ORCID Profile
0000-0003-3441-3113
Current Organisations
University of Massachusetts Medical School
,
Michigan State University
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Publisher: American Society for Microbiology
Date: 16-02-2023
DOI: 10.1128/IAI.00510-22
Abstract: Mycobacterium tuberculosis ( Mtb ) is a bacterium that exclusively resides in human hosts and remains a dominant cause of morbidity and mortality among infectious diseases worldwide. Host protection against Mtb infection is dependent on the function of immunity-related GTPase clade M (IRGM) proteins.
Publisher: Cold Spring Harbor Laboratory
Date: 12-2020
DOI: 10.1101/2020.12.01.405514
Abstract: The outcome of an encounter with Mycobacterium tuberculosis depends on the pathogen’s ability to adapt to the variable immune pressures exerted by the host. Understanding this interplay has proven difficult, largely because experimentally tractable animal models do not recapitulate the heterogeneity of tuberculosis disease. We leveraged the genetically erse Collaborative Cross (CC) mouse panel in conjunction with a library of Mtb mutants to associate bacterial genetic requirements with host genetics and immunity. We report that CC strains vary dramatically in their susceptibility to infection and produce qualitatively distinct immune states. Global analysis of Mtb mutant fitness across the CC panel revealed that many virulence pathways are only in specific host microenvironments, identifying the large fraction of the pathogen’s genome that has been maintained to ensure fitness in a erse population. Both immunological and bacterial traits were associated with genetic variants distributed across the mouse genome, identifying the specific host-pathogen genetic interactions that influence pathogenesis.
Publisher: eLife Sciences Publications, Ltd
Date: 24-01-2022
Publisher: Oxford University Press (OUP)
Date: 2008
Publisher: Cold Spring Harbor Laboratory
Date: 27-07-2020
DOI: 10.1101/2020.07.27.223362
Abstract: Cell-intrinsic immune mechanisms control intracellular pathogens that infect eukaryotes. The intracellular pathogen Mycobacterium tuberculosis ( Mtb ) evolved to withstand cell-autonomous immunity to cause persistent infections and disease. A potent inducer of cell-autonomous immunity is the lymphocyte-derived cytokine IFNγ. While the production of IFNγ by T cells is essential to protect against Mtb , it is not capable of fully eradicating Mtb infection. This suggests that Mtb evades a subset of IFNγ-mediated antimicrobial responses, yet what mechanisms Mtb resists remains unclear. The IFNγ-inducible Guanylate binding proteins (GBPs) are key host defense proteins able to control infections with intracellular pathogens. GBPs were previously shown to directly restrict Mycobacterium bovis BCG yet their role during Mtb infection has remained unknown. Here, we examine the importance of a cluster of five GBPs on mouse chromosome 3 in controlling Mycobacterial infection. While M. bovis BCG is directly restricted by GBPs, we find that the GBPs on chromosome 3 do not contribute to the control of Mtb replication or the associated host response to infection. The differential effects of GBPs during Mtb versus M. bovis BCG infection is at least partially explained by the absence of the ESX1 secretion system from M. bovis BCG, since Mtb mutants lacking the ESX1 secretion system become similarly susceptible to GBP-mediated immune defense. Therefore, this specific genetic interaction between the murine host and Mycobacteria reveals a novel function for the ESX1 virulence system in the evasion of GBP-mediated immunity.
Publisher: The American Association of Immunologists
Date: 15-09-2018
Abstract: Protection from infectious disease relies on two distinct strategies: antimicrobial resistance directly inhibits pathogen growth, whereas infection tolerance protects from the negative impact of infection on host health. A single immune mediator can differentially contribute to these strategies in distinct contexts, confounding our understanding of protection to different pathogens. For ex le, the NADPH-dependent phagocyte oxidase (Phox) complex produces antimicrobial superoxide and protects from tuberculosis (TB) in humans. However, Phox-deficient mice display no sustained resistance defects to Mycobacterium tuberculosis, suggesting a more complicated role for NADPH Phox complex than strictly controlling bacterial growth. We examined the mechanisms by which Phox contributes to protection from TB and found that mice lacking the Cybb subunit of Phox suffered from a specific defect in tolerance, which was caused by unregulated Caspase-1 activation, IL-1β production, and neutrophil influx into the lung. These studies imply that a defect in tolerance alone is sufficient to compromise immunity to M. tuberculosis and highlight a central role for Phox and Caspase-1 in regulating TB disease progression.
Publisher: Cold Spring Harbor Laboratory
Date: 18-08-2016
DOI: 10.1101/064253
Abstract: The outcome of Mycobacterium tuberculosis (Mtb) infection and the immunological response to the Bacille Calmette Guerin (BCG) vaccine are highly variable in humans. Deciphering the relative importance of host genetics, environment, and vaccine preparation on BCG efficacy has proven difficult in natural populations. We developed a model system that captures the breadth of immunological responses observed in outbred in iduals, which can be used to understand the contribution of host genetics to vaccine efficacy. This system employs a panel of highly- erse inbred mouse strains, consisting of the founders and recombinant progeny of the “Collaborative Cross”. Unlike natural populations, the structure of this panel allows the serial evaluation of genetically-identical in iduals and quantification of genotype-specific effects of interventions such as vaccination. When analyzed in the aggregate, our panel resembled natural populations in several important respects the animals displayed a broad range of Mtb susceptibility, varied in their immunological response to infection, and were not durably protected by BCG vaccination. However, when analyzed at the genotype level, we found that these phenotypic differences were heritable. Mtb susceptibility varied between lines, from extreme sensitivity to progressive Mtb clearance. Similarly, only a minority of the genotypes was protected by vaccination. BCG efficacy was genetically separable from susceptibility, and the lack of efficacy in the aggregate analysis was driven by nonresponsive lines that mounted a qualitatively distinct response to infection. These observations support an important role for host genetic ersity in determining BCG efficacy, and provide a new resource to rationally develop more broadly efficacious vaccines. Importance: Tuberculosis (TB) remains an urgent global health crisis, and the efficacy of the currently used TB vaccine, M. bovis BCG, is highly variable. The design of more broadly-efficacious vaccines depends on understanding the factors that limit the protection imparted by BCG. While these complex factors are difficult to disentangle in natural populations, we used a model population of mice to understand the role of host genetic composition to BCG efficacy. We found that the ability of BCG to protect an in idual genotype was remarkably variable. BCG efficacy did not depend on the intrinsic susceptibility of the animal, but instead correlated with qualitative differences in the immune response to the pathogen. These studies suggest that host genetic polymorphism is a critical determinant of vaccine efficacy and provides a model system to develop interventions that will be useful in genetically erse populations.
Publisher: eLife Sciences Publications, Ltd
Date: 03-02-2022
DOI: 10.7554/ELIFE.74419
Abstract: The outcome of an encounter with Mycobacterium tuberculosis ( Mtb ) depends on the pathogen’s ability to adapt to the variable immune pressures exerted by the host. Understanding this interplay has proven difficult, largely because experimentally tractable animal models do not recapitulate the heterogeneity of tuberculosis disease. We leveraged the genetically erse Collaborative Cross (CC) mouse panel in conjunction with a library of Mtb mutants to create a resource for associating bacterial genetic requirements with host genetics and immunity. We report that CC strains vary dramatically in their susceptibility to infection and produce qualitatively distinct immune states. Global analysis of Mtb transposon mutant fitness (TnSeq) across the CC panel revealed that many virulence pathways are only required in specific host microenvironments, identifying a large fraction of the pathogen’s genome that has been maintained to ensure fitness in a erse population. Both immunological and bacterial traits can be associated with genetic variants distributed across the mouse genome, making the CC a unique population for identifying specific host-pathogen genetic interactions that influence pathogenesis.
Publisher: Cold Spring Harbor Laboratory
Date: 09-11-2022
DOI: 10.1101/2022.11.09.515519
Abstract: Mycobacterium tuberculosis ( Mtb ) is a bacterium that exclusively resides in human hosts and remains a dominant cause of morbidity and mortality among infectious diseases worldwide. Host protection against Mtb infection is dependent on the function of immunity-related GTPase clade M (IRGM) proteins. Polymorphisms in human IRGM associate with altered susceptibility to mycobacterial disease, and human IRGM promotes the delivery of Mtb into degradative autolysosomes. Among the three murine IRGM orthologs, Irgm1 has been singled out as essential for host protection during Mtb infections in cultured macrophages and in vivo . However, whether the paralogous murine Irgm genes, Irgm2 and Irgm3 , play roles in host defense against Mtb or exhibit functional relationships with Irgm1 during Mtb infection remains undetermined. Here, we report that Irgm1 -/- mice are indeed acutely susceptible to aerosol infection with Mtb , yet the additional deletion of the paralogous Irgm3 gene restores protective immunity to Mtb infections in Irgm1 -deficient animals. Mice lacking all three Irgm genes (pan Irgm -/- ) are characterized by shifted lung cytokine profiles at 4 and 24 weeks post infection, but control disease until the very late stages of the infection, when pan Irgm -/- mice display increased mortality compared to wild type mice. Collectively, our data demonstrate that disruptions in the balance between Irgm isoforms is more detrimental to the Mtb -infected host than total loss of Irgm -mediated host defense, a concept that also needs to be considered in the context of human Mtb susceptibility linked to IRGM polymorphisms.
Publisher: MDPI AG
Date: 02-02-2023
DOI: 10.3390/IJMS24032861
Abstract: Cell-intrinsic immune mechanisms control intracellular pathogens that infect eukaryotes. The intracellular pathogen Mycobacterium tuberculosis (Mtb) evolved to withstand cell-autonomous immunity to cause persistent infections and disease. A potent inducer of cell-autonomous immunity is the lymphocyte-derived cytokine IFNγ. While the production of IFNγ by T cells is essential to protect against Mtb, it is not capable of fully eradicating Mtb infection. This suggests that Mtb evades a subset of IFNγ-mediated antimicrobial responses, yet what mechanisms Mtb resists remains unclear. The IFNγ-inducible Guanylate binding proteins (GBPs) are key host defense proteins able to control infections with intracellular pathogens. GBPs were previously shown to directly restrict Mycobacterium bovis BCG yet their role during Mtb infection has remained unknown. Here, we examine the importance of a cluster of five GBPs on mouse chromosome 3 in controlling Mycobacterial infection. While M. bovis BCG is directly restricted by GBPs, we find that the GBPs on chromosome 3 do not contribute to the control of Mtb replication or the associated host response to infection. The differential effects of GBPs during Mtb versus M. bovis BCG infection is at least partially explained by the absence of the ESX1 secretion system from M. bovis BCG, since Mtb mutants lacking the ESX1 secretion system become similarly susceptible to GBP-mediated immune defense. Therefore, this specific genetic interaction between the murine host and Mycobacteria reveals a novel function for the ESX1 virulence system in the evasion of GBP-mediated immunity.
Publisher: Cold Spring Harbor Laboratory
Date: 21-08-2020
DOI: 10.1101/2020.08.21.260737
Abstract: In order to sustain a persistent infection, Mycobacterium tuberculosis ( Mtb ) must adapt to a changing environment that is shaped by the developing immune response. This necessity to adapt is evident in the flexibility of many aspects of Mtb metabolism, including a respiratory chain that consists of two distinct terminal cytochrome oxidase complexes. Under the conditions tested thus far, the bc 1 /aa 3 complex appears to play a dominant role, while the alternative bd oxidase is largely redundant. However, presence of two terminal oxidases in this obligate pathogen implies that respiratory requirements might change during infection. We report that the cytochrome bd oxidase is specifically required for resisting the adaptive immune response. While the bd oxidase was dispensable for growth in resting macrophages and the establishment of infection in mice, this complex was necessary for optimal fitness after the initiation of adaptive immunity. This requirement was dependent on lymphocyte-derived interferon gamma (IFNγ), but did not involve nitrogen and oxygen radicals that are known to inhibit respiration in other contexts. Instead, we found that ΔcydA mutants were hypersusceptible to the low pH encountered in IFNγ-activated macrophages. Unlike wild type Mtb , cytochrome bd -deficient bacteria were unable to sustain a maximal oxygen consumption rate (OCR) at low pH, indicating that the remaining cytochrome bc 1 /aa 3 complex is preferentially inhibited under acidic conditions. Consistent with this model, the potency of the cytochrome bc 1 /aa 3 inhibitor, Q203, is dramatically enhanced at low pH. This work identifies a critical interaction between host immunity and pathogen respiration that influences both the progression of the infection and the efficacy of potential new TB drugs. Tuberculosis, caused by Mycobacterium tuberculosis ( Mtb ) is a serious global health problem that is responsible for over one million deaths annually, more than any other single infectious agent. In the host, Mtb can adapt to a wide variety of immunological and environmental pressures which is integral to its success as a pathogen. Accordingly, the respiratory capacity of Mtb is flexible. The electron transport chain of Mtb has two terminal oxidases, the cytochrome bc 1 /aa 3 super complex and cytochrome bd , that contribute to the proton motive force and subsequent production of energy in the form of ATP. The bc 1 /aa 3 super complex is required for optimal growth during infection but the role of cytochrome bd is unclear. Here we report that the cytochrome bd oxidase is required for resisting the adaptive immune response, in particular, acidification of the phagosome induced by lymphocyte-derived IFNγ. We found that the cytochrome bd oxidase is specifically required under acidic conditions, where the bc 1 /aa 3 complex is preferentially inhibited. Additionally, we show that acidic conditions increased the potency of Q203, a cytochrome bc 1 /aa 3 inhibitor and candidate tuberculosis therapy. This work defines a new link between the host immune response and the respiratory requirements of Mtb that affects the potency of a potential new therapeutic.
Publisher: Public Library of Science (PLoS)
Date: 28-07-2021
DOI: 10.1371/JOURNAL.PPAT.1008911
Abstract: In order to sustain a persistent infection, Mycobacterium tuberculosis ( Mtb ) must adapt to a changing environment that is shaped by the developing immune response. This necessity to adapt is evident in the flexibility of many aspects of Mtb metabolism, including a respiratory chain that consists of two distinct terminal cytochrome oxidase complexes. Under the conditions tested thus far, the bc 1 /aa 3 complex appears to play a dominant role, while the alternative bd oxidase is largely redundant. However, the presence of two terminal oxidases in this obligate pathogen implies that respiratory requirements might change during infection. We report that the cytochrome bd oxidase is specifically required for resisting the adaptive immune response. While the bd oxidase was dispensable for growth in resting macrophages and the establishment of infection in mice, this complex was necessary for optimal fitness after the initiation of adaptive immunity. This requirement was dependent on lymphocyte-derived interferon gamma (IFNγ), but did not involve nitrogen and oxygen radicals that are known to inhibit respiration in other contexts. Instead, we found that ΔcydA mutants were hypersusceptible to the low pH encountered in IFNγ-activated macrophages. Unlike wild type Mtb , cytochrome bd -deficient bacteria were unable to sustain a maximal oxygen consumption rate (OCR) at low pH, indicating that the remaining cytochrome bc 1 /aa 3 complex is preferentially inhibited under acidic conditions. Consistent with this model, the potency of the cytochrome bc 1 /aa 3 inhibitor, Q203, is dramatically enhanced at low pH. This work identifies a critical interaction between host immunity and pathogen respiration that influences both the progression of the infection and the efficacy of potential new TB drugs.
Publisher: American Society for Microbiology
Date: 02-11-2016
Abstract: The outcome of Mycobacterium tuberculosis infection and the immunological response to the bacillus Calmette-Guerin (BCG) vaccine are highly variable in humans. Deciphering the relative importance of host genetics, environment, and vaccine preparation for the efficacy of BCG has proven difficult in natural populations. We developed a model system that captures the breadth of immunological responses observed in outbred in idual mice, which can be used to understand the contribution of host genetics to vaccine efficacy. This system employs a panel of highly erse inbred mouse strains, consisting of the founders and recombinant progeny of the “Collaborative Cross” project. Unlike natural populations, the structure of this panel allows the serial evaluation of genetically identical in iduals and the quantification of genotype-specific effects of interventions such as vaccination. When analyzed in the aggregate, our panel resembled natural populations in several important respects: the animals displayed a broad range of susceptibility to M. tuberculosis , differed in their immunological responses to infection, and were not durably protected by BCG vaccination. However, when analyzed at the genotype level, we found that these phenotypic differences were heritable. M. tuberculosis susceptibility varied between lines, from extreme sensitivity to progressive M. tuberculosis clearance. Similarly, only a minority of the genotypes was protected by vaccination. The efficacy of BCG was genetically separable from susceptibility to M. tuberculosis , and the lack of efficacy in the aggregate analysis was driven by nonresponsive lines that mounted a qualitatively distinct response to infection. These observations support an important role for host genetic ersity in determining BCG efficacy and provide a new resource to rationally develop more broadly efficacious vaccines. IMPORTANCE Tuberculosis (TB) remains an urgent global health crisis, and the efficacy of the currently used TB vaccine, M. bovis BCG, is highly variable. The design of more broadly efficacious vaccines depends on understanding the factors that limit the protection imparted by BCG. While these complex factors are difficult to disentangle in natural populations, we used a model population of mice to understand the role of host genetic composition in BCG efficacy. We found that the ability of BCG to protect mice with different genotypes was remarkably variable. The efficacy of BCG did not depend on the intrinsic susceptibility of the animal but, instead, correlated with qualitative differences in the immune responses to the pathogen. These studies suggest that host genetic polymorphism is a critical determinant of vaccine efficacy and provide a model system to develop interventions that will be useful in genetically erse populations.
Publisher: Springer Science and Business Media LLC
Date: 15-05-2017
Location: United States of America
No related grants have been discovered for Andrew Olive.