Role of Nitric Oxide Synthase Type 2 in Acute Infection with Murine Cytomegalovirus

Noda, Shinichi; Tanaka, Kazuo; Sawamura, Sadaaki; Sasaki, Mitsuyoshi; Matsumoto, Takako; Mikami, Katsunaka; Aiba, Yuji; Hasegawa, Hideaki; Kawabe, Noboru; Koga, Yuichi

doi:10.4049/jimmunol.166.5.3533

Cited by 52 publications

(51 citation statements)

References 65 publications

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“…In contrast, IL-12-induced inhibition of vesicular stomatitis virus in the CNS required neither TNF-␣ nor IFN-␥ but was dependent on NOS-1 (17,18). A recent study extended these findings by demonstrating that IFN-␥-inducible NOS-2 is crucial for eliminating murine cytomegalovirus (27). In the cerebellum of BDV-infected GF-IL-12 mice, we observed induction of TNF-␣, IFN-␥, and IL-1 as well as NOS-2 genes, while NOS-1 and NOS-3 transcripts remained at control levels.…”

Section: Vol 76 2002 Interactions Of Bdv and Il-12 In The Cns 12229supporting

confidence: 58%

Borna Disease Virus Accelerates Inflammation and Disease Associated with Transgenic Expression of Interleukin-12 in the Central Nervous System

Freude

Hausmann

Höfer

et al. 2002

J Virol

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Targeted expression of biologically active interleukin-12 (IL-12) in astrocytes of the central nervous system (CNS) results in spontaneous neuroimmunological disease of aged mice. Borna disease virus (BDV) can readily multiply in the mouse CNS but does not trigger disease in most strains. Here we show that a large percentage of IL-12 transgenic mice developed severe ataxia within 5 to 10 weeks after infection with BDV. By contrast, no disease developed in mock-infected IL-12 transgenic and wild-type mice until 4 months of age. Neurological symptoms were rare in infected wild-type animals, and if they occurred, these were milder and appeared later. Histological analyses showed that the cerebellum of infected IL-12 transgenic mice, which is the brain region with strongest transgene expression, contained large numbers of CD4 ؉ and CD8 ؉ T cells as well as lower numbers of B cells, whereas other parts of the CNS showed only mild infiltration by lymphocytes. The cerebellum of diseased mice further showed severe astrogliosis, calcifications and signs of neurodegeneration. BDV antigen and nucleic acids were present in lower amounts in the inflamed cerebellum of infected transgenic mice than in the noninflamed cerebellum of infected wild-type littermates, suggesting that IL-12 or IL-12-induced cytokines exhibited antiviral activity. We propose that BDV infection accelerates the frequency by which immune cells such as lymphocytes and NK cells enter the CNS and then respond to IL-12 present in the local milieu causing disease. Our results illustrate that infection of the CNS with a virus that is benign in certain hosts can be harmful in such normally disease-resistant hosts if the tissue is unfavorably preconditioned by proinflammatory cytokines.

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Section: Vol 76 2002 Interactions Of Bdv and Il-12 In The Cns 12229supporting

confidence: 58%

Borna Disease Virus Accelerates Inflammation and Disease Associated with Transgenic Expression of Interleukin-12 in the Central Nervous System

Freude

Hausmann

Höfer

et al. 2002

J Virol

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“…5B). It has been reported that iNOS deficiency leads to increased replication of MCMV after long infection periods with low MOI in peritoneal exudate macrophages (48). We determined whether the defective NO production in Tyk2-deficient cells contributes to the increased replication of MCMV in our experimental system.…”

Section: Tyk2 Is Required For Mcmv-induced Production Of Nomentioning

confidence: 99%

“…It has been previously reported that NO plays an important role in MCMV infections in vivo (13,48). We therefore determined NO production in the supernatants of MCMVinfected macrophages derived from Tyk2 Ϫ/Ϫ and WT mice.…”

Section: Tyk2 Is Required For Mcmv-induced Production Of Nomentioning

confidence: 99%

Novel Functions of Tyrosine Kinase 2 in the Antiviral Defense against Murine Cytomegalovirus

Strobl

Bubić

Bruns

et al. 2005

The Journal of Immunology

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We have recently reported that tyrosine kinase 2 (Tyk2)-deficient mice have a selective defect in the in vivo defense against certain viruses. In our current study we show that Tyk2 is essential for the defense against murine CMV (MCMV). In vivo challenges with MCMV revealed impaired clearance of virus from organs and decreased survival of mice in the absence of Tyk2. Our in vitro studies demonstrate that MCMV replicates to dramatically higher titers in Tyk2-deficient macrophages compared with wild-type cells. We show an essential role of type I IFN (IFN-αβ) in the control of MCMV replication, with a prominent role of IFN-β. MCMV infection leads to the activation of STAT1 and STAT2 in an IFN-αβ receptor 1-dependent manner. Consistent with the role of Tyk2 in IFN-αβ signaling, activation of STAT1 and STAT2 is reduced in Tyk2-deficient cells. However, lack of Tyk2 results in impaired MCMV-mediated gene induction of only a subset of MCMV-induced IFN-αβ-responsive genes. Taken together, our data demonstrate a requirement for Tyk2 in the in vitro and in vivo antiviral defense against MCMV infection. In addition to the established role of Tyk2 as an amplifier of Jak/Stat signaling upon IFN-αβ stimulation, we provide evidence for a novel role of Tyk2 as a modifier of host responses.

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“…18,19 PB monocytes and macrophages have been identified as host cells that support viral replication 11,16,17,[20][21][22][23] and latency 22,24,25 ; however, these cells also have been implicated in host defense. 20,23,[26][27][28] The differentiation-dependent susceptibility of monocytes and macrophages to MCMV infection 22,23 has led to a consensus view that nonpermissive monocytes may disseminate infection and differentiate into permissive mature cells upon entry into tissues. This pattern is similar to that proposed to explain viral reactivation from latency 29 and has been reinforced by the apparent central role of myelomonocytic lineage cells in HCMV infection [30][31][32] and latency.…”

Section: Introductionmentioning

confidence: 99%

Cytomegalovirus MCK-2 controls mobilization and recruitment of myeloid progenitor cells to facilitate dissemination

Noda

Aguirre

BitMansour

et al. 2006

Blood

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100

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IntroductionHuman cytomegalovirus (HCMV) is an opportunistic pathogen of widespread medical importance, causing congenital disease following a primary infection during pregnancy, as well as a wide range of organ-specific diseases following reactivation in immunocompromised patients. 1 Murine CMV (MCMV) has proven to be an excellent model of HCMV infection and disease, providing information on the basic patterns of pathogenesis, latency, immunity, and dissemination. 2-4 Dissemination of HCMV or MCMV requires a population of host mononuclear leukocytes that traverse the bloodstream. [5][6][7] Based on comparisons of wild-type and mutant MCMV-infected mice, MCMV enhances dissemination levels by expressing a pro-inflammatory chemokine-like gene product called MCMV chemokine (MCK). 2,7,8 MCK appears to increase the recruitment of leukocytes to initial sites of infection and to allow a greater number of virus-positive leukocytes to traverse the bloodstream to salivary glands (SGs), 3,7 a site of prolonged replication and shedding. This process likely provides a source of virus for transmission to naive mice. 2 The human pathogen HCMV also encodes chemokine homologs: one CC chemokine homolog (UL128) that may be analogous to MCK, 9 as well as one very potent CXC chemokine (gpUL146/vCXCL1) that is as potent as human interleukin-8 (IL-8) and acts via CXCR2. 10 The carboxyl terminal 81 aa m131 ORF encodes a predicted gene product, MCK-1, 8 that elicits both calcium mobilization and adherence in resident or elicited peritoneal exudate cells (PECs). 11 mRNA splicing adds 199 aa to this chemokine-like domain to make MCK-2 the natural, secreted gene product. 12 Studies on virusinfected mice have suggested that MCK-2 influences levels of viremia as well as patterns of dissemination 11,13 by increasing the inflammatory response at sites of infection. 14 An MCK-2-dependent influx of leukocytes into initial sites of infection is followed by a mononuclear-cell (MNC)-associated viremia that peaks at day 5 after infection 14 and leads to viral seeding of the SGs. 2,15-17 Although MCK-2 is pro-inflammatory and a determinant of both viremia and dissemination 11,14 and was also associated with both natural killer and adaptive immune defects, 13 this chemokinelike function is not involved in immune evasion. On the one hand, MCK-2 control of viremia and dissemination is preserved in mice that lack the ability to mount an adaptive immune response. 2,16 On the other hand, virus replication levels and clearance from inoculated foot pads (FPs) or sites of systemic infection, including 11,16,17,[20][21][22][23] and latency 22,24,25 ; however, these cells also have been implicated in host defense. 20,23,[26][27][28] The differentiation-dependent susceptibility of monocytes and macrophages to MCMV infection 22,23 has led to a consensus view that nonpermissive monocytes may disseminate infection and differentiate into permissive mature cells upon entry into tissues. This pattern is similar to that proposed to explain viral reactivation from lat...

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Role of Nitric Oxide Synthase Type 2 in Acute Infection with Murine Cytomegalovirus

Cited by 52 publications

References 65 publications

Borna Disease Virus Accelerates Inflammation and Disease Associated with Transgenic Expression of Interleukin-12 in the Central Nervous System

Borna Disease Virus Accelerates Inflammation and Disease Associated with Transgenic Expression of Interleukin-12 in the Central Nervous System

Novel Functions of Tyrosine Kinase 2 in the Antiviral Defense against Murine Cytomegalovirus

Cytomegalovirus MCK-2 controls mobilization and recruitment of myeloid progenitor cells to facilitate dissemination

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