Interleukin-8 Receptor 2 (IL-8R2)-Deficient Mice Are More Resistant to Pulmonary Coccidioidomycosis than Control Mice

The pathology of human coccidioidomycosis is granulomatous inflammation with many neutrophils surrounding ruptured spherules, but the chemotactic pathways that draw neutrophils into the infected tissues are not known. We previously showed that formalin-killed spherules (FKS) stimulate mouse macrophages to secret macrophage inflammatory protein 2 (MIP-2), which suggested that CXC ELR + chemokines might be involved in neutrophil recruitment in vivo. To test that hypothesis, we intranasally infected interleukin-8R2 (IL-8R2) (Cxcr2)-deficient mice on a BALB/c background with Coccidioides immitis RS. IL-8R2-deficient mice had fewer neutrophils in infected lungs than controls, but unexpectedly the IL-8R2-deficient mice had fewer organisms in their lungs than the control mice. Infected IL-8R2-deficient mouse lungs had higher expression of genes associated with lymphocyte activation, including the Th1 and Th17-related cytokines Ifn gamma and Il17a and the transcription factors Statl and Rorc. Additionally, bronchial alveolar lavage fluid from infected IL-8R2-deficient mice contained more IL-17A and interferon-gamma (IFN-gamma). We postulate that neutrophils in the lung directly or indirectly interfere with the development of a protective Th1/Th17 immune response to C. immitis at the site of infection.

Automated summary

IL-8R2-deficient mice infected with Coccidioides immitis show decreased neutrophils in the lungs, lower organism count, higher expression of genes associated with lymphocyte activation, and increased levels of IL-17A and IFN-γ in bronchial alveolar lavage fluid, suggesting a potential role of neutrophils in interfering with the protective Th1/Th17 immune response to the infection.