Host response associated with dormant and persister cells of C. neoformans – VBNCrypto

Dormancy is one of the main features of Cryptococcus neoformans related to the natural history of cryptococcosis where a phase of latency of the disease have been described in the late 1990’s (Alanio et al JCI 2020). The phenotype associated with dormancy have been described in details as “viable but non culturable cells” (VBNC,Hommel et al. PLoS pathogens 2019). VBNCs are induced in vitro by nutrient and oxygen deprivation (HypNos protocol, Agrawal Meth Mol Biol 2024). VBNCs interacts with native macrophages through phagocytosis and then non-lytic exocytosis allowing VBNC to reactivate after this type of interactions. In addition, VBNCs does not promote increased immune response as expected upon BMDM interaction (de Castro et al. PLoS Pathogens 2023). In humans, in the frame of the Ambition study, we discovered that some cryptococcus cells recovered from the cerebrospinal fluid of patients with cryptococcosis harbored a VBNC phenotype as transcriptional activity was noticed but growth on agar plate was lacking (Mgangiwa et al. Lancet Microbe 2024). To go further in the understanding of the role of VBNC cells in vitro and in vivo, we propose to build a consortium of partners experts in Cryptococcus VBNC in vitro (Alexandre Alanio’s lab), in mice cryptococcosis (Carlos Taborda’s lab) and in human cryptococcosis (Gil Benard’s lab) focusing on the characterization of stress granules in VBNC and on the immune response and tissue damage associated with VBNC in mice together with the characterization of a subpopulation of VBNC cells in the CSF of patients with cryptococcosis.