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Macrophage and Dendritic Cell Activation and Polarization in Response to Coccidioidesposadasii Infection
Anh L Diep1, Susana Tejeda-Garibay1, Nadia Miranda1
1Quantitative Systems Biology Graduate Programme, University of California Merced, Merced, CA 95343, USA.
Abstract:
Coccidioidomycosis is a fungal, respiratory disease caused by Coccidioides immitis and Coccidioides posadasii. The host immune responses that define disease outcome during infection are largely unknown, although T helper responses are required. Adaptive immunity is influenced by innate immunity as antigen-presenting cells activate and educate adaptive responses. Macrophage and dendritic cell (DC) recognition of pathogen surface molecules are critical for Coccidioides clearance. We characterize the broad innate immune responses to Coccidioides by analyzing macrophage and dendritic cell responses to Coccidioides arthroconidia using avirulent, vaccine Coccidioides strain NR-166 (Δcts2/Δard1/Δcts3), developed from parental virulent strain C735. We developed a novel flow cytometry-based method to analyze macrophage phagocytosis to complement traditional image-scoring methods. Our study found that macrophage polarization is blocked at M0 phase and activation reduced, while DCs polarize into proinflammatory DC1s, but not anti-inflammatory DC2, following interaction with Coccidioides. However, DCs exhibit a contact-dependent reduced activation to Coccidioides as defined by co-expression of MHC-II and CD86. In vivo, only modest DC1/DC2 recruitment and activation was observed with avirulent Coccidioides infection. In conclusion, the vaccine Coccidioides strain recruited a mixed DC population in vivo, while in vitro data suggest active innate immune cell inhibition by Coccidioides.
Insights
This study reveals that the vaccine strain of Coccidioides actively inhibits innate immune cells, blocking macrophage polarization and reducing dendritic cell activation, impacting host immune responses to fungal respiratory disease.
Area of Science:
- Immunology
- Mycology
- Infectious Diseases
Background:
- Coccidioidomycosis is a fungal respiratory disease caused by Coccidioides species.
- Host immune responses, particularly T helper cells, influence disease outcome, but innate immunity's role is not fully understood.
- Macrophage and dendritic cell (DC) recognition of Coccidioides is crucial for pathogen clearance.
Purpose of the Study:
- To characterize innate immune responses to Coccidioides.
- To analyze macrophage and dendritic cell responses to an avirulent Coccidioides vaccine strain (NR-166).
- To investigate Coccidioides's impact on innate immune cell activation and polarization.
Main Methods:
- Utilized an avirulent Coccidioides vaccine strain (NR-166) for in vitro and in vivo studies.
- Developed a novel flow cytometry method to assess macrophage phagocytosis.
- Analyzed macrophage and dendritic cell polarization and activation markers (e.g., MHC-II, CD86).
Main Results:
- Macrophage polarization was blocked at the M0 phase, with reduced activation.
- Dendritic cells (DCs) polarized into pro-inflammatory DC1s but not anti-inflammatory DC2s.
- DCs showed contact-dependent reduced activation, indicated by lower MHC-II and CD86 co-expression.
- In vivo, avirulent Coccidioides infection resulted in modest DC1/DC2 recruitment and activation.
Conclusions:
- The avirulent Coccidioides vaccine strain elicits a mixed dendritic cell population in vivo.
- In vitro findings suggest Coccidioides actively inhibits innate immune cell function.
- Understanding these interactions is key to developing effective strategies against coccidioidomycosis.
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