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Characterization of IL-22 and antimicrobial peptide production in mice protected against pulmonary Cryptococcus
Karen L Wozniak1,2, Camaron R Hole1,2, Junko Yano3,4
1The South Texas Center for Emerging Infectious Diseases, The University of Texas at San Antonio, San Antonio, TX, USA.
Abstract:
Cryptococcus neoformans is a significant cause of fungal meningitis in patients with impaired T cell-mediated immunity (CMI). Experimental pulmonary infection with a C. neoformans strain engineered to produce IFN-γ, H99γ, results in the induction of Th1-type CMI, resolution of the acute infection, and protection against challenge with WT Cryptococcus. Given that individuals with suppressed CMI are highly susceptible to pulmonary C. neoformans infection, we sought to determine whether antimicrobial peptides were produced in mice inoculated with H99γ. Thus, we measured levels of antimicrobial peptides lipocalin-2, S100A8, S100A9, calprotectin (S100A8/A9 heterodimer), serum amyloid A-3 (SAA3), and their putative receptors Toll-like receptor 4 (TLR4) and the receptor for advanced glycation end products (RAGE) in mice during primary and recall responses against C. neoformans infection. Results showed increased levels of IL-17A and IL-22, cytokines known to modulate antimicrobial peptide production. We also observed increased levels of lipocalin-2, S100A8, S100A9 and SAA3 as well as TLR4(+) and RAGE(+) macrophages and dendritic cells in mice inoculated with H99γ compared with WT H99. Similar results were observed in the lungs of H99γ-immunized, compared with heat-killed C. neoformans-immunized, mice following challenge with WT yeast. However, IL-22-deficient mice inoculated with H99γ demonstrated antimicrobial peptide production and no change in survival rates compared with WT mice. These studies demonstrate that protection against cryptococcosis is associated with increased production of antimicrobial peptides in the lungs of protected mice that are not solely in response to IL-17A and IL-22 production and may be coincidental rather than functional.
Insights
Protection against Cryptococcus neoformans lung infection involves increased antimicrobial peptides, but this response may not be solely due to IL-17A and IL-22 and might be coincidental rather than functional.
Area of Science:
- Immunology
- Mycology
- Infectious Diseases
Background:
- Cryptococcus neoformans causes fungal meningitis in immunocompromised individuals.
- T cell-mediated immunity (CMI) is crucial for controlling C. neoformans.
- Experimental C. neoformans infection with IFN-γ-producing strain (H99γ) induces protective Th1-type CMI.
Purpose of the Study:
- To investigate antimicrobial peptide (AMP) production in mice infected with H99γ.
- To determine the role of IL-17A and IL-22 in AMP production and protection against cryptococcosis.
Main Methods:
- Mice were inoculated with H99γ or wild-type (WT) C. neoformans.
- Levels of AMPs (lipocalin-2, S100A8, S100A9, SAA3) and their receptors (TLR4, RAGE) were measured.
- Cytokine levels (IL-17A, IL-22) were assessed.
- IL-22-deficient mice were used to evaluate the role of IL-22.
Main Results:
- H99γ infection increased IL-17A and IL-22 levels.
- Increased lipocalin-2, S100A8, S100A9, and SAA3 were observed in H99γ-infected mice.
- Macrophages and dendritic cells expressing TLR4 and RAGE were elevated.
- IL-22-deficient mice showed AMP production but no change in survival compared to WT mice.
Conclusions:
- Protection against cryptococcosis is linked to increased pulmonary AMP production.
- AMP production is not solely dependent on IL-17A and IL-22.
- The observed AMP response may be coincidental rather than functionally protective.
