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Chemical Conjugation of a Purified DEC-205-Directed Antibody with Full-Length Protein for Targeting Mouse Dendritic Cells In Vitro and In Vivo
Published on: February 5, 2021
DECTIN-1 stalk length determines binding ability, immune response, and survival in a mouse model of
Daniel A Powell1,2, Lisa F Shubitz2, Christine D Butkiewicz2
1BIO5 Institute, University of Arizona, Tucson, AZ, United States.
Abstract:
Coccidioidomycosis is a leading cause of pneumonia in the endemic area of the Sonora desert and the central valley of California. The causative agent are the fungi Coccidioides immitis and C. posadasii. While most infections ultimately resolve without treatment, some infections spread to the periphery and cause serious and even fatal illness. Much work has shown that a T cell response with production of interleukin-17A and interferon ɣ is critical. Less work has focused on innate responses that ultimately set the stage for the adaptive response. Genetic analysis in both mice and man have shown an important role for DECTIN-1. DECTIN-1 is a C-type lectin receptor that recognizes β-glucans, the main cell wall component of many fungi. Initial recognition through DECTIN-1 modulates fungal binding, host cell uptake, and induces production of a number of cytokines and chemokines. C57BL/6 mice carry a point mutation altering splicing of exon 3, leading to a shorter DECTIN-1 protein lacking a portion of the extracellular stalk. We created mutant C57BL/6 mice to allowing expression of a long-stalk DECTIN-1 consistent with other mouse strains and humans. We directly examined the role of DECTIN-1 stalk length on resistance to infection with the β-glucan-dominant pathogen, C. posadasii. C57BL/6 mice expressing long-stalk DECTIN-1 bound more β-glucan per cell, produced more cytokines, and decreased mortality and dissemination after Coccidioides infection compared with wild-type littermates. The length of the DECTIN-1 stalk controls the outcome of Coccidiodes infection by differential binding and early production of protective cytokines.
Insights
Coccidioidomycosis, a fungal pneumonia, is better resisted when the DECTIN-1 receptor has a long stalk. This enhances fungal recognition, boosts protective cytokines, and reduces disease severity.
Area of Science:
- Immunology
- Mycology
- Infectious Diseases
Background:
- Coccidioidomycosis is a significant cause of pneumonia in endemic regions, caused by Coccidioides fungi.
- While T cell responses are crucial, innate immune responses, particularly involving DECTIN-1, are less understood.
- DECTIN-1, a receptor recognizing fungal beta-glucans, plays a role in modulating fungal interactions and host immune signaling.
Purpose of the Study:
- To investigate the role of DECTIN-1 stalk length in host resistance to Coccidioides posadasii infection.
- To compare the effects of short-stalk DECTIN-1 (found in C57BL/6 mice) versus long-stalk DECTIN-1 (found in other strains and humans).
Main Methods:
- Generated mutant C57BL/6 mice expressing long-stalk DECTIN-1.
- Infected mice with Coccidioides posadasii, a beta-glucan-rich fungus.
- Assessed fungal binding, cytokine production, mortality, and dissemination.
Main Results:
- Mice with long-stalk DECTIN-1 exhibited increased beta-glucan binding per cell.
- Long-stalk DECTIN-1 expression led to enhanced production of protective cytokines.
- These mice showed significantly decreased mortality and dissemination of the infection compared to wild-type littermates.
Conclusions:
- The length of the DECTIN-1 stalk is a critical factor in controlling the outcome of Coccidioidomycosis.
- Long-stalk DECTIN-1 promotes better fungal recognition and earlier cytokine responses, leading to improved host defense.
