Abstract
ABSTRACTA delayed type of multicellular process could be crucial during chronic candidiasis in determining the course of infection. This reaction, consisting of organized immune cells surrounding the pathogen, initiates an inflammatory response to avoid fungal dissemination. The goal of the present study was to examine, at an in vitro cellular scale, Candida and human immune cell interaction dynamics during a long-term period. By challenging human peripheral blood immune cells from 10 healthy donors with 32 Candida albicans and non-albicans (C. glabrata, C. tropicalis, C. parapsilosis, C. dubliniensis, C. lusitaniae, C. krusei, and C. kefyr) clinical isolates, we showed that Candida spp. induced the formation of granuloma-like structures within 6 days after challenge, but their sizes and the respective fungal burdens differed according to the Candida species. These two parameters are positively correlated. Phenotypic characteristics, such as hypha formation and higher axenic growth rate, seem to contribute to yeast persistence within granuloma-like structures. We showed an interindividual variability of the human response against Candida spp. Higher proportions of neutrophils and elevated CD4+/CD8+ T cell ratios during the first days after challenge were correlated with early production of gamma interferon (IFN-γ) and associated with controlled infection. In contrast, the persistence of Candida could result from upregulation of proinflammatory cytokines such as interleukin-6 (IL-6), IFN-γ, and tumor necrosis factor alpha (TNF-α) and a poor anti-inflammatory negative feedback (IL-10). Importantly, regulatory subsets of NK cells and CD4lo CD8hi doubly positive (DP) lymphocytes at late stage infiltrate granuloma-like structures and could correlate with the IL-10 and TNF-α production. These data offer a base frame to explain cellular events that guide infection control or fungal persistence.
Highlights
A delayed type of multicellular process could be crucial during chronic candidiasis in determining the course of infection
We investigated the release of gamma interferon (IFN-␥), interleukin-10 (IL-10), IL-4, IL-6, IL-17A, IL-17F, and tumor necrosis factor alpha (TNF-␣)
The efficiency of human innate and adaptive immunity in controlling Candida infections is underscored by the wide range of Candida species, by their pathogenic adaptations, by the diversity of clinical manifestations and by the variety of pathophysiological niches [43]
Summary
A delayed type of multicellular process could be crucial during chronic candidiasis in determining the course of infection. By challenging human peripheral blood immune cells from 10 healthy donors with 32 Candida albicans and non-albicans (C. glabrata, C. tropicalis, C. parapsilosis, C. dubliniensis, C. lusitaniae, C. krusei, and C. kefyr) clinical isolates, we showed that Candida spp. induced the formation of granuloma-like structures within 6 days after challenge, but their sizes and the respective fungal burdens differed according to the Candida species Hepatic lesions are usually characterized by areas of central necrosis or fibrosis, surrounded by granulation tissue, macrophages, fibroblasts, and multinuclear giant cells [27] While these delayed multicellular reactions are clinically rare during candidiasis, they could play a role in controlling infection at local tissue levels. A better dissection of these reactions could allow the identification of fungal and human determinants of clearance or persistence
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