부산대학교 도서관

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. Author summary: The genetic makeup of people contributes to their susceptibility to infection and to their ability to be protected by vaccines. This is the case with Mycobacterium tuberculosis and the lung disease caused by this bacterium, known as tuberculosis, where host genetics plays an important role in susceptibility to infection. However, less is known about genetic control of whether vaccination can protect people against developing tuberculosis. We used a small animal model called Diversity Outbred mice to study genetic control of successful vaccination with M. bovis BCG, the only tuberculosis vaccine used worldwide. We found sixteen gene regions associated with different outcomes after vaccination, such as how vaccination impacted lung bacterial burdens, systemic bacterial burdens, or weight loss. Importantly, the results imply that successful vaccination results from the combined activities of multiple genes which affect different features of immune responses. [ABSTRACT FROM AUTHOR]