Characterization of P38 Activation During Mycobacterium tuberculosis Infection
(TB) is one of the greatest public health issues of our time. It is estimated that
Mycobacterium tuberculosis (Mtb), the causative agent of TB, infects about one-third of
the world's population. Causing more than a million deaths worldwide every year, Mtb is
now the leading cause of death from infectious disease. Interestingly, only about 10% of
healthy individuals infe... read morected with Mtb will develop active TB. Currently, we do not
understand what factors determine if the host immune response will be successful in
protecting against Mtb. Alveolar macrophages are among the first host innate immune
cells encountered by M. tuberculosis and are thought to be the primary niche for M.
tuberculosis. To defend against M. tuberculosis, macrophages employ a variety of
antimicrobial defenses against Mtb, such as through maturation and acidification of
phagolysosomes, the production of inflammatory cytokines, the production of ROS and RNS,
autophagy, and apoptosis. These antimicrobial defenses are regulated either directly or
indirectly by the mitogen activated protein kinase (MAPK) p38. Therefore, we hypothesize
that p38 activation protects against Mtb infection via the specific antimicrobial
defense of inducing macrophage apoptosis. To investigate our hypothesis we combined bulk
assays, such as Western blots and plate-based assays, with live cell microscopy and
single-cell analysis. Using the p38 inhibitor, SB203580, we began to characterize the
role of p38 during Mtb infection. We are the first to report that bacterial burden
correlates with both p38 activation in macrophages and macrophage death. We also found
that p38 inhibition decreased macrophage death and increased total Mtb. Overall, these
findings support the conclusion that p38 activation contributes to the defense against
Thesis (M.S.)--Tufts University, 2017.
Submitted to the Dept. of Immunology.
Advisors: Bree Aldridge, and Joan Mecsas.
Committee: Stephen Bunnell, and Alexander Poltorak.
Keyword: Immunology.read less