Perspective

Across the globe, fungal infections are a significant cause of human morbidity and mortality, with disease manifestations ranging from cutaneous to systemic dissemination^1,2. Furthermore, fungal infections have been increasing at such rapid levels, the World Health Organization (WHO) has declared this a public health crisis³. In response to the crisis, the WHO published a list of 19 fungal pathogens that are considered high priority to bring attention to these historically neglected diseases based on multiple criteria including antifungal resistance, pathogen-associated deaths, lack of treatment options or inappropriate treatment, poor diagnostics, and annual incidence⁴. The fungal priority pathogens list includes Coccidioides immitis and C. posadasii (causative agents of Valley fever) both of which are highly pathogenic during infection.

In the United States, conservative estimates suggest that 150,000 people are infected with C. immitis and C. posadasiieach year, with approximately 22,000 cases reported each year in Arizona and California alone^5-7. In endemic and highly populated areas, such as Phoenix and Tucson, Arizona and the San Joaquin Valley in California, up to 30% of community acquired pneumonia may be attributed to Valley fever⁸. While the mechanisms that allow Valley fever to occur remain poorly understood, there are multiple factors associated with increased risk for infection, such as immune suppression or occupation (e.g. construction, farmwork, etc.). In particular, severe respiratory viral infections are becoming recognized as a risk factor for coinfections or secondary infections with other microbes, specifically fungi, and are often associated with high patient morbidity and mortality². The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has the potential to lead to more severe outcomes when coinfections occur with other established pathogens, such as endemic fungi. Coinfection may play an important and underexplored role in increasing morbidity and mortality of patients with COVID-19^9,10.

Research Summary

To examine the pathogenesis and immune response of a SARS-CoV-2/Coccidioides posadasii coinfection we established a model of sequential lung infections in transgenic K18-hACE2 mice. We observe higher morbidity and mortality in mice that are challenged with both the fungus and virus compared to mice that are challenged with either pathogen alone. We also find that the order in which the pathogens are introduced to the mice play an important role in both disease dynamics as well as immune responses, implying that different criteria may be required for diagnosis/treatment. Because SARS-CoV-2 is now endemic in the human population with new variants emerging frequently, and the increasing emergence of new viral pathogens or pandemic strains (influenza), this data provides the groundwork for understanding how viral coinfection with fungi can exacerbate disease progression. 

In conclusion, our study provides experimental evidence of differential disease outcomes in mice coinfected with SARS-CoV-2 and the fungal pathogen C. posadasii. Our study also provides a framework to examine viral/fungal co-infections in vivo with other pathogens. As fungal pathogens continue to become more prevalent as so will polymicrobial infections; therefore, understanding how these infections affect a host is imperative.

 References 

1          Brown, G. D. et al. Hidden killers: human fungal infections. Science translational medicine 4, 165rv113-165rv113 (2012).

2          Salazar, F., Bignell, E., Brown, G. D., Cook, P. C. & Warris, A. Pathogenesis of respiratory viral and fungal coinfections. Clinical Microbiology Reviews 35, e00094-00021 (2022).

3          Fisher, M. C. & Denning, D. W. The WHO fungal priority pathogens list as a game-changer. Nature Reviews Microbiology 21, 211-212 (2023).

4          Organization, W. H. WHO fungal priority pathogens list to guide research, development and public health action.  (World Health Organization, 2022).

5          Benedict, K. et al. Surveillance for Coccidioidomycosis - United States, 2011-2017. MMWR Surveill Summ 68, 1-15 (2019). https://doi.org:10.15585/mmwr.ss6807a1

6          Hector, R. F. et al. The public health impact of coccidioidomycosis in Arizona and California. International journal of environmental research and public health 8, 1150-1173 (2011).

7          McCotter, O. Z. et al. Update on the Epidemiology of coccidioidomycosis in the United States. Med Mycol 57, S30-S40 (2019). https://doi.org:10.1093/mmy/myy095

8          Valdivia, L. et al. Coccidioidomycosis as a common cause of community-acquired pneumonia. Emerging infectious diseases 12, 958 (2006).

9          Chen, Y.-Q. et al. Influenza infection in humans induces broadly cross-reactive and protective neuraminidase-reactive antibodies. Cell 173, 417-429. e410 (2018).

10        Krammer, F. & Palese, P. Influenza virus hemagglutinin stalk-based antibodies and vaccines. Current opinion in virology 3, 521-530 (2013).