AUTHOR=Martínez Alba , Bono Cristina , Megías Javier , Yáñez Alberto , Gozalbo Daniel , Gil M. Luisa TITLE=Systemic Candidiasis and TLR2 Agonist Exposure Impact the Antifungal Response of Hematopoietic Stem and Progenitor Cells JOURNAL=Frontiers in Cellular and Infection Microbiology VOLUME=8 YEAR=2018 URL=https://www.frontiersin.org/journals/cellular-and-infection-microbiology/articles/10.3389/fcimb.2018.00309 DOI=10.3389/fcimb.2018.00309 ISSN=2235-2988 ABSTRACT=

We have previously demonstrated that Candida albicans induces differentiation of hematopoietic stem and progenitor cells (HSPCs) toward the myeloid lineage both in vitro and in vivo in a TLR2- and Dectin-1-dependent manner, giving rise to functional macrophages. In this work, we used an ex vivo model to investigate the functional consequences for macrophages derived from HSPCs in vivo-exposed to Pam₃CSK₄ (a TLR2 agonist) or C. albicans infection. Short in vivo treatment of mice with Pam₃CSK₄ results in a tolerized phenotype of ex vivo HSPC-derived macrophages, whereas an extended Pam₃CSK₄ treatment confers a trained phenotype. Early during candidiasis, HSPCs give rise to macrophages trained in their response to Pam₃CSK₄ and with an increased fungicidal activity; however, as the infection progresses to higher fungal burden, HSPC-derived macrophages become tolerized, while their fungicidal capacity is maintained. These results demonstrate that memory-like innate immune responses, already described for monocytes and macrophages, also take place in HSPCs. Interestingly, extended Pam₃CSK₄ treatment leads to an expansion of spleen HSPCs and myeloid cells, and drastically reduces the fungal burden in the kidney and spleen during systemic C. albicans infection. This protection against tissue invasion is abrogated by immunodepletion of HSPCs, suggesting their protective role against infection in this model. In addition, HSPCs produce in vitro cytokines and chemokines in response to C. albicans and Pam₃CSK₄, and these secretomes are capable of inducing myeloid differentiation of HSPCs and modulating peritoneal macrophage cytokine responses. Taken together, these data assign an active role for HSPCs in sensing pathogens during infection and in contributing to host protection by diverse mechanisms.