuberculosis, Mycobacterium tuberculosis, Animals, Memory Responses, Vaccination, Lung, T lymphocytes, Sigma Factors, Rhesus Monkey, Rhesus macaques, Macaca Mulatta, Transcriptomics and Microarray Data Analysis, Nature Communications, Lymphoid Tissue, Innate and Adaptive Immunity, Bronchoalveolar lavage, BCG vaccine, and Tuberculosis vaccines
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Tuberculosis (TB) vaccine development has focused largely on targeting T helper type 1 (Th1) cells. However, despite inducing Th1 cells, the recombinant TB vaccine MVA85A failed to enhance protection against TB disease in humans. In... more
Tuberculosis (TB) vaccine development has focused largely on targeting T helper type 1 (Th1) cells. However, despite inducing Th1 cells, the recombinant TB vaccine MVA85A failed to enhance protection against TB disease in humans. In recent years, Th17 cells have emerged as key players in vaccine-induced protection against TB. However, the exact cytokine and immune requirements that enable Th17-induced recall protection remain unclear. In this study, we have investigated the requirements for Th17 cell-induced recall protection against Mycobacterium tuberculosis (Mtb) challenge by utilizing a tractable adoptive transfer model in mice. We demonstrate that adoptive transfer of Mtb-specific Th17 cells into naive hosts, and upon Mtb challenge, results in Th17 recall responses that confer protection at levels similar to vaccination strategies. Importantly, although interleukin (IL)-23 is critical, IL-12 and IL-21 are dispensable for protective Th17 recall responses. Unexpectedly, we demons...
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The identification of a new T cell subset referred to as T helper 17 (Th17) cells and its role in protective immunity against extracellular bacterial infections is well established. In contrast, initial studies suggested that the... more
The identification of a new T cell subset referred to as T helper 17 (Th17) cells and its role in protective immunity against extracellular bacterial infections is well established. In contrast, initial studies suggested that the IL-23-IL-17 pathway was not required for protection against intracellular pathogens such as mycobacterial infections. However, recent studies demonstrate that Th17-IL-23 pathway may play a crucial role in protective immunity against other intracellular pathogens by regulating the innate and adaptive immune responses. The current outlook on the role of IL-23-IL-17 pathway in protective immunity to intracellular pathogens is discussed here.
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Rationale: Hypoxia promotes dormancy by causing physiological changes to actively replicating Mycobacterium tuberculosis (Mtb). DosR controls the response of Mtb to hypoxia. Objectives: To understand its contribution in the persistence of... more
Rationale: Hypoxia promotes dormancy by causing physiological changes to actively replicating Mycobacterium tuberculosis (Mtb). DosR controls the response of Mtb to hypoxia. Objectives: To understand its contribution in the persistence of Mtb, we compared the phenotype of various DosR regulon mutants and a complemented strain, to Mtb in macaques, which faithfully model Mtb infection. Methods: We measured clinical and microbiological correlates of infection with Mtb, relative to mutant/complemented strains in the DosR regulon, studied lung pathology and hypoxia and compared immune responses in lung, using transcriptomics and flow-cytometry. Measurements and Main Results: Despite being able to replicate initially, mutants in DosR regulon failed to persist or cause disease. On the contrary, Mtb and a complemented strain were able to establish infection and TB. The attenuation of pathogenesis in animals infected with the mutants coincided with the appearance of a Th1 response and organi...
Research Interests: Immune response, DNA MICROARRAYS, Hypoxia, Tuberculosis and Infectious Disease, Tuberculosis, and 13 moreAnoxia, Mycobacterium tuberculosis, Protein Kinases, Histopathology, Animals, T lymphocytes, Macaca Mulatta, Granuloma, Murine macrophages, Dormancy, Gene Expression by qRT PCR, CFU assay, and Hypoxia Detection in Lung Granuloma
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Research Interests: Immunology, Gene regulation, Flow Cytometry, Biology, Cytokines, and 19 moreImmunohistochemistry, Innate immunity, Apoptosis, Medicine, Nature, Tuberculosis, Mycobacterium tuberculosis, Mice, Female, Animals, Male, Antigen Presentation, Immune system, Bacterial growth, Signaling, Enzyme Linked Immunosorbent Assay, Immunologist, Interleukin, and Tuberculosis vaccines
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Migration of dendritic cells (DCs) to the draining lymph node (DLN) is required for the activation of naive T cells. We show here that migration of DCs from the lung to the DLN after Mycobacterium tuberculosis (Mtb) exposure is defective... more
Migration of dendritic cells (DCs) to the draining lymph node (DLN) is required for the activation of naive T cells. We show here that migration of DCs from the lung to the DLN after Mycobacterium tuberculosis (Mtb) exposure is defective in mice lacking interleukin (IL)-12p40. This defect compromises the ability of IL-12p40-deficient DCs to activate naive T cells in vivo; however, DCs that express IL-12p40 alone can activate naive T cells. Treatment of IL-12p40-deficient DCs with IL-12p40 homodimer (IL-12(p40)(2)) restores Mtb-induced DC migration and the ability of IL-12p40-deficient DCs to activate naive T cells. These data define a novel and fundamental role for IL-12p40 in the pathogen-induced activation of pulmonary DCs.
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Mycobacterium tuberculosis (Mtb) is the intracellular pathogen that causes the disease, tuberculosis. Chemokines and chemokine receptors are key regulators in immune cell recruitment to sites of infection and inflammation. This review... more
Mycobacterium tuberculosis (Mtb) is the intracellular pathogen that causes the disease, tuberculosis. Chemokines and chemokine receptors are key regulators in immune cell recruitment to sites of infection and inflammation. This review highlights our recent advances in understanding the role of chemokines and chemokine receptors in cellular recruitment of immune cells to the lung, role in granuloma formation and host defense against Mtb infection.