Innate cells and STAT1-dependent signals orchestrate vaccine-induced protection against invasive Cryptococcus infection.

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  • Additional Information
    • Source:
      Publisher: American Society for Microbiology Country of Publication: United States NLM ID: 101519231 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2150-7511 (Electronic) NLM ISO Abbreviation: mBio Subsets: MEDLINE
    • Publication Information:
      Original Publication: Washington, D.C. : American Society for Microbiology
    • Subject Terms:
      Cryptococcosis*/immunology ; Cryptococcosis*/prevention & control ; Cryptococcosis*/microbiology ; Fungal Vaccines*/immunology ; Fungal Vaccines*/administration & dosage ; Cryptococcus neoformans*/immunology ; Cryptococcus neoformans*/genetics ; STAT1 Transcription Factor*/genetics ; STAT1 Transcription Factor*/metabolism ; STAT1 Transcription Factor*/immunology ; Immunity, Innate* ; Interferon-gamma*/immunology ; Interferon-gamma*/metabolism ; Mice, Inbred C57BL* ; Monocytes*/immunology; Animals ; Mice ; Mice, Knockout ; Female ; Neutrophils/immunology ; Dendritic Cells/immunology
    • Abstract:
      Fungal pathogens are underappreciated causes of significant morbidity and mortality worldwide. In previous studies, we determined that a heat-killed, Cryptococcus neoformans fbp1-deficient strain (HK-fbp1) is a potent vaccine candidate. We determined that vaccination with HK-fbp1 confers protective immunity against lethal Cryptococcosis in an interferon γ (IFNγ)-dependent manner. In this study, we set out to uncover cellular sources and relevant targets of the protective effects of IFNγ in response to the HK-fbp1 vaccine. We found that early IFNγ production peaks at day 3 and that monocytes and neutrophils are important sources of this cytokine after vaccination. Neutralization of IFNγ at day 3 results in impaired CCR2 + monocyte recruitment and reduced differentiation into monocyte-derived dendritic cells (Mo-DC). In turn, depletion of CCR2 + cells prior to immunization results in impaired activation of IFNγ-producing CD4 and CD8 T cells. Thus, monocytes are important targets of innate IFNγ and help promote further IFNγ production by lymphocytes. We employed monocyte-fate mapper and conditional STAT1 knockout mice to uncover that STAT1 activation in CD11c + cells, including alveolar macrophages, Mo-DCs, and monocyte-derived macrophages (Mo-Mac) is essential for HK-fbp1 vaccine-induced protection. Altogether, our aggregate findings suggest critical roles for innate cells as orchestrators of vaccine-induced protection against Cryptococcus infection.IMPORTANCEThe number of patients susceptible to invasive fungal infections across the world continues to rise at an alarming pace yet current antifungal drugs are often inadequate. Immune-based interventions and novel antifungal vaccines hold the promise of significantly improving patient outcomes. In previous studies, we identified a Cryptococcus neoformans mutant strain (Fbp1-deficient) as a potent, heat-inactivated vaccine candidate capable of inducing homologous and heterologous antifungal protection. In this study, we used a combination of methods together with a cohort of conditional knockout mouse strains to interrogate the roles of innate cells in the orchestration of vaccine-induced antifungal protection. We uncovered novel roles for neutrophils and monocytes as coordinators of a STAT1-dependent cascade of responses that mediate vaccine-induced protection against invasive cryptococcosis. This new knowledge will help guide the future development of much-needed antifungal vaccines.
      Competing Interests: The authors declare no conflict of interest.
    • Grant Information:
      R01 AI123315 United States AI NIAID NIH HHS; R01 AI141368 United States AI NIAID NIH HHS; R01 AI155647 United States AI NIAID NIH HHS; R01 AI169769 United States AI NIAID NIH HHS; R01AI141368-01A, R01 AI169769 HHS | National Institutes of Health (NIH)
    • Contributed Indexing:
      Keywords: Cryptococcus neoformans; antifungal therapy; immunization; innate immunity; monocytes; neutrophils
    • Accession Number:
      0 (Fungal Vaccines)
      0 (STAT1 Transcription Factor)
      82115-62-6 (Interferon-gamma)
      0 (Stat1 protein, mouse)
    • Publication Date:
      Date Created: 20240926 Date Completed: 20241019 Latest Revision: 20241019
    • Publication Date:
      20241019
    • Accession Number:
      PMC11481872
    • Accession Number:
      10.1128/mbio.01944-24
    • Accession Number:
      39324785