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Project description:Infections with mycobacteria, including Mycobacterium tuberculosis (Mtb) and Mycobacterium bovis (M. bovis) BCG, are a leading cause of morbidity and mortality for HIV-infected persons. In contrast to HIV, SIV infection of sooty mangabeys is nonpathogenic, characterized by a lack of clinical disease including an absence of opportunistic infections. The goal of this study was to identify innate immune responses to M. bovis BCG maintained during nonpathogenic lentiviral infections, through a comparison of functional responses during pathogenic HIV or nonpathogenic SIV infections. Monocytes were evaluated for their ability to express key anti-mycobacterial cytokines TNF-α and IL-12 following a six-hour ex vivo BCG exposure. While HIV-infection was associated with a decreased percentage of IL-12-producing monocytes, nonpathogenic SIV-infection was associated with an increased percentage of monocytes producing both cytokines. Gene expression analysis of PBMC following ex vivo BCG exposure identified differential expression of NK cell-related genes and several cytokines, including IFN-γ and IL-23, between HIV-infected and control subjects. In contrast, SIV-infected and uninfected-control mangabeys exhibited no significant differences in gene expression after BCG exposure. Finally, differential gene expression patterns were identified between species, with mangabeys exhibiting lower IL-6 and higher IL-17 in response to BCG when compared to humans. Overall, this comparison of immune responses to M. bovis BCG identified unique immune signatures (involving cytokines IL-12, TNF-α, IL-23, IL-17, and IL-6) that are altered during HIV, but maintained or increased during nonpathogenic SIV infections. These unique cytokine and transcriptome signatures provide insight into the differential immune responses to Mycobacteria during pathogenic HIV-infection of humans or nonpathogenic SIV-infection of mangabeys.
2016-05-27 | GSE81926 | GEO
Project description:Mycobacterium tuberculosis (Mtb) is the leading cause of death from infection worldwide. Intradermal (ID) vaccination with BCG has variable efficacy against pulmonary tuberculosis, the major cause of mortality and disease transmission. Here we show that the route and dose of BCG vaccination alters circulating and lung resident T cells and subsequent protection against Mtb challenge in nonhuman primates (NHP). NHP immunized with BCG by the intravenous (IV) route induced substantially higher antigen-specific CD4 (Th1 or Th17) and CD8 responses in blood, spleen, bronchoalveolar lavage (BAL), and lung lymph nodes compared to the same BCG dose administered by ID or aerosol (AE) routes. Moreover, IV immunization was the only route that induced a high frequency of antigen-specific tissue resident T cells in lung parenchyma. Six months after BCG vaccination, NHP were challenged with virulent Mtb. Strikingly, 9 of 10 NHP that received BCG IV were highly protected, with 6 NHP showing no detectable infection as determined by PET CT imaging, mycobacterial growth, pathology, granuloma formation, or de novo immune responses to Mtb-specific antigens. The finding that BCG IV prevents or significantly limits Mtb infection in NHP has important implications for vaccine development and provides a model for determining immune correlates and mechanisms of protection against TB.
2020-01-01 | GSE139598 | GEO
Project description:To determine the blood transcriptional response to intravenous (IV) BCG vaccination in rhesus macaques and identify correlates of vaccine-mediated protection against Mycobacterium tuberculosis (Mtb) challenge.
2023-06-19 | GSE218270 | GEO
Project description:Lassa fever (LF) is a rodent-borne viral disease that can be fatal for human beings. In this study, an attenuated Lassa vaccine candidate, ML29, was tested in SIV-infected rhesus macaques for its ability to elicit immune responses without instigating signs of virulent disease. ML29 is a reassortant between Lassa and Mopeia viruses that causes a transient infection in non-human primates and confers sterilizing protection from lethal Lassa viral challenge. However, since the LF endemic area of West Africa also has high HIV seroprevalence, it is important to determine whether vaccination could be safe in the context of AIDS. SIV-infected and uninfected rhesus macaques were vaccinated with the ML29 virus and monitored for classical and non-classical signs of arenavirus disease. Classical disease signs included viremia, rash, weight loss, high liver enzyme levels, and virus invasion of the central nervous system. Non-classical signs derived from profiling the blood transcriptome of virulent and non-virulent arenavirus infections included increased expression of interferon response genes and decreased expression of COX2, IL-1?, coagulation intermediates and nuclear receptors needed for stress signaling. Here it is demonstrated that SIV-infected and uninfected rhesus macaques responded similarly to ML29 vaccination, and that none developed signs of arenavirus disease or persistence. Furthermore, 5 of 5 animals given a heterologous challenge with a lethal dose of LCMV-WE survived without developing disease signs. 30 RNA samples from Monkey PBMC: 4 uninf. Monkey PBMC, 8 SIV-infected Monkey PBMC(From 8 Monkeys), 5 SIV+ML29-sc infected week1(Monkey PBMC), 5 SIV+ML29-sc infected week2(Monkey PBMC), 1 SIV+ML29-ig infected week1(Monkey PBMC), 1 SIV+ML29-ig infected week2(Monkey PBMC), 2 SIV+Arm-sc infected week1(Monkey PBMC), 2 SIV+Arm-sc infected week2(Monkey PBMC), 1 only ML29-iv infected week1(Monkey PBMC), 1 only ML29-iv infected week2(Monkey PBMC)
2013-11-04 | E-GEOD-33687 | biostudies-arrayexpress
Project description:After a century of the Bacillus Calmette-Guérin (BCG) vaccine, our understanding of its protection against homologous (Mycobacterium tuberculosis) or heterologous (e.g. influenza virus) infections is still limited. Here we show that systemic (intravenous) BCG vaccination (BCG-iv) provides significant protection against subsequent influenza A virus (IAV) infection in mice. We further demonstrate that the BCG-mediated cross-protection against IAV is largely due to the enrichment of conventional CD4+ αβ effector memory T cells that express high levels of CX3CR1hi in circulation trafficking into the lung parenchyma. Importantly, pulmonary CX3CR1hi T cells limit early viral infection in an antigen-independent manner via potent IFNγ production, which subsequently enhances long-term antimicrobial activity of the innate immune system like alveolar macrophages. Similarly, we uncover a prominent IFNγ signature in which its increased basal production was associated with enhanced BCG-mediated heterologous innate memory responses in BCG-vaccinated humans. These results offer insight into the unknown mechanism by which BCG has persistently displayed broad protection against non-tuberculous infections via a crosstalk between adaptive and innate memory responses.
2023-11-01 | GSE246201 | GEO
Project description:Interferons (IFNs) are critical for anti-viral host defence. Type-1 and type-3 IFNs are typically associated with early control of viral replication and promotion of inflammatory immune responses; however, less is known about the role of IFNγ in anti-viral immunity, particularly in the context of SARS-CoV-2. We have previously observed that lung infection with attenuated bacteria M. bovis BCG achieved though intravenous (iv) administration provides strong protection against SARS-CoV-2 (SCV2) infection and disease in two mouse models. Assessment of the pulmonary cytokine milieu revealed that iv BCG induces a robust IFNγ response and low levels of IFNβ. Here we examined the role of ongoing IFNγ responses due to concurrent bacterial infection on SCV2 disease outcomes in two murine models. We report that IFNγ is required for iv BCG induced reduction in pulmonary viral loads and that this outcome is dependent on IFNγ receptor expression by non-hematopoietic cells. Further analysis revealed that BCG infection promotes the upregulation of ISGs with reported anti-viral activity by pneumocytes and bronchial epithelial cells in an IFNγ dependent manner, suggesting a possible mechanism for the observed protection. Finally, we confirmed the importance of IFNγ in these anti-viral effects by demonstrating that the recombinant cytokine itself provides strong protection against SCV2 challenge when administered intranasally. Together, our data show that a pre-established IFNγ response within the lung is protective against SCV2 infection, suggesting that concurrent or recent infections that drive IFNγ may limit the pathogenesis of this virus and supporting possible prophylactic uses of this cytokine in COVID-19 management.
2023-11-01 | GSE236601 | GEO
Project description:Live-attenuated SIV vaccines (LAVs) remain the most efficacious of all vaccines in nonhuman primate models of HIV/AIDS, yet the basis of their robust protection remains poorly understood. Here, we demonstrate that the degree of LAV-mediated protection against intravenous (IV) wildtype (wt) SIVmac239 challenge strongly correlates with the magnitude and function of SIV-specific, effector-differentiated T cells in lymph node (LN), but not with such T cell responses in blood or with other cellular, humoral and innate immune parameters. Maintenance of protective T cell responses was associated with persistent LAV replication in LN, which occurred almost exclusively in follicular helper T cells. Thus, effective LAVs maintain lymphoid tissue-based, effector-differentiated, SIV-specific T cells that intercept and suppress early wt SIV amplification and, if present in sufficient frequencies, can completely control and perhaps clear infection -- an observation that provides rationale for development of safe, persistent vectors that can elicit and maintain such responses.
2012-08-09 | GSE39967 | GEO
Project description:Live-attenuated SIV vaccines (LAVs) remain the most efficacious of all vaccines in nonhuman primate models of HIV/AIDS, yet the basis of their robust protection remains poorly understood. Here, we demonstrate that the degree of LAV-mediated protection against intravenous (IV) wildtype (wt) SIVmac239 challenge strongly correlates with the magnitude and function of SIV-specific, effector-differentiated T cells in lymph node (LN), but not with such T cell responses in blood or with other cellular, humoral and innate immune parameters. Maintenance of protective T cell responses was associated with persistent LAV replication in LN, which occurred almost exclusively in follicular helper T cells. Thus, effective LAVs maintain lymphoid tissue-based, effector-differentiated, SIV-specific T cells that intercept and suppress early wt SIV amplification and, if present in sufficient frequencies, can completely control and perhaps clear infection -- an observation that provides rationale for development of safe, persistent vectors that can elicit and maintain such responses.
2012-08-09 | GSE39968 | GEO
Project description:Live-attenuated SIV vaccines (LAVs) remain the most efficacious of all vaccines in nonhuman primate models of HIV/AIDS, yet the basis of their robust protection remains poorly understood. Here, we demonstrate that the degree of LAV-mediated protection against intravenous (IV) wildtype (wt) SIVmac239 challenge strongly correlates with the magnitude and function of SIV-specific, effector-differentiated T cells in lymph node (LN), but not with such T cell responses in blood or with other cellular, humoral and innate immune parameters. Maintenance of protective T cell responses was associated with persistent LAV replication in LN, which occurred almost exclusively in follicular helper T cells. Thus, effective LAVs maintain lymphoid tissue-based, effector-differentiated, SIV-specific T cells that intercept and suppress early wt SIV amplification and, if present in sufficient frequencies, can completely control and perhaps clear infection -- an observation that provides rationale for development of safe, persistent vectors that can elicit and maintain such responses. There are two protection outcome groups, complete protect (CP) and non-protect (NP) animals. Memory T cells (CD4+ or CD8+) were sorted for three time points, seven days pre-challenge, four days post-challenge and fourteen days post-challenge.
2012-08-08 | E-GEOD-39968 | biostudies-arrayexpress