# Molecular pathogenesis of blastomycosis

> **NIH NIH R37** · UNIVERSITY OF WISCONSIN-MADISON · 2022 · $648,248

## Abstract

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.

## Key facts

- **NIH application ID:** 10519822
- **Project number:** 2R37AI035681-25
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** BRUCE Steven KLEIN
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $648,248
- **Award type:** 2
- **Project period:** 1995-01-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10519822

## Citation

> US National Institutes of Health, RePORTER application 10519822, Molecular pathogenesis of blastomycosis (2R37AI035681-25). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10519822. Licensed CC0.

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