The early monocytic response to cytomegalovirus infection is MyD88 dependent but occurs independently of common inflammatory cytokine signals

Abstract

Cytomegalovirus latently infects myeloid cells; however, the acute effects of the virus on this cell subset are poorly characterised. We demonstrate that systemic cytomegalovirus infection induced rapid activation of monocytes in the bone marrow, characterised by upregulation of CD69, CD11c, Ly6C and M-CSF receptor. Activated bone marrow monocytes were more sensitive to M-CSF and less sensitive to granulocyte-monocyte colony stimulating factor in vitro, resulting in the generation of more macrophages and fewer dendritic cells, respectively. Monocyte activation was also observed in the periphery and resulted in significant accumulation of monocytes in the spleen. MyD88 expression was required within the haematopoietic compartment to initiate monocyte activation and recruitment. However, monocytes lacking MyD88 were activated and recruited in the presence of MyD88-sufficient cells in mixed bone marrow chimeras, indicating that once initiated, the process was MyD88 independent. Interestingly, we found that monocyte activation occurred in the absence of the common inflammatory cytokines, namely type I interferons (IFNs), IL-6, TNF-α and IL-1 as well as the NLRP3 inflammasome adaptor protein, ASC. We also excluded a role for the chemokine-like protein MCK-2 (m131/129) expressed by murine CMV. Taken together, these results challenge the notion that a single inflammatory cytokine mediates activation and recruitment of monocytes in response to infection.Keywords: bone marrow r cytokines r infectious diseases r innate immunity r monocytes IntroductionMonocytes and granulocytes serve as a front line defence against pathogens. These blood-borne cells are equipped with a battery of PRRs, secrete a range of cytokines and are capable of phagocytosis. In addition, monocytes and granulocytes are rapidly recruited to sites of infection and inflammation, where they contend with Correspondence: Prof. Mariapia A. Degli-Esposti e-mail: mariapia@lei.org.au the pathogen directly or differentiate into specialised cell types [1,2]. In this regard, monocytes have enormous potential since they are capable of differentiating into a variety of macrophages and dendritic cells that comprise the mononuclear phagocyte system [3][4][5].As our understanding of haematopoiesis has grown, we have also gained insights into the mechanisms that modulate this process. Early work with a variety of pathogens demonstrated infection can have profound effect on the bone marrow (BM) by favouring the production of some cell types, particularly myeloidwww.eji-journal.eu 410Matthew E. Wikstrom et al. Eur. J. Immunol. 2014. 44: 409-419 cells, while inducing the loss of others [6,7]. Similar effects were also observed for adjuvants [8], but it was not until the identification of toll-like receptors (TLRs) and other pathogen-sensing receptors in the BM that the capacity of progenitors to respond directly to infectious agents was appreciated [9]. At the same time, a growing understanding of cytokine and growth factor biology has given us insight into the indirec...

Role of G-CSF in monophosphoryl lipid A-mediated augmentation of neutrophil functions after burn injury

“…This is likely a result of concomitant recruitment of monocytes by MPLA. Our studies show that intraperitoneal treatment with MPLA potently induces the recruitment of monocytes into the peritoneal cavity (data not shown), and monocyte recruitment can occur independently of G-CSF [46,47]. In the context of a more progressive burn-wound infection, G-CSF was required for MPLA-mediated control of bacterial clearance and survival.…”

Tumor Necrosis Factor Alpha-Induced Recruitment of Inflammatory Mononuclear Cells Leads to Inflammation and Altered Brain Development in Murine Cytomegalovirus-Infected Newborn Mice

“…Findings from previous studies in WNV encephalitis models have also argued that infiltration of iMo into the brains of WNV-infected mice was dependent on CCR2/CCL2 monocytosis in peripheral blood and not secondary to CCR2/CCL2-driven recruitment of iMo to the infected brain (73,86). It is also of interest that MCMV infection of adult mice results in Myd88-dependent mobilization and activation of monocytes in the bone marrow and that, in contrast to type I IFNs, IL-6, or IL-1, TNF-␣ appeared to potentially have a direct role in mobilization and activation of monocytes from the bone marrow (87). Although our results are consistent with TNF-NAb inhibition of mobilization and activation of monocytes from the bone marrow and decreased blood and brain iMo, it is important to note that these observations were made in adult mice, in which the bone marrow is a major source of myeloid mononuclear cells.…”

Mck2-dependent infection of alveolar macrophages promotes replication of MCMV in nodular inflammatory foci of the neonatal lung

“…17,18,21 However, in a recent study a role of Mck2 for monocyte recruitment to the spleen has been questioned. 22 The recruitment of monocytes has additionally been implicated in interfering with CD8 þ T-cell immune response. 20,23 Thus, Mck2 is a well-established pathogenicity factor of MCMV, which, although not threatening the immunocompetent host's life, promotes viral dissemination to the salivary gland, the virus' favorite niche and important reservoir for transmission.…”