Title: Growth regulation of Mycobacterium tuberculosis in vivo and in vitro
Description: Tuberculosis afflicts millions of people each year and causes high levels of global morbidity and mortality. New therapies are urgently needed that will increase the effectiveness of host immunity and decrease the pathogenicity of Mycobacterium tuberculosis, the causative agent of this disease. We studied this host-pathogen interaction by examining the way that the requirements for M. tuberculosis survival change when a key mediator of immunity, nitric oxide, is removed from the host. The removal of inducible nitric oxide synthase (iNOS), the predominant source of NO during infection, adversely affected several mutant M. tuberculosis strains while benefiting others. The virulence lipid phthiocerol dimycocerosate (PDIM) was previously implicated in NO resistance, indicating that mutants lacking this lipid might replicate better when NO is removed. To the contrary, we found that PDIM mutants actually did more poorly when NO was removed. These mutants appear to be restricted by an IFN-γ-independent mechanism of immunity that is suppressed by NO. Among those that benefited from the removal of iNOS were mutants lacking a specific toxin-antitoxin system. This locus checks the growth of M. tuberculosis during infection through the inhibitory activities of both its toxin and its antitoxin. These proteins have very different effects on growth in liquid broth cultures, where they actually facilitate an increased growth rate. This observation suggests that M. tuberculosis maintains these factors within its genome because they increase overall fitness, even though they decrease growth during murine infection.