According to the World Health Organization, it is estimated that, by 2020, up to 36 million people will die annually of tuberculosis (TB). The recent discovery of extensively- (XDR), extremely- (XXDR) and total- (TDR) drug resistant M.tb strains further aggravates this worldwide health problem making it an uncontrollable burden for the fight to control TB in endemic areas. Although current efforts are directed to the development of new therapies and vaccines, there is still a lack of understanding of how the environments that M.tb encounters during its path(s) of infection influence disease dynamics.
Jordi B. Torrelles, a scientist in Ohio State College of Medicine’s Department of Microbial Infection and Immunity, focuses his research on the biology of antimicrobial enzymes, called hydrolases, of the lung alveolar mucosa and their impact on the course of infection by altering the M.tb cell wall. Bacteria are deposited and settle in the alveolar spaces of the lungs when M.tb is transmitted through the air. It is believed that M.tb remains “static” during the first phase of infection, does not induce an immune response and is absorbed by non-activated macrophages, which are a subset of immune cells, located in the alveoli.
However, according to Torrelles and colleagues, they hypothesize that alveolar called hydrolases present in the human lung prompt an active phase by significantly altering the M.tb cell envelope during the first stages of infection and releasing bioactive cell wall fragments into the lung environment.
Torrelles’ research proposes to determine the structure of M.tb cell wall fragments released following exposure to the human alveolar hydrolases; determine how M.tb wall modifications and released cell wall fragments generated by alveolar hydrolases influence the establishment of M.tb infection using human primary alveolar compartment cells; and determine how M.tb cell wall modifications and released cell wall fragments generated by alveolar hydrolases influence the course of M.tb infection in vivo.
Torrelles’ studies have the potential to add a new dimension to our basic understanding of macrophage-M.tb interactions in the lung mucosa. Identification of novel signatures on the M.tb cell surface and released fragments due to the action of human alveolar hydrolases may identify relevant cell targets that could be highly immunogenic vaccine candidates. Data gained from this award will also provide the background to establish if down- or up-regulation of alveolar hydrolases could serve as therapy to better handle infection, and add more information about the little known role of the human lung environment in M.tb pathogenesis in vivo.