The intracellular bacterial pathogen Listeria monocytogenes (Lm) is capable of causing serious invasive disease with a high mortality rate; recently, it has been determined that subpopulations of Lm have the capacity to target the heart. Notably, Lm cardiac infections occur in up to an estimated 10% of invasive disease cases and mortality rates can be as high as 35% despite treatment. Little is known regarding Lm colonization of cardiac tissue and its resultant pathologies. Two major bacterial surface proteins known as internalin A and B (encoded by inlA and inlB) facilitate Lm host cell invasion, and recent data suggests that a specific allele of inlB is linked to cardiotropism based on its ability to enhance Lm cardiac infections in mice. This proposal will investigate the molecular mechanisms of Lm tropism for cardiac cells (Aim 1) as well as how common the cardiotropic allele of inlB (inlBC) is within the Lm population and how it is passed to other Lm strains (Aim 2). My working hypothesis regarding the role of InlB in cardiac cell invasion is that heparan sulfate proteoglycans (HSPGs) on heart cell surfaces contribute to cardiotropism for Lm through the recruitment of InlB from the bacterial cell surface and by facilitating interaction of InlB with its host cell receptor Met. Aim 1 will test InlB's contributions to host cell tropism by examining the binding affinity of InlB variants to HSPGs and the influence of InlB-HSPG interactions on Met signaling and cardiac cell invasion. Aim 2 will determine how prevalent the inlBC variant is within Lm populations. inlB sequences will be analyzed from 150 Lm genomes sequences that include representatives of all major groups within the Lm population. The phylogenetic relationship is known for these strains, hence this analysis will illuminate whether inlBC is transferred horizontally or vertically between strains. Knowledge of the route of transmission of cardiotropic inlB alleles within the Lm population will help in the identification and tracking of cardiotropic strains. As the heart has not generally been investigated as an organ of Lm infection, strains specifically isolated from infected hearts are not common. However, one of the largest Lm collections contains eleven Lm strains isolated from cardiac tissue. The analysis of these eleven inlB sequences will provide additional insight into the correlation between inlB alleles and Lm heart infections.
|Program type||Postdoctoral Fellowship|
|Effective start/end date||07/01/2015 → 06/30/2017|