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Multiple genetic loci influence vaccine-induced protection against Mycobacterium tuberculosis in genetically diverse mice.
Kurtz, Sherry L; Baker, Richard E; Boehm, Frederick J; Lehman, Chelsea C; Mittereder, Lara R; Khan, Hamda; Rossi, Amy P; Gatti, Daniel M; Beamer, Gillian; Sassetti, Christopher M; Elkins, Karen L.
Afiliação
  • Kurtz SL; Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, United States of America.
  • Baker RE; Department of Microbiology and Physiological Systems, UMass Chan Medical School, Worcester, Massachusetts, United States of America.
  • Boehm FJ; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.
  • Lehman CC; Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, United States of America.
  • Mittereder LR; Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, United States of America.
  • Khan H; Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, United States of America.
  • Rossi AP; Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, United States of America.
  • Gatti DM; College of Medicine, University of Cincinatti, Cincinatti, Ohio, United States of America.
  • Beamer G; The Jackson Laboratory, Bar Harbor, Maine, United States of America.
  • Sassetti CM; Texas Biomedical Research Institute, San Antonio, Texas, United States of America.
  • Elkins KL; Department of Microbiology and Physiological Systems, UMass Chan Medical School, Worcester, Massachusetts, United States of America.
PLoS Pathog ; 20(3): e1012069, 2024 Mar.
Article em En | MEDLINE | ID: mdl-38452145
ABSTRACT
Mycobacterium tuberculosis (M.tb.) infection leads to over 1.5 million deaths annually, despite widespread vaccination with BCG at birth. Causes for the ongoing tuberculosis endemic are complex and include the failure of BCG to protect many against progressive pulmonary disease. Host genetics is one of the known factors implicated in susceptibility to primary tuberculosis, but less is known about the role that host genetics plays in controlling host responses to vaccination against M.tb. Here, we addressed this gap by utilizing Diversity Outbred (DO) mice as a small animal model to query genetic drivers of vaccine-induced protection against M.tb. DO mice are a highly genetically and phenotypically diverse outbred population that is well suited for fine genetic mapping. Similar to outcomes in people, our previous studies demonstrated that DO mice have a wide range of disease outcomes following BCG vaccination and M.tb. challenge. In the current study, we used a large population of BCG-vaccinated/M.tb.-challenged mice to perform quantitative trait loci mapping of complex infection traits; these included lung and spleen M.tb. burdens, as well as lung cytokines measured at necropsy. We found sixteen chromosomal loci associated with complex infection traits and cytokine production. QTL associated with bacterial burdens included a region encoding major histocompatibility antigens that are known to affect susceptibility to tuberculosis, supporting validity of the approach. Most of the other QTL represent novel associations with immune responses to M.tb. and novel pathways of cytokine regulation. Most importantly, we discovered that protection induced by BCG is a multigenic trait, in which genetic loci harboring functionally-distinct candidate genes influence different aspects of immune responses that are crucial collectively for successful protection. These data provide exciting new avenues to explore and exploit in developing new vaccines against M.tb.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Tuberculose / Vacinas contra a Tuberculose / Mycobacterium bovis / Mycobacterium tuberculosis Limite: Animals / Humans Idioma: En Revista: PLoS Pathog Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Tuberculose / Vacinas contra a Tuberculose / Mycobacterium bovis / Mycobacterium tuberculosis Limite: Animals / Humans Idioma: En Revista: PLoS Pathog Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos