Role of Neutrophils in IL-17–Dependent Immunity to Mucosal Candidiasis

Abstract

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 antibodies and subjected to OPC. These mice displayed increased oral fungal burdens compared to 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 antibodies exhibited a robust infiltrate of CD11b+Ly-6GlowF4/80− 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 antibody 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 IL-23/17 axis cause a potent but incomplete deficiency in the neutrophil response to oral candidiasis.

Vulvovaginal Candida albicans infections: pathogenesis, immunity and vaccine prospects

“…Recruitment of polymorphonuclear cells to the vagina, cytokine (particularly IL-1b and IL-18) production and activation of the lymphocyte subsets T-helper 1 and (with some controversy) T-helper 17 have been attributed a role in anti-Candida protection (Figure 2). [53][54][55][56][57] Notably, the same mechanisms, if inappropriately or excessively stimulated, cause damage through stimulation of an overwhelming inflammation, hence impairing the anti-Candida defense. 58 The vagina is also a special tolerogenic site as it must accept both constant (the vaginal microbiota) and occasional (semen and fetal) non-self-material.…”

Immunity against fungi

“…In C. albicans-infected kidneys, IL-17-dependent responses include activation of the kallikrein/kinin system, which prevents apoptosis of tubular cells (84). Neutrophil recruitment to infected oral tissues is complex, with reports of IL-17-dependent and -independent trafficking pathways (85,86). One IL-17-independent mechanism involves IL-1α/β-sensing oral keratinocytes that regulate neutrophil influx via CXC-chemokine release and indirect control over G-CSF-dependent granulopoiesis (87).…”

Control of Mucosal Candidiasis in the Zebrafish Swim Bladder Depends on Neutrophils That Block Filament Invasion and Drive Extracellular-Trap Production

“…To protect from mucosal invasion in OPC, neutrophils must be present in the blood, be recruited to the site of infection, and possess a fully functional antimicrobial arsenal (9)(10)(11)(12). Neutrophils attack both the yeast and filamentous forms of C. albicans and are associated with vulvovaginal candidiasis (13)(14)(15).…”