Heterogeneity in Evolutive Patterns of Inbred Mice Infected with a Cloned Substrain of Mouse Hepatitis Virus Type 3

Dupuy, J. M.; Rodrigue, Debra

doi:10.1159/000149255

Cited by 14 publications

(9 citation statements)

References 11 publications

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“…Viruses. Highly pathogenic MHV3 is a cloned substrain isolated from the liver of an infected DBA2 mouse and maintained in L2 cells for less than three passages, as described previously (27). The mildly virulent MHV-A59 strain was obtained from the American Type Culture Collection (ATCC) (Rockville, MD, USA).…”

Section: Methodsmentioning

confidence: 99%

Brain Invasion by Mouse Hepatitis Virus Depends on Impairment of Tight Junctions and Beta Interferon Production in Brain Microvascular Endothelial Cells

Bleau

Filliol

Samson

et al. 2015

J Virol

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Coronaviruses (CoVs) have shown neuroinvasive properties in humans and animals secondary to replication in peripheral organs, but the mechanism of neuroinvasion is unknown. The major aim of our work was to evaluate the ability of CoVs to enter the central nervous system (CNS) through the blood-brain barrier (BBB). Using the highly hepatotropic mouse hepatitis virus type 3 (MHV3), its attenuated variant, 51.6-MHV3, which shows low tropism for endothelial cells, and the weakly hepatotropic MHV-A59 strain from the murine coronavirus group, we investigated the virus-induced dysfunctions of BBB in vivo and in brain microvascular endothelial cells (BMECs) in vitro. We report here a MHV strain-specific ability to cross the BBB during acute infection according to their virulence for liver. Brain invasion was observed only in MHV3-infected mice and correlated with enhanced BBB permeability associated with decreased expression of zona occludens protein 1 (ZO-1), VE-cadherin, and occludin, but not claudin-5, in the brain or in cultured BMECs. BBB breakdown in MHV3 infection was not related to production of barrier-dysregulating inflammatory cytokines or chemokines by infected BMECs but rather to a downregulation of barrier protective beta interferon (IFN-␤) production. Our findings highlight the importance of IFN-␤ production by infected BMECs in preserving BBB function and preventing access of blood-borne infectious viruses to the brain. IMPORTANCECoronaviruses (CoVs) infect several mammals, including humans, and are associated with respiratory, gastrointestinal, and/or neurological diseases. There is some evidence that suggest that human respiratory CoVs may show neuroinvasive properties. Indeed, the severe acute respiratory syndrome coronavirus (SARS-CoV), causing severe acute respiratory syndrome, and the CoVs OC43 and 229E were found in the brains of SARS patients and multiple sclerosis patients, respectively. These findings suggest that hematogenously spread CoVs may gain access to the CNS at the BBB level. Herein we report for the first time that CoVs exhibit the ability to cross the BBB according to strain virulence. BBB invasion by CoVs correlates with virus-induced disruption of tight junctions on BMECs, leading to BBB dysfunction and enhanced permeability. We provide evidence that production of IFN-␤ by BMECs during CoV infection may prevent BBB breakdown and brain viral invasion.T he blood-brain barrier (BBB) is a highly selective barrier critical for central nervous system (CNS) homeostasis in controlling peripheral blood-brain exchange and preventing neurotoxins and pathogens from access to the CNS. The functional and structural integrity of the BBB mainly relies on specific features of the brain microvascular endothelial cells (BMECs) lining the brain capillaries. These cells are tightly connected by a unique assembly of adherens junctions composed of transmembrane cadherin and tight-junction complexes (e.g., claudins and occludin) anchored to actin filaments via adaptor molecules, such as zona occlu...

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Section: Methodsmentioning

confidence: 99%

Brain Invasion by Mouse Hepatitis Virus Depends on Impairment of Tight Junctions and Beta Interferon Production in Brain Microvascular Endothelial Cells

Bleau

Filliol

Samson

et al. 2015

J Virol

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“…L2-MHV3 is a cloned pathogenic substrain isolated from the liver of infected DBA2 mice and maintained in L2 cells, as described previously [30]. Escape mutants 51·6-MHV3 and CL12-MHV3 were selected from the pathogenic L2-MHV3 virus in the presence of S protein-specific A51 and A37 monoclonal antibodies respectively [25].…”

Section: Virusesmentioning

confidence: 99%

Intrahepatic endothelial and Kupffer cells involved in immunosuppressive cytokines and natural killer (NK)/NK T cell disorders in viral acute hepatitis

Jacques

Bleau

Martín

et al. 2008

Clinical and Experimental Immunology

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“…Pathogenic MHV3 was a cloned substrain produced in L2 cells (L2-MHV3) as described previously [26]. The YAC-MHV3 variant was a cloned virus derived from persistently infected lymphoid YAC cell [17].…”

Section: Virusesmentioning

confidence: 99%

Murine viral hepatitis involves NK cell depletion associated with virus-induced apoptosis

Lehoux

Jacques

Lusignan

et al. 2004

Clinical and Experimental Immunology

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SUMMARYMouse hepatitis virus type 3 (MHV3), a coronavirus, is an excellent animal model for the study of immunological disorders related to acute and chronic hepatitis. In this study, we have verified if the fulminant hepatitis induced by MHV3 could be related to an impairment of innate immunity. Groups of three C57BL/6 mice were infected with the pathogenic L2-MHV3 or attenuated YAC-MHV3 viruses, and the natural killer (NK) cell populations from liver, spleen and bone marrow were analysed. The percentage of intrahepatic NK1·1 + T cell receptor (TCR) -cells did not increase while NK1·1 + TCR inter cells decreased in both L2-MHV3-and YAC-MHV3-infected mice. Concurrently, splenic and myeloid NK1·1 + cells decreased in L2-MHV3-infected mice. However, the cytotoxic activity of NK cells increased in liver and decreased in bone marrow from pathogenic L2-MHV3-infected mice while no modification was detected in YAC-MHV3-infected mice. Flow cytometric analysis revealed that both normal and larger splenic or myeloid NK cells decreased more in pathogenic L2-MHV3-infected mice than in attenuated YAC-MHV3-infected mice. In vitro viral infections of interleukin (IL)-15-stimulated lymphoid cells from liver and bone marrow revealed that L2-MHV3 induced higher decreases in cell viability of NK1·1 + cells than the YAC-MHV3 variant. The NK cell decreases were due to the viral permissivity leading to cytopathic effects characterized by cell rounding, syncytia formation and apoptosis. Larger NK + syncytia were observed in L2-MHV3-infected cells than in YAC-MHV3-infected cells. These results suggest that NK cell production is impaired by viral infection favouring fulminant hepatitis.

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Heterogeneity in Evolutive Patterns of Inbred Mice Infected with a Cloned Substrain of Mouse Hepatitis Virus Type 3

Cited by 14 publications

References 11 publications

Brain Invasion by Mouse Hepatitis Virus Depends on Impairment of Tight Junctions and Beta Interferon Production in Brain Microvascular Endothelial Cells

Brain Invasion by Mouse Hepatitis Virus Depends on Impairment of Tight Junctions and Beta Interferon Production in Brain Microvascular Endothelial Cells

Intrahepatic endothelial and Kupffer cells involved in immunosuppressive cytokines and natural killer (NK)/NK T cell disorders in viral acute hepatitis

Murine viral hepatitis involves NK cell depletion associated with virus-induced apoptosis

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