That gastrointestinal tract is the point of entry for many disease-causing organisms. The intestinal wall is very thin, which maximizes absorption of nutrients but also minimizes the distance pathogens must traverse to gain entry. Immune cells are positioned at both local and distant sites to monitor for infection originating from the intestine. However, immune responses must be tightly regulated so as to not result in tissue damage and autoimmunity. This is illustrated by the gut-liver axis, a communication between the gastrointestinal tract and the liver. The portal vein, which drains the gastrointestinal tract, relys substances from the gut to the liver where immune cells monitor for antigens but can also become activated against innocuous molecules. Recently, our lab identified a novel lineage of natural killer (NK) cells, peculiar in its restriction to the liver, expression of CD49a, transcripion factor dependence, and cytokine production. Liver-resident NK cells are anchored in the sinusoids, where they encounter blood that enters through the portal vein. This suggests that liver-resident NK cells can respond to stimuli originating from the gastrointestinal tract. To determine if liver- resident NK cells play a role during gastrointestinal infection, we propose to study these cells in the context of infection with Toxoplasma gondii, an intracellular parasite tha spreads orally and penetrates the intestinal epithelium. Preliminary data show that following intraperitoneal injection of parasites, CD49a+DX5+ NK cells appear in the peritoneum. These cells differ from conventional NK cells by expressing markers of both circulating and tissue-resident NK cells, and infection of parabiotic mice reveals that they are not native peritoneal cells. We hypothesize that liver-resident NK cells are mobilized during T. gondii infection and migrate to the peritoneum. There, they may contribute to clearance of the parasite or regulation of the immune response.
We aim to definitively determine the source of peritoneal CD49a+DX5+ NK cells, their mechanisms of recruitment and activation, and their function in order to elucidate novel mechanisms of immune response to gastrointestinal infection.

Public Health Relevance

Recently, our lab identified a natural killer (NK) cell population in the liver that may respond to gastrointestinal infections. We will study these NK cells in infection with Toxoplasma gondii, an intestinal parasite, to better understand their capabilities. We aim to uncover novel immune mechanisms that may pertain to pathology of the gastrointestinal tract and liver, such as pathogen clearance and development of autoimmunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30DK108472-02
Application #
9223571
Study Section
Special Emphasis Panel (ZDK1-GRB-2 (O1)L)
Program Officer
Densmore, Christine L
Project Start
2016-03-01
Project End
2020-02-29
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
2
Fiscal Year
2017
Total Cost
$30,152
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Patel, Swapneel J; Zhao, Guoyan; Penna, Vinay R et al. (2017) A Murine Herpesvirus Closely Related to Ubiquitous Human Herpesviruses Causes T-Cell Depletion. J Virol 91: