Many studies have documented the essential role that specific intestinal bacteria play in tuning mucosal immunity and in instructing tissue development and repair, but we know very little about how intestinal fungi interact with the immune system or contribute to intestinal inflammatory diseases. Studies cataloging intestinal microbes have typically focused on the bacteria, and the terms "intestinal bacteria" and "intestinal microbiome" are often used interchangeably. Two barriers to developing a better understanding of the role of gut fungi in health and disease are having a good sense of the numbers and types of fungi in the gut and having a model in which immune responses to gut fungi can be manipulated. My laboratory has been studying the role of the ?-glucan receptor Dectin-1 in host defense. Dectin-1 is expressed on macrophages and dendritic cells and is essential for defense against fungi. Dectin-1 signals inflammatory responses through an intracellular signaling adaptor molecule called CARD9, a protein for which specific genetic variants are strongly associated with ulcerative colitis and Crohn's disease. We have observed that mice lacking Dectin-1 are more susceptible to acute colitis induced by DSS than wild type mice and that this enhanced sensitivity is due to intestinal fungi. We have begun to characterize the intestinal fungal microflora by high throughput multitag pyrosequencing and have identified several hundred intestinal fungi. Thus, we are developing a sense of the numbers and types of fungi in the gut and a model in which immune responses to gut fungi can be manipulated. Our overall hypothesis is that the ?-glucan receptor Dectin-1 is responsible for surveying the gut microflora for fungi and orchestrating a host immune response that shapes the microflora and contributes to intestinal inflammatory conditions. We will explore this hypothesis in four aims.
In aim 1 we will characterize the fungal microbiome in wild type, Dectin-1-/-, and CARD9-/- mice in resting and inflamed conditions.
In aim 2 we will define the role of Decitn-1 in sampling intestina fungi and the role of intestinal fungi in driving inflammatory responses.
In aim 3 we will determine whether mice lacking CARD9 exhibit the same fungal-driven intestinal inflammation as observed in Dectin-1 knockout mice.
In aim 4 we will determine whether Dectin-1 and CARD9 knockout mice also exhibit enhanced susceptibility to spontaneous disease and disease induced by T cell transfer.

Public Health Relevance

The intestines are full of microbes, and the numbers and kinds of microbes found there can be a significant factor in intestinal chronic inflammatory disease such as Inflammatory Bowel Disease. While many studies have focused on how intestinal bacteria are detected by the immune system, little is known about how intestinal fungi are detected. This study aims to define the repertoire of fungi found in mouse intestines and use mice lacking specific genes to understand how the immune system interacts with intestinal fungi.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK093426-02
Application #
8490371
Study Section
Special Emphasis Panel (ZRG1-DKUS-C (03))
Program Officer
Hamilton, Frank A
Project Start
2012-07-01
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$431,160
Indirect Cost
$169,851
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
Underhill, David M; Iliev, Iliyan D (2014) The mycobiota: interactions between commensal fungi and the host immune system. Nat Rev Immunol 14:405-16
Iliev, Iliyan D; Underhill, David M (2013) Striking a balance: fungal commensalism versus pathogenesis. Curr Opin Microbiol 16:366-73