title: First human model of in vitro Candida albicans persistence within granuloma for the reliable study of host-fungi interactions.
abstract: BACKGROUND
  The balance between human innate immune system and Candida albicans virulence signaling mechanisms ultimately dictates the outcome of fungal invasiveness and its pathology. To better understand the pathophysiology and to identify fungal virulence-associated factors in the context of persistence in humans, complex models are indispensable. Although fungal virulence factors have been extensively studied in vitro and in vivo using different immune cell subsets and cell lines, it is unclear how C. albicans survives inside complex tissue granulomas.
  
  
  RESULTS
  We developed an original model of in vitro human granuloma, reproducing the natural granulomatous response to C. albicans. Persistent granulomas were obtained when the ratio of phagocytes to fungi was high. This in vitro fungal granuloma mimics natural granulomas, with infected macrophages surrounded by helper and cytotoxic T lymphocytes. A small proportion of granulomas exhibited C. albicans hyphae. Histological and time-lapse analysis showed that C. albicans blastoconidia were located within the granulomas before hyphae formation. Using staining techniques, fungal load calculations, as well as confocal and scanning electron microscopy, we describe the kinetics of fungal granuloma formation. We provide the first direct evidence that C. albicans are not eliminated by immunocompetent cells inside in vitro human granulomas. In fact, after an initial candicidal period, the remaining yeast proliferate and persist under very complex immune responses.
  
  
  CONCLUSIONS
  Using an original in vitro model of human fungal granuloma, we herein present the evidence that C. albicans persist and grow into immunocompetent granulomatous structures. These results will guide us towards a better understanding of fungal invasiveness and, henceforth, will also help in the development of better strategies for its control in human physiological conditions.
authors: Département de Parasitologie et de Mycologie Médicale, Université de Nantes, Nantes Atlantique Universités, EA1155- IICiMed, Faculté de Pharmacie de Nantes, France. nidia.alvarez-rueda@univ-nantes.fr
authors: Nidia
authors: N
authors: Alvarez-Rueda
authors: Marjorie
authors: M
authors: Albassier
authors: Sophie
authors: S
authors: Allain
authors: Florence
authors: F
authors: Deknuydt
authors: Frédéric
authors: F
authors: Altare
authors: Patrice
authors: P
authors: Le Pape
mesh_terms: D002176:Candida albicans / Q000166:cytology / Q000302:isolation & purification / Q000502:physiology* / Q000648:ultrastructure; D002449:Cell Aggregation; D018450:Disease Progression; D006099:Granuloma / Q000382:microbiology* / Q000473:pathology*; D006262:Health; D054884:Host-Pathogen Interactions; D006801:Humans; D016131:Lymphocyte Subsets / Q000382:microbiology / Q000473:pathology; D050296:Microbial Viability; D008954:Models, Biological; D009504:Neutrophils / Q000382:microbiology / Q000473:pathology; D014019:Tissue Donors