Molecular pathogenesis of blastomycosis

ABSTRACT This longstanding R01, reviewed for the past 25 years in study section PTHE, has investigated the pathogenesis of blastomycosis with an emphasis on the causative fungus Blastomcyes dermatitidis. While pathogenesis of B. dermatitidis infection is still our focus, we now investigate the immunopathogenesis of B. dermatitidis infection. In the last funding cycle, we uncovered a unique susceptibility to B. dermatitidis infection in the Hmong population of Wisconsin. We discovered that an Interleukin 6 (IL-6) defect in patients underpins their impaired immunity and susceptibility to B. dermatitidis, and we modeled the scenario during murine infection. In patients, we traced the underlying molecular mechanism of this IL-6 defect to polymorphisms in the gene that affect the long non-coding RNA (lncRNA), IL6-AS1. We have now generated compelling preliminary data with induced pluripotent stem cells (iPSC) from patients and healthy control subjects that have been gene-edited. The data support our model that impaired resistance to B. dermatitidis in susceptible hosts like the Hmong population results from altered/im- paired IL6-AS1 lncRNA regulation of IL-6 expression. This defect in turn impairs development of acquired re- sistance to B. dermatitidis mediated by Th17 cells. Here, we propose three aims that will uncover the poorly understood mechanism of action of IL6-AS1 in regulating IL-6 gene expression, decipher how IL6-AS1 polymor- phisms in the Hmong alter the function of IL6-AS1 and expression of IL-6, and analyze the downstream conse- quence on the function, phenotype and gene expression of T cells that help resist B. dermatitidis infection. Our work has implicaitons for understanding the basis of susceptibility to B. dermatifidis and other infectious diseases, including COVID, that hinge on proper regulation and tuning of IL-6 production.