The human gut is home to a vast consortium of symbiotic bacteria. Members of this complex microflora metabolize dietary substances, such as plant polysaccharides, that are otherwise indigestible by their human hosts. Indigenous gut microbes thus make essential contributions to human nutrient metabolism, and in return inhabit a protected, nutrient rich environment. Maintaining the mutually beneficial nature of this relationship requires strict sequestration of resident bacteria in the intestinal lumen, since microbial invasion of epithelia can elicit inflammation and sepsis.
My lab is focused on understanding the mechanisms by which resident microbes are prevented from crossing epithelial barriers. To address these questions, we have established a germ-free mouse colony where mice are raised under completely sterile conditions inside plastic germ-free isolators. We are using germ-free mouse models to investigate how intestinal surfaces detect bacterial threats and how gut epithelia are protected from invasion by the enormous bacterial populations in the lumen.
Our studies in germ-free mice have led to the discovery of a family of secreted C-type lectins that bind bacterial surface peptidoglycan and are directly bactericidal. Bacterial invasion of intestinal epithelia triggers lectin expression, suggesting these proteins play a critical role in defending gut epithelial barriers. Ongoing work includes investigating the biochemical basis of peptidoglycan recognition by these lectins and understanding the molecular mechanisms by which they kill bacteria. In addition, we are using genetically-engineered mouse models to determine how intestinal epithelia sense bacterial invasion and upregulate bactericidal lectin expression.
A second line of investigation in my lab is centered on understanding how intestinal epithelia detect damage and initiate repair. As intestinal bacteria pose a serious threat of opportunistic infection in the face of epithelial damage, gut epithelia must be able to rapidly detect injury and heal mucosal breaches. We have gained new insights into this process by studying γδ intraepithelial lymphocytes (γδ IELs) in an experimental mouse model of intestinal epithelial damage. γδ IELs form intimate contacts with intestinal epithelial cells and play a key role in promoting epithelial repair by secreting epithelial growth factors. We are currently investigating what signals are required to trigger growth factor expression in γδ IELs. These studies will give us a better understanding of how intestinal surfaces sense injury and initiate localized epithelial repair.
RESEARCH INTERESTS
Host-microbial interactions
Mucosal immunology
Innate immunity
RECENT PUBLICATIONS
Cash, H. L., Whitham, C. V., Behrendt, C. L., and Hooper, L. V., "Symbiotic bacteria direct expression of an intestinal bactericidal lectin" Science, 313:1126-30, August 2006
Vaishnava, S., Behrendt, C. L., Ismail, A.S., Eckmann, L., and Hooper, L. V., "Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface." Proceedings of the National Academy of Sciences USA, 105:20858-20863, 2008
Mukherjee, S., Partch, C.L., Lehotzky, R.E., Whitham, C.V., Chu, H., Bevins, C.L., Gardner, K.H., and Hooper, L.V., "Regulation of C-type lectin antimicrobial activity by a flexible N-terminal prosegment." Journal of Biological Chemistry, 284:4881-4888, 2009
Ismail, A. S., Behrendt, C. L., and Hooper, L. V., "Reciprocal interactions between commensal bacteria and γδ intraepithelial lymphocytes during mucosal injury." Journal of Immunology, 182:3047-3054, 2009
Cash, H. L., Whitham, C. V., Behrendt, C. L., and Hooper, L. V., "Symbiotic bacteria direct expression of an intestinal bactericidal lectin" Science, 313:1126-30, August 2006
Vaishnava, S., Behrendt, C. L., Ismail, A.S., Eckmann, L., and Hooper, L. V., "Paneth cells directly sense gut commensals and maintain homeostasis at the intestinal host-microbial interface." Proceedings of the National Academy of Sciences USA, 105:20858-20863, 2008
Ismail, A. S., Behrendt, C. L., and Hooper, L. V., "Reciprocal interactions between commensal bacteria and γδ intraepithelial lymphocytes during mucosal injury." Journal of Immunology, 182:3047-3054, 2009
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