Hematopoietic and nonhematopoietic cells promote Type I interferon‐ and TLR7‐dependent monocytosis during low‐dose LCMV infection

Abstract

Summary Release of inflammatory monocytes from the bone marrow (BM) into the blood is an important physiological response to infection, but the mechanisms regulating this phenomenon during viral infection are not completely defined. Here, we show that low-dose infection with Lymphocytic Choriomeningitis Virus (LCMV) caused rapid, transient inflammatory monocytosis that required type I IFN and TLR7 signaling. Both signals were critical for induction of IFN stimulated gene expression and CCR2 ligand upregulation in the BM microenvironment in response to LCMV infection. Experiments utilizing bone marrow chimeric mice demonstrated that type I IFN- and TLR7-signaling on either hematopoietic or non-hematopoietic cells was sufficient to initiate monocytosis in response to LCMV infection. BM plasmacytoid dendritic cells (pDC) generated type I IFN directly ex vivo, suggesting that pDC are a hematopoietic contributor of type I IFN in the BM early during LCMV infection. Overall, we describe novel roles for type I IFN and TLR7 signaling in non-hematopoietic cells and BM pDC in directing interferon stimulated gene and CCR2 ligand expression in the BM to initiate an increase in blood inflammatory monocytes during viral infection.

MicroRNA-22 controls interferon alpha production and erythroid maturation in response to infectious stress in mice

“…LCMV is a model pathogen that has been widely used to study interferon-mediated immune responses to viral infections 25, 26 . We found that following infection erythropoiesis was impaired in miR-22 KO animals while megakaryopoiesis was enhanced, suggesting that miR-22 functions to control the balance of erythroid and megakaryocyte differentiation from their common precursor.…”

BCAP inhibits proliferation and differentiation of myeloid progenitors in the steady state and during demand situations

“…12,13 Lineage 2 BM cells were isolated using a Lineage Cell Depletion Kit (Miltenyi Biotec). Intracellular staining for BCAP was conducted by fixing lineage 2 BM cells with Cytofix/ Cytoperm buffer (BD Biosciences) and staining in Perm/Wash buffer (BD Biosciences).…”

“…Samples were prepared as previously described, 12,13 and SYBR green-based quantitative real-time polymerase chain reaction (qRT-PCR) was performed on an ABI 7500 Fast Real-Time PCR system (Applied Biosystems). Primer sequences are listed in supplemental Table 2.…”

Review of Mammarenavirus Biology and Replication

“…However, induction of this response did not result in decreased viral replication in brain cells. Old World LCMV has been shown to produce a TLR 7 and TLR 9 mediated Type I response ( Lee et al, 2009 ; Macal et al, 2012 ; Walsh et al, 2012 ; Buechler et al, 2015 ). A productive TLR 7 mediated response was also shown to be necessary for robust adaptive immune responses as well as monocyte recruitment ( Macal et al, 2012 ; Walsh et al, 2012 ).…”