期刊
JOURNAL OF IMMUNOLOGY
卷 192, 期 4, 页码 1745-1752出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1302265
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资金
- National Institutes of Health [DE022550, AI054624, F32-DE023293]
- Children's Hospital of Pittsburgh of UPMC Health System
- Pediatric Infectious Disease Society Fellowship Award
- Stanley A. Plotkin Sanofi Pasteur Fellowship Award
- Division of Rheumatology and Clinical Immunology, UPMC
Oropharyngeal candidiasis (OPC), caused by the commensal fungus Candida albicans, is an opportunistic infection associated with infancy, AIDS, and IL-17-related primary immunodeficiencies. The Th17-associated cytokines IL-23 and IL-17 are crucial for immunity to OPC, but the mechanisms by which they mediate immunity are poorly defined. IL-17RA-deficient humans and mice are strongly susceptible to OPC, with reduced levels of CXC chemokines and concomitantly impaired neutrophil recruitment to the oral mucosa. Paradoxically, humans with isolated neutropenia are typically not susceptible to candidiasis. To determine whether immunity to OPC is mediated via neutrophil recruitment, mice lacking CXCR2 were subjected to OPC and were found to be highly susceptible, although there was no dissemination of fungi to peripheral organs. To assess whether the entire neutrophil response is IL-17 dependent, IL-17RA(-/-) and IL-23(-/-) mice were administered neutrophil-depleting Abs and subjected to OPC. These mice displayed increased oral fungal burdens compared with IL-17RA(-/-) or IL-23(-/-) mice alone, indicating that additional IL-17-independent signals contribute to the neutrophil response. WT mice treated with anti-Gr-1 Abs exhibited a robust infiltrate of CD11b(+)Ly-6G(low)F4/80(-) cells to the oral mucosa but were nonetheless highly susceptible to OPC, indicating that this monocytic influx is insufficient for host defense. Surprisingly, Ly-6G Ab treatment did not induce the same strong susceptibility to OPC in WT mice. Thus, CXCR2(+) and Gr-1(+) neutrophils play a vital role in host defense against OPC. Moreover, defects in the IL23/17 axis cause a potent but incomplete deficiency in the neutrophil response to oral candidiasis.
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