The endozoan, small-mammal reservoir hypothesis and the life cycle of Coccidioides species

Abstract

The prevailing hypothesis concerning the ecology of Coccidioides immitis and C. posadasii is that these human pathogenic fungi are soil fungi endemic to hot, dry, salty regions of the New World and that humans and the local, small-mammal fauna are only accidental hosts. Here we advance an alternative hypothesis that Coccidioides spp. live in small mammals as endozoans, which are kept inactive but alive in host granulomas and which transform into spore-producing hyphae when the mammal dies. The endozoan hypothesis incorporates results from comparative genomic analyses of Coccidioides spp. and related taxa that have shown a reduction in gene families associated with deconstruction of plant cell walls and an increase in those associated with digestion of animal protein, consistent with an evolutionary shift in substrate from plants to animals. If true, the endozoan hypothesis requires that models of the prevalence of human coccidioidomycosis account not only for direct effects of climate and soil parameters on the growth and reproduction of Coccidioides spp. but also consider indirect effects on these fungi that come from the plants that support the growth and reproduction of the small mammals that, in turn, support these endozoic fungi.

Figure 1.

Endozoan-based Life cycle of Coccidioides species. Beginning at the asterisk (*), arthroconidia travel from the hyphae that produced them short distances among small mammals in burrows, or longer distances above ground, to be inhaled by uninfected animals. In the lungs, the arthroconidia convert to spherules and are either controlled by the host cell-mediated immune reaction or develop endospores, which disseminate to produce grave disease. The infected animal dies, either from disseminated coccidioidomycosis or from other causes and, in either case, living Coccidioides present in the animal, now freed from the action of the host immune system and living at lower temperatures, convert to hyphae. The hyphae grow through the dead animal and then produce abundant arthroconidia, which initiate a new cycle of life for the fungus. Photos: Living San Joaquin Pocket Mouse, Perognathus inornatus, Moose Petersen, http://www.mnh.si.edu/mna/images/images/san_joaquin_pocket_mouse_thumb.jpg ; Coccidioides spherules and endospores, Dr. Edward Klatt, WebPath's Internet Pathology Laboratory for Medical Education; Granuloma constraining Coccidioides; Dead Perognathus longimembris, Little Pocket Mouse, Jonah Evans, Texas Parks and Wildlife Department, http://www.inaturalist.org/photos/407437. This Figure is reproduced in color in the online version of Medical Mycology.

Figure 2.

Modern, medical life cycle of Coccidioides species. In the environment, Coccidioides is thought to grow as a septate mycelium, and every other cell will mature into arthroconidia. Arthroconidia of both Coccidioides immitis and C. posadasii shift into a parasitic spherule cycle in a susceptible host. It has been observed that spherules become mature in 5–10 days, although exact timing is dependent on complex host-pathogen interactions. The mature spherule is an encasement for uninucleate endospores, which are released if rupture occurs. The 1–3 μM diameter endospores can remain in the lung tissue, or disseminate to multiple body sites including liver, spleen, lymph nodes, meninges, joints, and bones. Mycelia can be cultured easily from these infected tissues or fluids. Image used under Creative Commons License. This Figure is reproduced in color in the online version of Medical Mycology.

Figure 3.

Effects of the physical environment on plants, animals and Coccidioides species. Environmental parameters of temperature, moisture and soil composition have a direct effect on Coccidioides fungi but also have indirect effects on the growth of plants that feed the small mammals and on the small mammals that provide nutrition for the fungi. Given that Coccidioides species evolved to live on animal protein and then lost genes coding for enzymes used to digest plant cell walls, the indirect effects of the physical environment on plants and animals are likely to be greater than any direct effects on the fungi.