Fungi are ubiquitous colonizers of skin and mucosal surfaces. While many individuals exhibit minor fungal outgrowth, millions of others experience systemic infections with life-threatening consequences. Polymorphisms in numerous genes have been associated with the ability of an individual to generate an inflammatory response to fungal pathogens. In many of these genes, rare high-penetrance alleles have been observed that strongly disrupt gene function, resulting in primary immunodeficiencies and an increase in infectious disease susceptibility. Additionally, common genetic variants have been reported in these genes that increase the risk of disease by modifying the activity or expression of the gene product to a small but significant degree. These genes offer a unique opportunity to understand how immune responses to pathogens are tuned to achieve an appropriate level of immune response. This hypothesis is well illustrated by the various phenotypes associated with different genetic variants of CARD9. CARD9 is a signaling protein that functions downstream of many C- type lectin receptors (CLRs), which recognize carbohydrate moieties on fungi and other pathogens. Understanding how these human disease-related CARD9 mutations affect CARD9 functions will advance our understanding of fungal immunity.
In Aim 1 of this proposal, we examine the role of Card9 ubiquitination on fungal detection by dendritic cells.
In Aim 2, we will identify the molecular mechanisms controlling Card9 phosphorylation and their consequences for fungal detection.
In Aim 3, we compare how Card9 genetic variants affect Candida infection and the development of colitis. Together, these aims will decipher the mechanistic basis of CARD9 regulation and characterize CARD9 genetic variants to identify novel molecular mechanisms with important roles in fungal defense and inflammation.
! Both mucosal and systemic immunity are important for controlling fungal infection; however, the precise mechanism whereby fungal defense is maintained without excessive inflammation is currently unclear. Inborn errors in CARD9 can dramatically increase susceptibility to fungal infections in human patients while other polymorphisms that alter CARD9 activity can protect or promote inflammation. The focus of this application is to understand how CARD9, and specifically human polymorphisms that abrogate or alter CARD9 function, contribute to fungal immunity and inflammation with the ultimate goal of elucidating novel therapeutic strategies to promote host defense to fungal infection without excessive inflammation. !
|Bakker, Olivier B; Aguirre-Gamboa, Raul; Sanna, Serena et al. (2018) Integration of multi-omics data and deep phenotyping enables prediction of cytokine responses. Nat Immunol 19:776-786|
|Leshchiner, Elizaveta S; Rush, Jason S; Durney, Michael A et al. (2017) Small-molecule inhibitors directly target CARD9 and mimic its protective variant in inflammatory bowel disease. Proc Natl Acad Sci U S A 114:11392-11397|