Erin E. McClelland, Ph.D.

Research Interests

Cryptococcus neoformans (Cn) is a facultative intracellular pathogen that infects most individuals before the age of 5 and establishes decades-long latent infections by residing in host macrophages. If not properly controlled by the immune system, Cn infection results in cryptococcosis, a systemic fungal infection that is lethal if not treated and is the cause of ~181,000 deaths annually. However, serious side-effects associated with current treatments and the emergence of new drug-resistant strains present a clear and escalating challenge for the management of cryptococcosis. To meet this challenge and develop new, effective treatments, an improved understanding of how Cn interacts with the immune system is required.

The two major projects in the lab encompass understanding host-Cn interactions: 1) at the level of macrophage polarization and 2) due to the sex of the host. My long-term goals are to better understand host-Cn interactions with macrophages and to explain the role of host sex in the pathogenesis and susceptibility of Cn infections. These goals aim to understand why 70 percent of patients with cryptococcosis are male and may identify sex-specific therapies for patients infected with Cn.

1) The Cn:macrophage interaction is critically important for determining the course and outcome of infections. While macrophages serve as a growth niche for Cn and facilitate the dissemination of Cn from the lungs, they also efficiently clear ingested yeast if polarized to the highly fungicidal M1 state. This state is controlled by STAT1 and NF-κB transcription factors and involves the differential expression of >1000 genes. NF-κB signaling is particularly important in macrophages as a regulator of cell survival and proinflammatory cytokine expression. Over the past decade, we and others have shown that Cn reduces macrophage fungicidal activity and alters host cell NF-κB-dependent gene expression, but the mechanisms regulating this have yet to be elucidated. Previously, we have shown that intracellular Cn infection attenuates the M1 phenotype by altering the transcriptome of host macrophages to more closely match naïve (M0) macrophages. We are currently characterizing how changes in the intracellular Cn transcriptome and virulence factor expression allow Cn to survive within macrophages polarized to the M1 or M2 phenotype.

2) An increasing population of immune compromised patients has led to a concomitant rise in the incidence of Cn infections, particularly in male AIDS patients. It is currently unknown why male AIDS patients comprise 70% of the patient population with Cn disease, though we have shown that an interaction with testosterone and male macrophages may be involved. The observed contrast in host sex susceptibility suggests a complex interaction of underlying differences in the immune response to Cn infection and differential expression of Cn microbial factors between males and females. My previous studies showed that testosterone induces release of Cn capsular polysaccharide, its major virulence factor, and that macrophages from males have increased mortality and fungal burden after Cn infection, likely due to the secretion of the growth hormone gibberellic acid in the presence of testosterone, and an impaired immune response to Cn infection in males. These data suggest the interaction of host sex hormones with Cn pathogenesis and possible reasons why males show increased incidence of disease. We are currently characterizing the mechanisms by which testosterone induces secretion of gibberellic acid plan to conduct structure-based drug design to test potential sex-specific antifungals.

Selected Publications

Subramani, A., Griggs, P., Frantzen, N., Mendez, J., Tucker, J., Murriel, J., Sircy, L.M., Millican, G.E., McClelland, E.E., Seipelt-Thiemann, R.L., and Nelson, D.E. 2020. Intracellular Cryptococcus neoformans disrupts the transcriptome profile of M1- and M2-polarized host macrophages. PloS One. 15(8):e0233818. doi: 10.1371/journal.pone.0233818

Tucker, J.S., Guess, T.E. and McClelland, E.E. 2020. The Role of Testosterone and Gibberellic Acid in the Melanization of Cryptococcus neoformans. Frontiers in Microbiology. Aug 13; 11:1921: doi.org/10.3389/fmicb.2020.01921.

Guess, T., Rosen, J., Castro-Lopez, N., Wormley, F.L. and McClelland, E.E. 2019. An inherent immune deficit in healthy males to C. neoformans infection may begin to explain gender gap in incidence of cryptococcosis. Biology of Sex Differences. Sep 2;10(1):44.

Guess, T.E., Rosen, J.A., McClelland, E.E. 2018. An Overview of Sex Bias in C. neoformans Infections. J Fungi (Basel). 2018 Apr 18;4(2). pii: E49. doi: 10.3390/jof4020049

Hayes J.B., Sircy, L.M., Heusinkveld, L.E., Ding, W., Leander, R.N., McClelland, E.E.* and Nelson, D.E.* 2016. Modulation of Macrophage Inflammatory Nuclear Factor κB (NF-κB) Signaling by Intracellular Cryptococcus neoformans. J Biol Chem.; 291(30): 15614-27. * Joint corresponding authors

McClelland, E.E., Hobbs, L.M., Rivera, J., Casadevall, A., Potts, W.K., Smith, J.M. and Ory, J.J. 2013. The Role of Host Gender in the Pathogenesis of Cryptococcus neoformans Infections. PLoS ONE 8(5): e63632.

McClelland, E.E. and Smith, J.M. 2011. Gender specific differences in the immune response to infection. Arch Immunol Ther Exp (Warsz). Jun;59(3):203-13.

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