Genetic and Other Determinants for the Severity of Coccidioidomycosis: A Clinician's Perspective

Abstract

The endemic fungal infection, coccidioidomycosis, occurs after inhalation of one or very few Coccidioides spp. spores. Infections produce diverse clinical manifestations, ranging from insignificant to extremely destructive, even fatal. Approaches to understanding this range of consequences have traditionally categorized patients into a small number of groups (asymptomatic, uncomplicated self-limited, fibro-cavitary, and extra-thoracic disseminated) and then looked for immunologic differences among them. Recently, variants within genes of innate pathways have been found to account, in part, for infections that result in disseminated disease. This discovery raises the very attractive theory that, in patients without severe immunosuppression, much of the disease spectrum can be accounted for by various combinations of such deleterious variants in innate pathways. In this review, we summarize what is known about genetic determinants that are responsible for the severity of coccidioidal infections and how complex innate genetic differences among different people might account for the spectrum of disease observed clinically.

Keywords: coccidioidomycosis; fungal infections; genetic variants; human disease; immunity; mice; pathogenesis.

Figure 1

Estimated annual United States cases of coccidioidomycosis with different forms of illness. Percentages with and without dissemination extrapolated from [20].

Figure 2

Differential responses to coccidioidal infection in mice. C57BL/6 mice are highly sensitive to coccidioidal infection and possess Dectin-1, which encodes a short stalk. DBA-2 mice are resistant to coccidioidal infection and possess Dectin-1 which encodes a long stalk. Expression of pro-inflammatory cytokines from immune cells stimulated by Coccidioides spp. differs between the two inbred strains of mice. The cytokine differences listed have been observed experimentally and are not the exclusive source of the cells listed. Illustration by Nicole Wolf, MS, ©2023.

Figure 3

The range of clinical manifestations of human coccidioidomycosis and their overall frequency of occurance in relation to common durations of illness and severity and the several genetic variants associated with each. Created in BioRender.