Abstract
As TLRs are expressed by haematopoietic stem and progenitor cells (HSPCs), these receptors may play a role in haematopoiesis in response to pathogens during infection. We have previously demonstrated that in in vitro defined conditions inactivated yeasts and hyphae of Candida albicans induce HSPCs proliferation and differentiation towards the myeloid lineage by a TLR2/MyD88 dependent pathway. In this work, we showed that C. albicans invasive infection with a low virulence strain results in a rapid expansion of HSPCs (identified as LKS cells: Lin− c-Kit+ Sca-1+ IL-7Rα−), that reach the maximum at day 3 post-infection. This in vivo expansion of LKS cells in TLR2−/− mice was delayed until day 7 post- infection. Candidiasis was, as expected, accompanied by an increase in granulopoiesis and decreased lymphopoiesis in the bone marrow. These changes were more pronounced in TLR2−/− mice correlating with their higher fungal burden. Accordingly, emigration of Ly6Chigh monocytes and neutrophils to spleen was increased in TLR2−/− mice, although the increase in macrophages and inflammatory macrophages was completely dependent on TLR2. Similarly, we detected for the first time, in the spleen of C. albicans infected control mice, a newly generated population of dendritic cells that have the phenotype of monocyte derived dendritic cells (moDCs) that were not generated in TLR2−/− infected mice. In addition, C. albicans signalling through TLR2/MyD88 and Dectin-1 promotes in vitro the differentiation of Lin− cells towards moDCs that secrete TNF-α and are able to kill the microorganism. Therefore, our results indicate that during infection C. albicans can directly stimulate progenitor cells through TLR2 and Dectin-1 to generate newly formed inflammatory macrophages and moDCs that may fulfill an essential role in defense mechanisms against the pathogen.
Highlights
Toll-like receptors (TLRs) constitute a family of patternrecognition receptors (PRRs) that recognize molecular signatures of microbial pathogens and function as sensors of infection that induce the activation of the innate immune responses as well as the subsequent development of adaptive immune responses [1]
When TLR22/2 and C57BL/6 mice were intravenously infected with 1.56106 yeasts, it was found that fungal cells are able to reach the bone marrow and the amount of yeasts recovered from this site at day 3 post-infection was roughly 6000 colony-forming units (CFUs) per animal
For the first time, that highly purified stem and progenitor cells directly responded to a microorganism such as C. albicans through TLR2/ myeloid differentiation factor 88 (MyD88) under defined conditions of culture [18,19]
Summary
Toll-like receptors (TLRs) constitute a family of patternrecognition receptors (PRRs) that recognize molecular signatures of microbial pathogens (microbial associated molecular patterns: MAMPs) and function as sensors of infection that induce the activation of the innate immune responses as well as the subsequent development of adaptive immune responses [1]. Murine haematopoietic stem cells (HSCs) and their progeny express TLRs, and upon in vitro exposure to soluble TLR ligands are stimulated to enter cell cycle and acquire lineage markers [3]; signalling through TLR7/8 induces the differentiation of human bone marrow CD34+ progenitor cells along the myeloid lineage [4], and the TLR1/2 agonist Pam3CSK4 instructs commitment of human HSCs to a myeloid cell fate [5] This new mechanism, that represents a potential means for pathogen products to signal the rapid generation of innate immune cells, has been explored in some in vivo infectious models showing that: (i) murine lymphoid precursors are directed to produce dendritic cells as a result of TLR9 ligation during herpes infection [6], (ii) vaccinia virus infection results in the expansion of HSCs in a myeloid differentiation factor 88 (MyD88)-dependent manner [7] and (iii) TLR-mediated signals play an essential role in the monocyte expansion during Listeria monocytogenes systemic infection [8]. Dectin-1 is a phagocytic receptor that recognizes bglucan in the cell wall of C. albicans, and collaborates with TLR2 in the elicitation of proinflammatory cytokines [16]
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