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

Abstract

Although there is a growing understanding of immunity against Candida albicans, efforts need to be pursued in order to decipher the cellular mechanisms leading to an uncontrolled immune response that eventually oppose disease eradication. We describe here significant intra-and inter-subject variations in immune response patterns of major human leucocyte subsets following an in vitro challenge with C. albicans clinical isolates. We also observed that there are Candida isolate-dependent changes in leucocyte phenotypes. Through a combination of multiple fungal growth and flow cytometric measurements, coupled to the tSNE algorithm, we showed that significant proliferation differences exist among C. albicans isolates, leading to the calculation of a strain specific persistent index. Despite substantial inter-subject differences in T cells and stability of myeloid cells at baseline, our experimental approach highlights substantial immune cell composition changes and cytokine secretion profiles after C. albicans challenge. The significant secretion of IL-17 by CD66+ cells, ifn-γ and IL-10 by CD4+ t cells 2 days after C. albicans challenge was associated with fungal control. fungal persistence was associated with delayed secretion of ifn-γ, IL-17, IL-4, TNF-α and IL-10 by myeloid cells and IL-4 and TNF-α secretion by CD4+ and CD8+ t cells. overall, this experimental and analytical approach is available for the monitoring of such fungal and human immune responses.As a saprophytic organism, Candida albicans colonizes the human gastrointestinal, genitourinary and skin microbiota 1-3 . Healthy subjects conserve C. albicans in a commensal state through immune sensing, leading to the recognition of the fungus by specific receptors. The fungus co-exists with humans without causing damage, indicating the existence of evolutionary and adaptive fungal responses to immune mechanisms 3-6 . Despite human immune sensing, opportunistic invasive fungal infections (IFIs) due to C. albicans occur in patients with a diversity of immunological disorders and surrounded therapies 7-10 . These invasive infections represent an important public health challenge. Their incidence has been estimated to be between 1.5 to 8 per 100,000 global population, and their mortality rate remains very high (30-50%) [11][12][13] .A large amount of work has demonstrated that anti-fungal immunity requires the orchestration of innate immune responses followed by adaptive immune mechanisms [14][15][16][17][18][19] . Activation of innate monocytes and neutrophils depends on an adequate interaction with T lymphocytes 20 . C. albicans blastoconidia, hyphae and fungal antigens induce the recruitment of multiple immune cell populations around localized areas of infection. Candida infections could arise either from fungus-mediated damage or host-mediated immunity or both 21 . Hence, by initiating an inflammatory response, the delayed type of multicellular reaction during candidiasis could not only avoid fungal dissemination but also, in some cases, result in a deleteriou...

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