Impaired calcineurin signaling in myeloid cells results in downregulation of pentraxin-3 and increased susceptibility to aspergillosis.
Treatment of post-transplant patients with immunosuppressive drugs targeting the calcineurin-nuclear factor of activated T cells (NFAT) pathway, including cyclosporine A or tacrolimus, is commonly associated with a higher incidence of opportunistic infections, such as Aspergillus fumigatus, which can lead to severe life-threatening conditions. A component of the A. fumigatus cell wall, β-glucan, is recognized by dendritic cells (DCs) via the Dectin-1 receptor, triggering downstream signaling that leads to calcineurin-NFAT binding, NFAT translocation, and transcription of NFAT-regulated genes. Here, we address the question of whether calcineurin signaling in CD11c-expressing cells, such as DCs, has a specific role in the innate control of A. fumigatus. Impairment of calcineurin in CD11c-expressing cells (CD11ccrecnb1loxP) significantly increased susceptibility to systemic A. fumigatus infection and to intranasal infection in irradiated mice undergoing bone marrow transplant. Global expression profiling of bone marrow-derived DCs identified calcineurin-regulated processes in the immune response to infection, including expression of pentraxin-3, an important antifungal defense protein. These results suggest that calcineurin inhibition directly impairs important immunoprotective functions of myeloid cells, as shown by the higher susceptibility of CD11ccrecnbloxPmice in models of systemic and invasive pulmonary aspergillosis, including after allogeneic bone marrow transplantation. These findings are relevant to the clinical management of transplant patients with severe Aspergillus infections.
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.|Department of Experimental Medicine, University of Perugia, Perugia, Italy.
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Zelante
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.|National University of Singapore Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore.
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Wong
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.|Emerging Infectious Diseases Programme, Duke-NUS, Singapore.
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Mencarelli
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
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Foo
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
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Zolezzi
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
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Lee
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.|Department of Biological Sciences, National University of Singapore, Singapore.
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Poidinger
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.
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Ricciardi-Castagnoli
Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore.|Center for Translational Medicine, International Clinical Research Center, St Anne's University Hospital Brno, Brno, Czech Republic.
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D000818:Animals; D001228:Aspergillosis / Q000276:immunology*; D001232:Aspergillus fumigatus / Q000276:immunology*; D016026:Bone Marrow Transplantation; D002097:C-Reactive Protein / Q000235:genetics / Q000378:metabolism*; D039521:CD11c Antigen / Q000378:metabolism; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D065095:Calcineurin Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D004198:Disease Susceptibility; D015536:Down-Regulation; D006084:Graft Rejection / Q000517:prevention & control; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000683:Serum Amyloid P-Component / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000099153:Pentraxins
D002097:C-Reactive Protein; D039521:CD11c Antigen; D019703:Calcineurin; D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D000683:Serum Amyloid P-Component; D000099153:Pentraxins