Specific Human and Candida Cellular Interactions Lead to Controlled or Persistent Infection Outcomes during Granuloma-Like Formation

Abstract

A 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.

Proteomic Analysis of the Responses of Candida albicans during Infection of Galleria mellonella Larvae

“…By 24 h larvae were heavily infected with disseminated C. albicans as observed by extensive cuticular melanization and the appearance of large nodules throughout the host. A similar process has been documented in patients with chronic candidiasis where immune cells surround the pathogen and initiate an inflammatory response to prevent dissemination [29]. Dissection of nodules at 6 and 24 h revealed the presence of hyphae at 6 hour with the addition of yeast cells at 24 h (Figure 3).…”

The impact of the Fungus-Host-Microbiota interplay uponCandida albicansinfections: current knowledge and new perspectives

“…For instance, if primary immune cells from healthy immunocompetent individuals are challenged with C. albicans in vitro , different outcomes are observed due to variation in their immune cell populations (Misme-Aucouturier et al . 2017 ). This can arise through genetic variation at the CR1 locus, which encodes a master regulator of C. albicans -specific immune responses (Piasecka et al .…”

In vitro immune responses of human PBMCs against Candida albicans reveals fungal and leucocyte phenotypes associated with fungal persistence

“…Efforts need to be pursued in order to decipher the cellular mechanisms leading to an uncontrolled immune response that eventually oppose disease eradication.The capture of these dynamic and complex interactions strongly depends on the study design (cell line types, single vs. multicellular models, Candida species and time interaction). In our lab, we have developed an in vitro Candida-leucocyte co-culture model consisting of a delayed type of multicellular reaction after the challenge of human leucocytes by Candida species 29,30 . The analysis of the diversity of these immune responses is crucial to understand the pathophysiologic profiles implicated during fungal persistence.…”