Myeloid Cells Restrict MCMV and Drive Stress-Induced Extramedullary Hematopoiesis through STAT1

Abstract

SUMMARY Cytomegalovirus (CMV) has a high prevalence worldwide, is often fatal for immunocompromised patients, and causes bone marrow suppression. Deficiency of signal transducer and activator of transcription 1 (STAT1) results in severely impaired antiviral immunity. We have used cell-type restricted deletion of Stat1 to determine the importance of myeloid cell activity for the defense against murine CMV (MCMV). We show that myeloid STAT1 limits MCMV burden and infection-associated pathology in the spleen but does not affect ultimate clearance of infection. Unexpectedly, we found an essential role of myeloid STAT1 in the induction of extramedullary hematopoiesis (EMH). The EMH-promoting function of STAT1 was not restricted to MCMV infection but was also observed during CpG oligodeoxynucleotide-induced sterile inflammation. Collectively, we provide genetic evidence that signaling through STAT1 in myeloid cells is required to restrict MCMV at early time points post-infection and to induce compensatory hematopoiesis in the spleen.

M-CSF induces a coordinated myeloid and NK cell differentiation program protecting against CMV after hematopoietic cell transplantation

“…This ambiguity might be dependent on the context of infection or on the specific monocyte subpopulation. Whereas Ly6C - CX3CR1 hi patrolling monocytes are involved in dissemination ( 32 ), Ly6C + CCR2 + inflammatory monocytes can engage antiviral responses in early infection via direct or indirect mechanisms ( 33, 34, 38, 80, 83 ). Ly6C + CCR2 + inflammatory monocytes could initiate differentiation of memory CD8 + T and NK cells into antimicrobial effector cells ( 33 ) or showed direct iNOS-mediated antiviral effects ( 34 ).…”

“…Interestingly, in the myeloid STAT1 deletion model, the ability to combat early MCMV infection correlated with the ability to mount extramedullary hematopoiesis ( 38 ). In this study we have specifically investigated the role of emergency hematopoiesis on MCMV infection under leukopenic conditions and report that M-CSF-induced myelopoiesis promotes rapid reconstitution of antiviral activity and protection from infection.…”

“…Culture models proved that the ability of macrophages to resist MCMV infection depends on signaling mechanisms via I-IFNs and type II IFNs (II-IFNs) (35)(36)(37), which might also be important in vivo. Myeloid-specific deletion of signal transducer and activator of transcription (STAT)1, a key transcription factor for mounting IFN responses, is also required for the early control of MCMV infection and spleen pathology but does not affect viral clearance (38). Hence, the role of myeloid cells in MCMV infection appears multifaceted and complex.…”

The Innate Immune Response to Infection Induces Erythropoietin-Dependent Replenishment of the Dendritic Cell Compartment

“…We observed an increase in TER119 + cells indicating the activation of extramedullary hematopoiesis, as was described after stimulation with TLR7 and TLR9 ligands as well as after infection with bacteria ( Salmonella spp ., Ehrlichia spp .) and virus (mouse cytomegalovirus) ( 19 , 21 – 23 , 38 – 40 ). Subsequently, we found that TER119 was also detectable on the surface of a small proportion of CD11c high cells.…”

“…Interestingly, inflammatory activation of the hematopoietic system is not limited to the bone marrow, but certain infections can induce the egress of early progenitor cells from the bone marrow to the spleen or expand spleen-resident progenitor cells to allow for extramedullary hematopoiesis ( 18 – 20 ). Extramedullary hematopoiesis critically depends on the presence of macrophages, on activation of pattern recognition receptors such as Toll-like Receptor 9 (TLR9), on MyD88/TRIF signaling and on STAT1 expression in myeloid cells, and is characterized by accumulation of TER119 + cells of the red blood cell lineage in the spleen ( 19 , 21 – 23 ). Of note, certain pathogens suppress extramedullary hematopoiesis as part of their immune evasion program ( 19 ), indicating an important role for this phenomenon in the innate immune defense.…”