Developing a Coccidioides posadasii and SARS-CoV-2 Co-infection Model in the K18-hACE2 Transgenic Mouse

Abstract

Early reports showed that patients with COVID-19 had recrudescence of previously resolved coccidioidomycosis (Valley fever, VF), and there were indications that coinfection had more severe outcomes. We therefore investigated serial infection of Coccidioides posadasii and SARS-CoV-2 in a K18-hACE2 mouse model to assess disease outcomes. In our model, we challenged K18-hACE2 mice sequentially with a sub-lethal dose of SARS-CoV-2 and 24 hours later with low virulence strain of Coccidioides posadasii, and vice versa, compared to mice that only received a single infection challenge. We performed survival and pathogenesis mouse studies as well as looked at the systemic immune response differences between treatment groups. Here we show that co-infected groups have a more severe disease progression as well as a decrease in survival. Importantly, results differ depending on the SARS-CoV-2 variant (WA-1, Delta, or Omicron) and infection timing (SARS-CoV-2 first, C. posadasii second or vice versa). We find that groups that are infected with the virus first had a decrease in survival, increased morbidity and weight loss, increased fungal and viral burdens, differences in immune responses, and the amount and size of fungal spherules. We also find that groups coinfected with C. posadasii first have a decrease fungal burden and inflammatory responses. This is the first in vivo model investigation of a coinfection of SARS-CoV-2 and Coccidioides. Because of the potential for increased severity of disease in a coinfection, we suggest populations that live in areas of high coccidioidomycosis endemicity may experience higher incidence of complicated disease progression with COVID-19. The Covid-19 pandemic presented significant challenges to healthcare systems. One of these was the increase in secondary infections, where a patient had both SARS-Cov2 and another infectious disease. Fungal infections co-occurring with or after a Covid-19 infection are of interest due to treatment challenges and more severe illness in patients. Valley fever is a fungal infection prevalent in the southwestern United States and arid regions of Central and South America. Reports from these regions showed an increase in Valley fever cases coinciding with the rise of Covid-19. We therefore investigated how these two pathogens interacted with each other and the host in laboratory-controlled mouse experiments. We observed increased mortality when mice were exposed to the virus first followed by a fungal infection. Although more investigations are needed, our results should be taken into consideration in a clinical setting. Kollath et al. develop a murine model for testing the pathogenesis of a SARS-CoV-2 and Coccidioides posadasii co-infection and find that when mice are infected first with the virus, greater disease severity occurs. This has implications for people living in the endemic area for coccidioidomycosis as well as other emerging viruses.