The intestinal mucosa serves as a barrier to infection from pathogens and normal gut flora. This barrier is defended by the mucosal immune system through a variety of innate and adaptive immune mechanisms. However, mucosal immune responses must be tightly regulated to maintain tolerance to resident normal flora and food antigens. Because peripheral tolerance cannot be explained completely by immunological ignorance or negative selection in the thymus, various mechanisms have been proposed for how lamina propria macrophages (MPs) and dendritic cells (DCs) capture and present luminal antigen in the steady-state to promote intestinal homeostasis. Recently, we described a novel luminal antigen transport mechanism that we've termed goblet cell associated antigen passages (GAPs). The role of GAPs in peripheral tolerance vs. immunity is relatively unexplored, but GAPs deliver small soluble antigens preferentially to CD103+ DCs, which have tolerogenic potential. A key question is whether pathogen invasion mechanisms have evolved to target steady-state antigen acquisition pathways (e.g., GAPs) as a strategy to evade the acute immune response. These studies will use a common and often deadly bacterial pathogen, Listeria monocytogenes (Lm), to investigate how initial host-bacterial interactions (minutes to hours) affects mucosal immunity and link invasion pathways to downstream infection outcomes. Our hypothesis is that bacterial invasion via GAPs will lead to inefficient innate and adaptive immune responses and increase bacterial persistence in the host. This hypothesis will be tested in vivo using a murinized Lm strain (Lm InlAMt) mouse that can infect mice orally and complemented by studying Lm InlAWt infection in explanted human intestinal tissues. These studies build on important recent developments including the murinized Lm oral infection model, in vivo two-photon imaging of the intestine and mesenteric lymph nodes, the development of a human explant infection system and state-of- the-art RNA sequencing approaches to characterize epithelial responses. This work is conceptually innovative in that it examines the first few minutes of an infection, which is rarely studied in vivo and impractical to study in human patients, but which may ultimately determine infection outcomes.

Public Health Relevance

The intestine is lined with a single layer of epithelial cells that serve both as a surface for nutrient uptake and a barrier to infection. Recent evidence suggests that luminal antigen from food and harmless microbes must be transported across the epithelium to maintain homeostasis and prevent inflammatory disease. This project will use live imaging, gene expression and histological methods to examine whether pathogenic bacteria (Listeria monocytogenes) can exploit basal antigen transport mechanisms to evade immune responses and infect the host. This proposal will examine the acute host response within the first few minutes of an infection and link different bacterial invasion pathways with immunological outcomes. This knowledge is relevant for designing vaccines and treatments for intestinal infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI077600-07
Application #
9395869
Study Section
Immunity and Host Defense (IHD)
Program Officer
Rothermel, Annette L
Project Start
2009-08-01
Project End
2021-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
7
Fiscal Year
2018
Total Cost
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
Mrass, Paulus; Oruganti, Sreenivasa Rao; Fricke, G Matthew et al. (2017) ROCK regulates the intermittent mode of interstitial T cell migration in inflamed lungs. Nat Commun 8:1010
Cain, Matthew D; Salimi, Hamid; Gong, Yongfeng et al. (2017) Virus entry and replication in the brain precedes blood-brain barrier disruption during intranasal alphavirus infection. J Neuroimmunol 308:118-130
Nishi, Hiroshi; Furuhashi, Kazuhiro; Cullere, Xavier et al. (2017) Neutrophil Fc?RIIA promotes IgG-mediated glomerular neutrophil capture via Abl/Src kinases. J Clin Invest 127:3810-3826
Spahn, Jessica H; Li, Wenjun; Bribriesco, Alejandro C et al. (2015) DAP12 expression in lung macrophages mediates ischemia/reperfusion injury by promoting neutrophil extravasation. J Immunol 194:4039-48
Angiari, Stefano; Rossi, Barbara; Piccio, Laura et al. (2013) Regulatory T cells suppress the late phase of the immune response in lymph nodes through P-selectin glycoprotein ligand-1. J Immunol 191:5489-500
Knoop, Kathryn A; Miller, Mark J; Newberry, Rodney D (2013) Transepithelial antigen delivery in the small intestine: different paths, different outcomes. Curr Opin Gastroenterol 29:112-8
Wang, Baomei; Zinselmeyer, Bernd H; Runnels, Herbert A et al. (2012) In vivo imaging implicates CCR2(+) monocytes as regulators of neutrophil recruitment during arthritis. Cell Immunol 278:103-12
Li, Wenjun; Nava, Ruben G; Bribriesco, Alejandro C et al. (2012) Intravital 2-photon imaging of leukocyte trafficking in beating heart. J Clin Invest 122:2499-508
McDole, Jeremiah R; Wheeler, Leroy W; McDonald, Keely G et al. (2012) Goblet cells deliver luminal antigen to CD103+ dendritic cells in the small intestine. Nature 483:345-9
Kreisel, Daniel; Sugimoto, Seiichiro; Zhu, Jihong et al. (2011) Emergency granulopoiesis promotes neutrophil-dendritic cell encounters that prevent mouse lung allograft acceptance. Blood 118:6172-82

Showing the most recent 10 out of 23 publications