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A Chronic Murine Disease Model of Coccidioidomycosis Using Coccidioides posadasii, Strain 1038
Lisa F Shubitz1, Daniel A Powell1,2, Christine D Butkiewicz1
1Valley Fever Center for Excellence, University of Arizona, Tucson, Arizona, USA.
Abstract:
Murine infections with most Coccidioides spp. strains are lethal by 3 weeks, limiting the study of immune responses. Coccidioides posadasii, strain 1038 (Cp1038), while slowly lethal, resulted in protracted survival of C57BL/6 (B6) mice. In resistant (B6D2)F1/J mice, lung fungal burdens stabilized by week 4 without progression through week 16, better modeling human coccidioidal infections after their immunologic control. Immunodeficient tumor necrosis factor (Tnf) α knockout (KO) and interferon (Ifn) γ receptor 1 (Ifn-γr1) KO mice survived a median of 22.5 and 34 days, compared with 70 days in B6 mice (P = .001 and P < .01, respectively), though 14-day lung fungal burden studies showed little difference between Ifn-γr1 KO and B6 mice. B6 mice showed peak concentrations of key inflammatory lung cytokines, including interleukin 6, 23, and 17A, Tnf-α, and Ifn-γ, only after 4 weeks of infection. The slower progression in B6 and the acquired fungal burden stability in B6D2 mice after Cp1038 infection greatly increases the array of possible immunologic studies.
Insights
Coccidioides posadasii strain 1038 allows for prolonged study of murine coccidioidomycosis, unlike rapidly lethal strains. This model enables research into immune responses and fungal burden control in mice.
Area of Science:
- Mycology
- Immunology
- Infectious Diseases
Background:
- Murine models of coccidioidomycosis are often limited by rapid lethality.
- Studying immune responses to Coccidioides spp. requires models with extended survival.
- Coccidioides posadasii strain 1038 (Cp1038) offers a unique, slowly lethal infection model in mice.
Purpose of the Study:
- To characterize the host-pathogen dynamics of Cp1038 infection in different mouse strains.
- To evaluate the utility of Cp1038 as a model for studying immune responses in coccidioidomycosis.
- To investigate the role of tumor necrosis factor-alpha (Tnf-α) and interferon-gamma receptor 1 (Ifn-γr1) in controlling Cp1038 infection.
Main Methods:
- Infection of C57BL/6 (B6) and resistant (B6D2)F1/J mice with Cp1038.
- Assessment of survival rates in wild-type and immunodeficient (Tnf-α KO, Ifn-γr1 KO) mice.
- Quantification of lung fungal burden at various time points.
- Measurement of inflammatory lung cytokine concentrations (IL-6, IL-23, IL-17A, Tnf-α, Ifn-γ).
Main Results:
- Cp1038 infection resulted in protracted survival in B6 mice (median 70 days).
- Resistant B6D2 mice showed stabilized lung fungal burdens by week 4.
- Immunodeficient Tnf-α KO and Ifn-γr1 KO mice exhibited significantly reduced survival compared to B6 mice.
- Peak inflammatory cytokine levels in B6 mice were observed after 4 weeks of infection.
Conclusions:
- Cp1038 infection in B6 mice provides a valuable model for studying immune responses in coccidioidomycosis due to prolonged survival.
- The acquired stability of fungal burden in B6D2 mice offers a model for studying immunologic control of the infection.
- This model system expands research possibilities for coccidioidomycosis immunology.
