Commensal intestinal microbes are now increasingly recognized to control systemic immune homeostasis and responsiveness. The greatest density of commensal bacteria reside within the intestinal lumen, and accumulating evidence shows these microbial communities play pivotal roles during infection with more pathogenic microbes. Studies using model viral pathogens to probe host defense shifts following antibiotic induced eradication of commensal enteric bacteria consistently show blunted expansion of protective virus specific CD8+ T cells that parallels increased susceptibility to viral infections. Interestinly, these immune modulatory benefits of commensal bacteria appear restricted to viral pathogens since our initial studies show commensal intestinal bacteria simultaneously impair host defense against disseminated infection with the human fungal pathogen, Candida albicans. Antibiotic induced eradication of commensal enteric bacteria accelerates C. albicans fungal clearance and improves host survival by unleashing more robust and sustained expansion of neutrophils. However, in addition to neutrophils, other protective antifungal adaptive immune components are also likely unleashed by depletion of commensal bacteria since differences in fungal pathogen burden and survival are only appreciated during later time points after infection (days 10-20), yet conspicuously absent at early post-infection time points (day 5) before adaptive immune components are fully engaged. In particular, the accelerated expansion and more efficient mobilization of neutrophils after antibiotic induced eradication of intestinal bacteria strongly suggests IL-17 producing (Th17) CD4+ T cells as the likely adaptive component responsible for these protective shifts in antifungal immunity. These findings form the scientific premise for our overall hypothesis that commensal enteric bacteria dampen the priming and differentiation of fungal-specific Th17 CD4+ T cells that promote antifungal immunity through IL-17 production. Furthermore, given the potent ability whereby the TLR4 ligand, lipopolysaccharide, restores susceptibility to disseminated C. albicans infection in a dose dependent fashion when administered intra-rectally to commensal bacteria eradicated mice, our secondary hypothesis is that shifts in systemic immune cell responsiveness that control antifungal immunity is dependent on intestinal recognition of commensal bacteria through toll-like receptor 4 (TLR4). These innovative hypotheses will be addressed with the following specific aims: (1) Identify shifts in C. albicans fungal-specific CD4+ T cell priming controlled by intestinal commensal bacteria; (2) Investigate the necessity for TLR4 in commensal enteric bacteria mediated susceptibility to systemic C. albicans infection; (3) Determine the contribution of commensal bacteria stimulation through TLR4 among intestinal epithelial cells compared with hematopoietic immune cells in controlling antifungal immunity. Successful completion of these studies will establish the molecular and cellular immune mechanisms whereby commensal enteric bacteria control systemic antifungal immunity.
The intestinal tract is colonized with trillions of commensal bacteria that are increasingly recognized to control the responsiveness of immune cells in extra-intestinal tissues. The experiments outlined in this application seek to dissect how these enteric commensal bacteria are sensed by specific subsets of intestinal cells and control the protective capacity of immune cells that protect against systemic fungal infections.
| Jiang, Tony T; Shao, Tzu-Yu; Ang, W X Gladys et al. (2017) Commensal Fungi Recapitulate the Protective Benefits of Intestinal Bacteria. Cell Host Microbe 22:809-816.e4 |
| Jiang, Tony T; Martinov, Tijana; Xin, Lijun et al. (2016) Programmed Death-1 Culls Peripheral Accumulation of High-Affinity Autoreactive CD4 T Cells to Protect against Autoimmunity. Cell Rep 17:1783-1794 |
