Vaccine Protection of Mice With Primary Immunodeficiencies Against Disseminated Coccidioidomycosis.

Daniel A. Powell,Jeffrey A. Frelinger,Christine D. Butkiewicz,Steven M. Holland,Lisa F. Shubitz,Amy P. Hsu,Hien T. Trinh,John N. Galgiani

doi:10.3389/fcimb.2021.790488

Abstract

Disseminated coccidioidomycosis (DCM), often a severe and refractory disease leading to poor outcomes, is a risk for people with certain primary immunodeficiencies (PID). Several DCM-associated PID (STAT4, STAT3, IFNγ, and Dectin-1) are modeled in mice. To determine if vaccination could provide these mice protection, mice with mutations in Stat4, Stat3, Ifngr1, Clec7a (Dectin-1), and Rag-1 (T- and B-cell deficient) knockout (KO) mice were vaccinated with the live, avirulent, Δcps1 vaccine strain and subsequently challenged intranasally with pathogenic Coccidioides posadasii Silveira strain. Two weeks post-infection, vaccinated mice of all strains except Rag-1 KO had significantly reduced lung and spleen fungal burdens (p<0.05) compared to unvaccinated control mice. Splenic dissemination was prevented in most vaccinated immunodeficient mice while all unvaccinated B6 mice and the Rag-1 KO mice displayed disseminated disease. The mitigation of DCM by Δcps1 vaccination in these mice suggests that it could also benefit humans with immunogenetic risks of severe disease.

Highlights

Coccidioidomycosis is a systemic fungal infection of the American southwest caused by the endemic fungi, Coccidioides immitis and C. posadasii
There were significant reductions in lung fungal burdens of the Stat4 KO, mut-Stat3, Ifngr KO, and Dectin-1 KO mice compared to the unvaccinated B6 mice (P
Vaccine Protection of Immunodeficient Mice B. This series of vaccination-challenge studies in mice with primary immunodeficiencies (PID) homologous to humans with Disseminated coccidioidomycosis (DCM) demonstrates that the avirulent Dcps1 vaccine induced some protection in all of them

Summary

Introduction

Coccidioidomycosis is a systemic fungal infection of the American southwest caused by the endemic fungi, Coccidioides immitis and C. posadasii. They are primary pathogens which cause disease in immunologically normal hosts (Nguyen et al, 2013). The consequences of infection, typically acquired by inhaling fungal spores in soil and air, range from asymptomatic in about 60% of people to a wide spectrum of clinical illness in the remainder (Drutz and Catanzaro, 1978; Nguyen et al, 2013). 1% of all infections result in progressive disease beyond the chest, a complication known as disseminated coccidioidomycosis (DCM) (Borchers and Gershwin, 2010; Odio et al, 2017). People with rare primary immunodeficiencies (PID) in a variety of signaling pathways, including

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Conclusion