Importance of Interleukin-10 in Genetic Susceptibility of Mice to Coccidioides immitis

Abstract

Inbred strains of mice vary in their susceptibility to Coccidioides immitis. We infected resistant DBA/2 (D2) mice and three susceptible strains of mice (C57BL/6 [B6], BALB/c, and CAST/Ei) by intraperitoneal injection of arthroconidia and determined the severity of infection based on colony counts of fungus in the spleens and lungs 14 days after infection. We used quantitative reverse transcription-PCR to measure the amounts of cytokines made in the spleens and lungs of infected mice. Susceptible mice made 1,000-fold more interleukin-10 (IL-10) than resistant D2 mice and about 10-fold more IL-4. In contrast, D2 mice had more IL-12 p40 in their lungs than did B6 mice. Resistant and susceptible mice made equivalent amounts of gamma interferon, IL-6, and IL-2. In order to determine whether IL-10 adversely affected the response to C. immitis, we infected IL-10-deficient mice, and they were found to be as resistant as D2 mice. This result indicates that IL-10 plays a crucial role in determining susceptibility to C. immitis in inbred mice. Because IL-4 mRNA levels were higher in most strains of susceptible mice, we also infected IL-4-deficient B6 mice. They were more resistant than B6 controls but not as resistant as IL-10-deficient mice. Thus, both IL-10 and IL-4 adversely affect the ability of C57BL mice to resist infection with C. immitis, but IL-10 has a larger effect and is the cytokine that is consistently associated with susceptibility in all strains of inbred mice.Editor: T. R. Kozel

The Role of IL‐10 in Genetic Susceptibility to Coccidioidomycosis on Mice

“…2B). 8 We were able to confirm the discovery of Magee et al that susceptible mice make more IL-4, 9 but that difference was not as great as the difference in IL-10. We repeated this experiment, infecting the mice intra-nasally (i.n.…”

Experimental Animal Models of Coccidioidomycosis

“…IL-10 knockouts were more resistant to infection than were normal control mice. [49][50][51][52] More recently, dendritic cells and their involvement in the development of adaptive immunity have been examined, further indicating differences in Toll-like receptors (TLR)2 or TLR4 and IL-12 expression between DBA/2 and BALB/c mice and that transfected dendritic cells could be used to immunize naïve mice. 53,54 A major tenet of fungal immunology is that a protective adaptive response is due to T cells and specifically a Th1 response.…”

Vaccinated C57BL/6 Mice Develop Protective and Memory T Cell Responses to Coccidioides posadasii Infection in the Absence of Interleukin-10

“…IL-10 has a major impact on the regulation of inflammation during the course of a wide range of infectious diseases (reviewed in references 3 and 5). Extensive evidence supports the notion that persistently elevated IL-10 production during onset of coccidioidomycosis contributes to pathogen proliferation, dissemination, and disease severity (11)(12)(13)(14). Fierer and coworkers (13,14) re-ported that nonvaccinated, Coccidioides-challenged C57BL/6 mice produce higher amounts of IL-10 than resistant DBA2 mice during the early stage of pulmonary infection (10 to 16 days postchallenge) when the pathogen is tissue invasive and disseminates from the lungs to other body organs.…”

“…Extensive evidence supports the notion that persistently elevated IL-10 production during onset of coccidioidomycosis contributes to pathogen proliferation, dissemination, and disease severity (11)(12)(13)(14). Fierer and coworkers (13,14) re-ported that nonvaccinated, Coccidioides-challenged C57BL/6 mice produce higher amounts of IL-10 than resistant DBA2 mice during the early stage of pulmonary infection (10 to 16 days postchallenge) when the pathogen is tissue invasive and disseminates from the lungs to other body organs. To explore the effects of IL-10 on development of vaccine immunity to Coccidioides infection, we analyzed the kinetics of IL-10 secretion in the lungs of C57BL/6 mice that had been vaccinated with a protective live, attenuated ⌬T vaccine (31).…”

“…(6), Cryptococcus neoformans (7), Histoplasma capsulatum (8), Pneumocystis carinii (9), and Aspergillus fumigatus (10). A correlation has been revealed between susceptibility to Coccidioides infection and the amount of IL-10 produced (11)(12)(13)(14). Loss of IL-10 production significantly improves the outcome of coccidioidomycosis in nonvaccinated mice (12,13).…”