Mouse Hepatitis Virus Liver Pathology Is Dependent on ADP-Ribose-1″-Phosphatase, a Viral Function Conserved in the Alpha-Like Supergroup

Eriksson, Klara Kristin; Cervantes-Barragán, Luisa; Ludewig, Burkhard; Thiel, Volker

doi:10.1128/jvi.02082-08

Cited by 144 publications

(199 citation statements)

References 39 publications

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“…Infection of un-injured C57BL/6 female mice with 5 × 10 5 PFU MHV leads to acute hepatitis infection, but all mice survive and recover and this is associated with clearance of virus from the liver to below levels detectable by plaque assay (~200PFU/g tissue) (Eriksson et al, 2008; Navas et al, 2001). In contrast, all mice that received 5 × 10 5 PFU of MHV 1 week following a complete bilateral crush SCI at thoracic level-T3 died by 6 days post-infection (p.i.)…”

Section: Resultsmentioning

confidence: 99%

Impaired immune responses following spinal cord injury lead to reduced ability to control viral infection

Held

Steward

Blanc

et al. 2010

Experimental Neurology

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Spinal cord injuries disrupt central autonomic pathways that regulate immune function, and increasing evidence suggests that this may cause deficiencies in immune responses in people with spinal cord injuries. Here we analyze the consequences of spinal cord injury (SCI) on immune responses following experimental viral infection of mice. Female C57BL/6 mice received complete crush injuries at either thoracic level 3 (T3) or 9 (T9), and 1 week post-injury, injured mice and un-injured controls were infected with different dosages of mouse hepatitis virus (MHV, a positive-strand RNA virus). Following MHV infection, T3- and T9-injured mice exhibited increased mortality in comparison to un-injured and laminectomy controls. Infection at all dosages resulted in significantly higher viral titer in both T3- and T9-injured mice compared to un-injured controls. Investigation of anti-viral immune responses revealed impairment of cellular infiltration and effector functions in mice with SCI. Specifically, cell-mediated responses were diminished in T3-injured mice, as seen by reduction in virus-specific CD4+ T lymphocyte proliferation and IFN-γ production and decreased numbers of activated antigen presenting cells compared to infected un-injured mice. Collectively, these data indicate that the inability to control viral replication following SCI is not level dependent and that increased susceptibility to infection is due to suppression of both innate and adaptive immune responses.

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Section: Resultsmentioning

confidence: 99%

Impaired immune responses following spinal cord injury lead to reduced ability to control viral infection

Held

Steward

Blanc

et al. 2010

Experimental Neurology

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“…Interestingly, DC-T cell interaction in the presence of high Ag doses favors the production of IL-6 and hence the suppression of Treg induction (43). Furthermore, IL-6 is one of the strongly induced proinflammatory cytokines in secondary lymphoid organs during acute MHV infection (46). It is therefore possible that Tregs exert their negative regulatory effects preferably under low Ag dose/low inflammation conditions such as late release of self-antigens during cytopathic virus infection.…”

Section: Discussionmentioning

confidence: 99%

Regulatory T Cells Selectively Preserve Immune Privilege of Self-Antigens during Viral Central Nervous System Infection

Cervantes-Barragán

Firner

Bechmann

et al. 2012

The Journal of Immunology

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Regulatory T cells (Tregs) are important for the attenuation of immune reactions. During viral CNS infections, however, an indiscriminate maintenance of CNS immune privilege through Treg-mediated negative regulation could prevent autoimmune sequelae but impair the control of viral replication. We analyzed in this study the impact of Tregs on the development of acute viral encephalomyelitis, T cell-mediated antiviral protection, and prevention of CNS autoimmunity following intranasal infection with the gliatropic mouse hepatitis virus strain A59. To assess the contribution of Tregs in vivo, we specifically depleted CD4+Foxp3+ T cells in a diphtheria toxin-dependent manner. We found that depletion of Tregs had no impact on viral distribution and clearance and did not significantly alter virus-specific CD4+ and CD8+ T cell responses. However, Treg depletion led to a more severe CNS inflammation associated with neuronal damage. Dissection of the underlying immunopathological mechanisms revealed the elaborate Treg-dependent regulation of self-reactive CD4+ T cell proliferation within the CNS-draining lymph node and downtuning of CXCR3 expression on T cells. Taken together, these results suggest that Tregs preserve CNS immune privilege through selective control of CNS-specific Th cells while keeping protective antiviral immunity fully operative.

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“…Our group has shown that the X domain (Mac1) is dispensable for RNA replication in the context of a SARS-CoV replicon (Kusov et al, 2015). Recently, evidence accumulated showing that the X domain plays a role in counteracting the host innate immune response (Eriksson et al, 2008;Kuri et al, 2011;Fehr et al, , 2016.…”

Section: Macrodomain I (Mac1 X Domain)mentioning

confidence: 99%

Nsp3 of coronaviruses: Structures and functions of a large multi-domain protein

2018

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The multi-domain non-structural protein 3 (Nsp3) is the largest protein encoded by the coronavirus (CoV) genome, with an average molecular mass of about 200 kD. Nsp3 is an essential component of the replication/transcription complex. It comprises various domains, the organization of which differs between CoV genera, due to duplication or absence of some domains. However, eight domains of Nsp3 exist in all known CoVs: the ubiquitin-like domain 1 (Ubl1), the Glu-rich acidic domain (also called "hypervariable region"), a macrodomain (also named "X domain"), the ubiquitin-like domain 2 (Ubl2), the papain-like protease 2 (PL2), the Nsp3 ectodomain (3Ecto, also called "zinc-finger domain"), as well as the domains Y1 and CoV-Y of unknown functions. In addition, the two transmembrane regions, TM1 and TM2, exist in all CoVs. The three-dimensional structures of domains in the N-terminal two thirds of Nsp3 have been investigated by X-ray crystallography and/or nuclear magnetic resonance (NMR) spectroscopy since the outbreaks of Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) in 2003 as well as Middle-East Respiratory Syndrome coronavirus (MERS-CoV) in 2012. In this review, the structures and functions of these domains of Nsp3 are discussed in depth.

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Mouse Hepatitis Virus Liver Pathology Is Dependent on ADP-Ribose-1″-Phosphatase, a Viral Function Conserved in the Alpha-Like Supergroup

Cited by 144 publications

References 39 publications

Impaired immune responses following spinal cord injury lead to reduced ability to control viral infection

Impaired immune responses following spinal cord injury lead to reduced ability to control viral infection

Regulatory T Cells Selectively Preserve Immune Privilege of Self-Antigens during Viral Central Nervous System Infection

Nsp3 of coronaviruses: Structures and functions of a large multi-domain protein

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