Our laboratory is interested in the microbial ecology of mucosal surfaces and the role of the microbiota in shaping mucosal immunity. Epidemiologic and clinical data support the hypothesis that perturbations in the microbiota due to antibiotic use and dietary differences in "industrialized” countries have disrupted the normal microbiota-mediated mechanisms of immunological tolerance in the mucosa, leading to an increase in the incidence of allergic airway disease and other inflammatory conditions. The data supporting this "Microflora Hypothesis" includes correlations between allergic airway disease and (1) antibiotic use early in life, (2) altered fecal microbiota and (3) dietary changes over the past two decades. Our laboratory has demonstrated that mice can develop allergic airway responses to allergens if their endogenous microbiota is altered at the time of first allergen exposure. These experimental and clinical observations are consistent with other studies demonstrating that the endogenous microbiota plays a significant role in shaping the development of the immune system. Data is beginning to accumulate that an "undisturbed" microbiota plays a positive role in maintaining mucosal immunologic tolerance long after post-natal development. Other studies have demonstrated that even small volumes delivered to the nasopharynx largely end up in the GI tract, suggesting that airway tolerance and oral tolerance may operate simultaneously. The mechanism of microbiota modulation of host immunity is not known. However, host and microbial oxylipins are one potential set of immunomodulatory molecules that may control mucosal tolerance, while probiotic and prebiotic immunotherapy may work through modulating the ecology of the GI microbiota. Conversely, colonization by Candida species may modify the resistance and resilience of the bacterial community structure in the gastrointestinal tract in response to ecologic stress or perturbation, including downstream effects on immune system regulation. Recent advances in high-throughput culture-independent microbiology are providing our group with novel insights into the microbial ecology of the lungs, GI tract and other mucosal surfaces. We have also recently begun investigations into the host response to Clostridium difficile infections in humans and in a mouse model of pseudomembranous colitis.
Huffnagle GB, McNeil LK, McDonald RA, Murphy JW, Toews GB, Maeda N, Kuziel WA. Cutting Edge: Role of CCR5 in organ-specific and innate immunity to Cryptococcus neoformans. J Immunol 1999, 163: 4642-4646.
Traynor TR, Kuziel WA, Toews GB, Huffnagle GB. CCR2 expression determines T1 vs. T2 polarization during pulmonary Cryptococcus neoformans infection. J Immunol 2000, 164(4):2021-2027.
Aliberti J, Reis e Sousa C, Schito M, Hieny S, Wells T, Huffnagle GB, Sher A. CCR5 provides a signal for microbial induced production of IL-12 by CD8a+ dendritic cells. Nature Immunol 2000, 1:83-87.
Olszewski MA, Huffnagle GB, McDonald RA, Lindell DM, Cook DN, Toews GB. The role of MIP-1a/CCL3 in regulation of T cell-mediated immunity to Cryptococcus neoformans infection. J Immunol 2000, 165(11):6429-36.
Noverr MC, Phare SM, Toews GB, Coffey MJ, Huffnagle GB. Production of immunomodulatory prostaglandins by the pathogenic yeast Cryptococcus neoformans and Candida albicans. Infect Immun 2001 (in press).