Distinct organ-dependent mechanisms for the control of murine cytomegalovirus infection by natural killer cells

Abstract

Antiviral mechanisms by which natural killer (NK) cells control murine cytomegalovirus (MCMV) infection in the spleens and livers of C57BL/6 mice were measured, revealing different mechanisms of control in different organs. Three days postinfection, MCMV titers in the spleens of perforin 0/0 mice were higher than in those of perforin ؉/؉ mice, but no elevation of liver titers was found in perforin 0/0 mice. NK cell depletion in MCMV-infected perforin 0/0 mice resulted only in an increase in liver viral titers and not in spleen titers. Depletion of gamma interferon (IFN-␥) in C57BL/6 mice by injections with monoclonal antibodies to IFN-␥ resulted in an increase of viral titers in the liver but not in the spleen. Analyses using IFN-␥-receptor-deficient mice, rendered chimeric with C57BL/6 bone marrow cells, indicated that in a recipient environment where IFN-␥ cannot exert its effects, the depletion of NK cells caused an increase in MCMV titers in the spleens but had little effect in the liver. IFN-␥ has the ability to induce a variety of cells to produce nitric oxide, and administrating the nitric oxide synthase inhibitor N-monomethyl-L-arginine into MCMV-infected C57BL/6 mice resulted in MCMV titer increases in the liver but not in the spleen. Taken together, these data suggest that in C57BL/6 mice, there is a dichotomy in the mechanisms utilized by NK cells in the regulation of MCMV in different organs. In the spleen NK cells exert their effects in a perforin-dependent manner, suggesting a cytotoxic mechanism, while in the liver the production of IFN-␥ by NK cells may be a predominant mechanism in the regulation of MCMV synthesis. These results may explain why the Cmv-1 r locus, which maps closely to genes regulating NK cell cytotoxic function, confers an NK cell-dependent resistance to MCMV infection in the spleen but not in the liver.

CXC Chemokine Ligand 10 Controls Viral Infection in the Central Nervous System: Evidence for a Role in Innate Immune Response through Recruitment and Activation of Natural Killer Cells

“…Moreover, the organs targeted by viral infection can also influence the participation of NK cells. Indeed, Tay et al (35) demonstrated that the NK response to murine cytomegalovirus is perforin dependent within the spleen, whereas production of IFN-␥ is required for viral clearance from the liver. These results indicate that the importance of the NK cell response to viral infection can depend upon multiple factors, including the tissue infected as well as the effector mechanisms induced.…”

UNC93B1 Mediates Innate Inflammation and Antiviral Defense in the Liver during Acute Murine Cytomegalovirus Infection

“…2D). NK cells are an important early source of IFNc in the liver during MCMV infection [24,25], and accumulated at this site in both WT and 3d mice ( Fig. 2E).…”

“…Early type I IFN signaling is necessary for NK cell recruitment to the liver, where they deliver the antiviral cytokine IFN-c within the first 48 h post-MCMV infection [23]. The NK cell IFN-c response is an important early step in the control of liver infection [24,25]. This response induces IFN-c-dependent chemokines, which contribute to the recruitment of CD8+ T cells to the liver [26].…”

Natural killer cells as an initial defense against pathogens

“…Natural killer cell antiviral effector mechanisms NK cells use two main effector mechanisms to control MCMV infection: the secretion of IFN-g and direct lysis of infected cells by exocytosis of granules that contain perforin and granzymes. Using mice deficient in perforin or IFN-g and mice depleted of IFN-g by antibody, organspecific control of MCMV infection by NK cells was observed: perforin mediated viral clearance in the spleen and IFN-g mediated protection in the liver [8]. A recent study re-evaluated the importance of these two effector mechanisms during MCMV infection and found that mice deficient in perforin or IFN-g had elevated viral Table 1 NK cells in immunity to pathogens.…”

“…Viruses MCMV TLR9 and MyD88 activation of DC-induced IFN-a and IL-12 production; this leads to NK cell IFN-g production and cytotoxicity [4,5,6 ,7 ] Perforin and IFN-g generation by NK cells limits viral replication in the spleen and liver [8,9] MCMV m157 binds Ly49H, induces NK cell IFN-g, MIP-1a, MIP-1b, RANTES and ATAC, and controls MCMV in C57BL/6 mice [17,18,19,20 ] NK cells mediate resistance in NZW mice by multiple gene products [21] NK cells protect MA/My mice from infection; Ly49P recognizes H-2Dk-restricted ligand in MCMV-infected cells [22 ,23 ] KLRG1 + NK cells expand and contract in response to infection [26] HCMV NK cell IFN-g, LTa/b and TNF induce IFN-b from infected cells and inhibit HCMV replication [10] A truncated form of MICA escapes HCMV down-regulation and activates NK cell NKG2D [13] CD94-NKG2C + NK cells preferentially expand in response to infected fibroblasts [25] Sendai virus Viral infection induces IFN-a and MICB gene transcription; this leads to NK cell IFN-g production [11] Influenza A virus Viral infection induces IFN-a and MICB gene transcription; this leads to NK cell IFN-g production [11] HIV Neonatal NK cells suppress replication of CCR5-trophic viruses [29] NK cells from viremic patients produce more IFN-g and TNF-a than NK cells from aviremic patients [30] MHV NK cell recruited to the CNS after intracerebral MHV infection enhance survival and decrease viral titers [33] Ebola titers in the spleen and the liver three days post-infection compared with wild-type C57BL/6 mice [9]. By six days post-infection, viral titers in the spleens and livers of perforin-deficient mice remained higher than those of wild-type mice, whereas viral titers in IFN-g-deficient mice were higher only in the livers [9].…”