ORCID Profile
0000-0003-0232-9953
Current Organisations
Politecnico di Milano
,
Moderna Therapeutics Inc
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Publisher: American Society for Microbiology
Date: 25-08-2020
DOI: 10.1128/MSYSTEMS.00396-20
Abstract: Understanding how Mycobacterium tuberculosis survives during antibiotic treatment is necessary to rationally devise more effective tuberculosis (TB) chemotherapy regimens. Using genome-wide mutant fitness profiling and the mouse model of TB, we identified genes that alter antibiotic efficacy specifically in the infection environment and associated several of these genes with natural genetic variants found in drug-resistant clinical isolates. These data suggest strategies for synergistic therapies that accelerate bacterial clearance, and they identify mechanisms of adaptation to drug exposure that could influence treatment outcome.
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: 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: American Society for Microbiology
Date: 27-08-2019
Abstract: TB control is limited in part by the length of antibiotic treatment needed to prevent recurrent disease. To probe mechanisms underlying survival under antibiotic pressure, we performed a genetic screen for M. tuberculosis mutants with altered susceptibility to treatment using the mouse model of TB. We identified multiple genes involved in a range of functions which alter sensitivity to antibiotics. In particular, we found glycerol catabolism mutants were less susceptible to treatment and that common variation in a homopolymeric region in the glpK gene was associated with drug resistance in clinical isolates. These studies indicate that reversible high-frequency variation in carbon metabolic pathways can produce phenotypically drug-tolerant clones and have a role in the development of resistance.
Publisher: eLife Sciences Publications, Ltd
Date: 24-01-2022
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: 20-09-2023
Publisher: CRC Press
Date: 25-09-2017
DOI: 10.1201/B22009
Location: United States of America
Location: Italy
Location: United States of America
Location: United States of America
No related grants have been discovered for Michelle Bellerose.