<i>Ly49h</i>-Deficient C57BL/6 Mice: A New Mouse Cytomegalovirus-Susceptible Model Remains Resistant to Unrelated Pathogens Controlled by the NK Gene Complex

Fodil-Cornu, Nassima; Lee, Seung Hwan; Bélanger, Simon; Makrigiannis, Andrew P.; Biron, Christine A.; Buller, R. Mark; Vidal, Silvia M.

doi:10.4049/jimmunol.181.9.6394

Cited by 98 publications

(98 citation statements)

References 86 publications

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“…Collectively, these results indicate that relatively lower MTHFR levels are associated with an enhanced control of acute MCMV infection. Uncontrolled MCMV replication is usually accompanied by massive production of pro-inflammatory cytokines, such as IFNa, IFNg and interleukin-12, and loss of spleen cell populations, which together contribute to MCMV-mediated pathology 23,24 In fact, detrimental effects of high levels of IFNa during viral infection have been observed 25,26 Abundant levels of IFNa can compromise host immune responses by inhibiting the differentiation of dendritic cells or by leading to CD8 þ T cell attrition 25,26 In contrast, MCMV-resistant mice showing low viral load present limited production of pro-inflammatory cytokines and increased specific subpopulations of spleen cells in comparison with susceptible mice 24,27 Thus, we monitored serum levels of IFNs at 1.5 days p.i., the peak of cytokine production and spleen cell numbers at 3 days p.i., the peak of cell loss. Mthfr À/À and Mthfr þ /À mice had lower cytokine levels than their wild-type counterparts even though the differences did not reach significance (Figure 1b).…”

Section: Resultsmentioning

confidence: 99%

Methylenetetrahydrofolate reductase (MTHFR) deficiency enhances resistance against cytomegalovirus infection

Fodil-Cornu

Kozij

et al. 2009

Genes Immun

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Folates provide one-carbon units for nucleotide synthesis and methylation reactions. A common polymorphism in the MTHFR gene (677C-T) results in reduced enzymatic activity, and is associated with an increased risk for neural tube defects and cardiovascular disease. The high prevalence of this polymorphism suggests that it may have experienced a selective advantage under environmental pressure, possibly an infectious agent. To test the hypothesis that methylenetetrahydrofolate reductase (MTHFR) genotype influences the outcome of infectious disease, we examined the response of Mthfr-deficient mice against mouse cytomegalovirus (MCMV) infection. Acute MCMV infection of Mthfr À/À mice resulted in early control of cytokine secretion, decreased viral titer and preservation of spleen immune cells, in contrast to Mthfr wild-type littermates. The phenotype was abolished in MTHFR transgenic mice carrying an extra copy of the gene. Infection of primary fibroblasts with MCMV showed a decrease in viral replication and in the number of productively infected cells in Mthfr þ /À fibroblasts compared with wild-type cells. These results indicate that Mthfr deficiency protects against MCMV infection in vivo and in vitro, suggesting that human genetic variants may provide an advantage in the host response against certain pathogens.

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Section: Resultsmentioning

confidence: 99%

Methylenetetrahydrofolate reductase (MTHFR) deficiency enhances resistance against cytomegalovirus infection

Fodil-Cornu

Kozij

et al. 2009

Genes Immun

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“…Ly49H ϩ mice (C57BL/6, BALB.B6-Cmv1 r ) and Ly49H Ϫ mice (B6.Ly49h Ϫ/Ϫ [15], BALB/c, and 129/SvJ) were housed and bred under specific-pathogen-free conditions at the Central Animal Facility of the Medical Faculty, University of Rijeka, in accordance with the guidelines contained in the International Guiding Principles for Biomedical Research Involving Animals. The Ethical Committee at the University of Rijeka approved all animal experiments described in this paper.…”

Section: Methodsmentioning

confidence: 99%

“…It has been shown previously that MCMV infection induces high serum levels of IFN-␣, IL-12, and IFN-␥ in B6.Ly49h Ϫ/Ϫ mice on day 1.5 p.i. (15). Based on this finding and in an attempt to explain the enhanced CD8 ϩ T-cell response in mice infected with ⌬m157 MCMV, we assessed the levels of proinflammatory cytokines in sera of infected mice on days 1.5 and 4 p.i.…”

Section: Secretion Of Ifn-␣ and Other Proinflammatory Cytokines Corrementioning

confidence: 99%

The NK Cell Response to Mouse Cytomegalovirus Infection Affects the Level and Kinetics of the Early CD8⁺T-Cell Response

Mitrović

Arapović

Jordan

et al. 2012

J Virol

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115

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Natural killer (NK) cells and CD8 ؉ T cells play a prominent role in the clearance of mouse cytomegalovirus (MCMV) infection.The role of NK cells in modulating the CD8 ؉ T-cell response to MCMV infection is still the subject of intensive research. For analyzing the impact of NK cells on mounting of a CD8 ؉ T-cell response and the contribution of these cells to virus control during the first days postinfection (p.i.), we used C57BL/6 mice in which NK cells are specifically activated through the Ly49H receptor engaged by the MCMV-encoded ligand m157. Our results indicate that the requirement for CD8 ؉ T cells in early MCMV control inversely correlates with the engagement of Ly49H. While depletion of CD8 ؉ T cells has only a minor effect on the early control of wild-type MCMV, CD8 ؉ T cells are essential in the control of ⌬m157 virus. The frequencies of virus epitope-specific CD8 ؉ T cells and their activation status were higher in mice infected with ⌬m157 virus. In addition, these mice showed elevated levels of alpha interferon (IFN-␣) and several other proinflammatory cytokines as early as 1.5 days p.i. Although the numbers of conventional dendritic cells (cDCs) were reduced later during infection, particularly in ⌬m157-infected mice, they were not significantly affected at the peak of the cytokine response. Altogether, we concluded that increased antigen load, preservation of early cDCs' function, and higher levels of innate cytokines collectively account for an enhanced CD8 ؉ T-cell response in C57BL/6 mice infected with a virus unable to activate NK cells via the Ly49H-m157 interaction. Mouse cytomegalovirus (MCMV) has been extensively used as a model for studying the role of NK cells in virus control. NK cells play a crucial role in the early stage of MCMV infection, prior to the induction of the adaptive immune response (20). However, the contribution of NK cells in the control of early MCMV infection varies among mouse strains (38; reviewed in reference 43). In C57BL/6 mice, the activating NK cell receptor Ly49H mediates resistance to MCMV infection due to the specific binding of m157, a virally encoded protein (6, 46). NK cell activation through Ly49H-m157 interaction is characterized by perforin-mediated cytotoxicity and specific proliferation of Ly49H ϩ NK cells (13,26,49). Unlike C57BL/6 mice, MCMV-susceptible mouse strains are unable to mount an effective NK cell response to this virus (reviewed in reference 42).In addition to their direct function, which results in the containment of viral infection, a large body of accumulated data suggests that NK cells play a role also in the shaping of the specific immune response (reviewed in reference 50). However, this topic is still controversial and the subject of intense studies. Robbins and colleagues (40) have shown that NK cell activation via the Ly49H-m157 pathway accelerates the CD8 ϩ T-cell response in vivo. According to the proposed scenario, the activation of NK cells via this axis limits alpha/beta interferon (IFN-␣/␤) production by plasmacytoid den...

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“…Dm157 MCMV was injected i.p. at three different doses (4 3 10 4 , 1.6 3 10 5 , and 3 3 10 5 ), and m157-Rev MCMV at one (1.6 3 10 5 ) (21). Viral titers in various organs were assessed by plaque assay as previously described (8).…”

Section: Virus Stocks and Mouse Infectionsmentioning

confidence: 99%

“…Reporter cell assay was performed as previously described (10). LAK cells were prepared as previously described (21). Lymphoma RMA (H2 b ) and its derivatives RMA-S (H2 b -deficient) and RMA-S-m157 (RMA-S expressing m157) were previously described (12).…”

Section: Cell Culturementioning

confidence: 99%

Viral MHC Class I–like Molecule Allows Evasion of NK Cell Effector Responses In Vivo

Pyzik

Dumaine

Charbonneau

et al. 2014

The Journal of Immunology

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The outcome of mouse CMV (MCMV) infection varies among different inbred mouse strains depending on NK cell effector functions governed through recognition receptor triggering. NK cells from different mouse strains possess diverse repertoires of activating or inhibitory Ly49 receptors, which share some of their polymorphic MHC class I (MHC-I) ligands. By examining the NK cell response to MCMV infection in novel BALB substrains congenic for different MHC (or H-2 in mice) haplotypes, we show that recognition of viral MHC-I–like protein m157 by inhibitory Ly49C receptor allows escape from NK cell control of viral replication. Dominant inhibition by Ly49C bound to self–H-2b encoded MHC-I molecules masks this effect, which only becomes apparent in distinct H-2 haplotypes, such as H-2f. The recognition of m157-expressing cells by Ly49C resulted in both decreased NK cell killing in vitro and reduced rejection in vivo. Further, control of infection with m157-deletant (Δm157) MCMV was improved in mice carrying H-2 molecules unrecognized by Ly49C but allowing expansion of NK cell effectors expressing activating Ly49L receptors. Hence, our study is the first, to our knowledge, to demonstrate that MHC-I mimicry strategies used by MCMV to avoid NK cell control are biologically relevant during in vivo viral infection. Of value for human studies is that only a few genetic assortments conditional on the repertoires of viral MHC-I–like proteins/host NK receptors/MHC haplotypes should allow efficient protection against CMV infection.

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Ly49h-Deficient C57BL/6 Mice: A New Mouse Cytomegalovirus-Susceptible Model Remains Resistant to Unrelated Pathogens Controlled by the NK Gene Complex

Cited by 98 publications

References 86 publications

Methylenetetrahydrofolate reductase (MTHFR) deficiency enhances resistance against cytomegalovirus infection

Methylenetetrahydrofolate reductase (MTHFR) deficiency enhances resistance against cytomegalovirus infection

The NK Cell Response to Mouse Cytomegalovirus Infection Affects the Level and Kinetics of the Early CD8⁺T-Cell Response

Viral MHC Class I–like Molecule Allows Evasion of NK Cell Effector Responses In Vivo

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Ly49h-Deficient C57BL/6 Mice: A New Mouse Cytomegalovirus-Susceptible Model Remains Resistant to Unrelated Pathogens Controlled by the NK Gene Complex

Cited by 98 publications

References 86 publications

Methylenetetrahydrofolate reductase (MTHFR) deficiency enhances resistance against cytomegalovirus infection

Methylenetetrahydrofolate reductase (MTHFR) deficiency enhances resistance against cytomegalovirus infection

The NK Cell Response to Mouse Cytomegalovirus Infection Affects the Level and Kinetics of the Early CD8+T-Cell Response

Viral MHC Class I–like Molecule Allows Evasion of NK Cell Effector Responses In Vivo

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The NK Cell Response to Mouse Cytomegalovirus Infection Affects the Level and Kinetics of the Early CD8⁺T-Cell Response