IFN-alphabeta-mediated inflammatory responses and antiviral defense in liver is TLR9-independent but MyD88-dependent during murine cytomegalovirus infection.
Chemokine responses critical for inflammation and promotion of effective innate control of murine CMV (MCMV) in liver have been shown to be dependent on immunoregulatory functions elicited by IFN-alphabeta. However, it remains to be determined whether upstream factors that promote viral sensing resulting in the rapid secretion of IFN-alphabeta in liver differ from those described in other tissues. Because plasmacytoid dendritic cells (pDCs) are known producers of high levels of systemic IFN-alpha in response to MCMV, this study examines the in vivo contribution of pDCs to IFN-alpha production in the liver, and whether production of the cytokine and ensuing inflammatory events are dependent on TLR9, MyD88, or both. We demonstrate that whereas MyD88 deficiency markedly impaired secretion of IFN-alpha, production of the cytokine was largely independent of TLR9 signaling, in the liver. MyD88 and TLR9 were needed for IFN-alpha production in the spleen. Moreover, hepatic but not splenic pDCs produced significant amounts of intracellular IFN-alpha in the absence of TLR9 function during infection. Furthermore, production of CCL2, CCL3, and IFN-gamma, as well as the accumulation of macrophages and NK cells, was not affected in the absence of functional TLR9 in the liver. In contrast, these responses were dramatically reduced in MyD88(-/-) mice. Additionally, MyD88(-/-) but not TLR9(-/-) mice exhibited increased sensitivity to virus infection in liver. Collectively, our results define contrasting compartmental functions for TLR9 and MyD88, and suggest that the infected tissue site uniquely contributes to the process of virus sensing and regulation of localized antiviral responses.
Hokeness-Antonelli
Kirsten L
KL
Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, Providence, RI 02912, USA.
Crane
Meredith J
MJ
Dragoi
Ana M
AM
Chu
Wen-Ming
WM
Salazar-Mather
Thais P
TP
D000818:Animals; D003586:Cytomegalovirus Infections / Q000235:genetics / Q000378:metabolism* / Q000821:virology*; D003713:Dendritic Cells / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D016898:Interferon-alpha / Q000096:biosynthesis; D016899:Interferon-beta / Q000096:biosynthesis; D008107:Liver Diseases / Q000378:metabolism* / Q000473:pathology / Q000821:virology*; D051379:Mice; D018345:Mice, Knockout; D018146:Muromegalovirus / Q000502:physiology*; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D016898:Interferon-alpha; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D016899:Interferon-beta