Mycobacterium tuberculosis, the causative agent of tuberculosis, has evolved a complex interface with the host macrophage in order to establish a replicative niche and promote infection. Upon infection, Mtb induces changes to host gene expression in order to down-regulate pro-inflammatory cytokines. Past work has provided overwhelming evidence that changes to host gene expression that occur in the hours immediately following infection are critical for Mtb to establish infection. However, very little i known about how gene expression changes are regulated at the level of mRNA processing and maturation. Our new work indicates that post-transcriptional control of gene expression is important during the response to Mtb and that pre- mRNA splicing is a major regulatory checkpoint during infection. The studies proposed here are intended to fill a critical void in our understanding of post-transcriptional control of the innate immune gene expression program and will shed light on how important human health pathogens like Mtb can manipulate host RNA processing in order to create a favorable niche. The information generated in these studies will contribute to the development of targeted vaccines and host-directed therapeutics aimed at modulating pre-mRNA splicing to enhance anti-bacterial and/or short circuit pro-bacterial gene expression programs.
Mycobacterium tuberculosis is an exquisitely evolved and incredibly successful human pathogen that currently infects one-third of the world's population. One way that M. tuberculosis establishes infection and promotes pathogenesis is by down-regulating expression of pro-inflammatory cytokines, including the powerful inflammatory mediator TNF-?. Virtually nothing is known about how Mtb manipulates expression of TNF-? and other genes in the host's innate immune program. Here, we will illuminate the mechanisms by which Mtb regulates changes to host pre-mRNA splicing in order to promote a pro-bacterial gene expression program in infected macrophages.
| Patrick, Kristin L; Wojcechowskyj, Jason A; Bell, Samantha L et al. (2018) Quantitative Yeast Genetic Interaction Profiling of Bacterial Effector Proteins Uncovers a Role for the Human Retromer in Salmonella Infection. Cell Syst 7:323-338.e6 |
| Patrick, Kristin L; Bell, Samantha L; Watson, Robert O (2016) For Better or Worse: Cytosolic DNA Sensing during Intracellular Bacterial Infection Induces Potent Innate Immune Responses. J Mol Biol 428:3372-86 |
