title: 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.
authors.affiliation: Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, Western Australia, Australia; Centre for Experimental Immunology, Lions Eye Institute, Nedlands, Western Australia, Australia.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Wikstrom
authors.forename: Andrea
authors.initials: A
authors.lastname: Khong
authors.forename: Peter
authors.initials: P
authors.lastname: Fleming
authors.forename: Rachel
authors.initials: R
authors.lastname: Kuns
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hertzog
authors.forename: Ian H
authors.initials: IH
authors.lastname: Frazer
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Andoniou
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Hill
authors.forename: Mariapia A
authors.initials: MA
authors.lastname: Degli-Esposti
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D000950:Antigens, Ly / Q000276:immunology / Q000378:metabolism; D001853:Bone Marrow / Q000276:immunology / Q000378:metabolism / Q000821:virology; D039521:CD11c Antigen / Q000276:immunology / Q000378:metabolism; D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D019742:Chemokines, CC / Q000276:immunology / Q000378:metabolism; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D005260:Female; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D007370:Interferon Type I / Q000276:immunology / Q000378:metabolism; D007375:Interleukin-1 / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D037181:Lectins, C-Type / Q000276:immunology / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000276:immunology / Q000378:metabolism; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000821:virology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D014764:Viral Proteins / Q000276:immunology / Q000378:metabolism; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000950:Antigens, Ly; D039521:CD11c Antigen; D002352:Carrier Proteins; D019742:Chemokines, CC; D007370:Interferon Type I; D007375:Interleukin-1; D015850:Interleukin-6; D037181:Lectins, C-Type; D016173:Macrophage Colony-Stimulating Factor; D053594:Myeloid Differentiation Factor 88; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D016186:Receptor, Macrophage Colony-Stimulating Factor; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; D000099192:CD69 Antigens; C494192:Ly-6C antigen, mouse; C121663:MCK-2 protein, Mouse cytomegalovirus 1; C507780:Myd88 protein, mouse; C492716:Nlrp3 protein, mouse
keywords: bone marrow; cytokines; infectious diseases; innate immunity; monocytes