Pathogenesis of neurotropic murine coronavirus is multifactorial

Phillips, Jonathan; Weiss, Susan R.

doi:10.1016/j.tips.2010.11.001

Cited by 7 publications

(7 citation statements)

References 58 publications

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“…We cannot exclude a component of adrenal insufficiency to the impaired HR response, or the development of cardiac contractile dysfunction related to cytokine activation or endothelial injury with impaired myocardial perfusion. The mechanisms underlying neuronal invasion is a long-standing mystery in the study of neurotropic betacoronaviruses (Miura et al, 2008;Perlman et al, 1989;Phillips and Weiss, 2011) and the immune and tissue responses in these privileged tissues remain to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Type I Interferon Limits Viral Dissemination-Driven Clinical Heterogeneity in a Native Murine Betacoronavirus Model of COVID-19

Qing

Sharma

Hilliard

et al. 2020

Preprint

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Emerging clinical data demonstrates that COVID-19, the disease caused by SARS-CoV2, is a syndrome that variably affects nearly every organ system. Indeed, the clinical heterogeneity of COVID-19 ranges from relatively asymptomatic to severe disease with death resultant from multiple constellations of organ failures. In addition to genetics and host characteristics, it is likely that viral dissemination is a key determinant of disease manifestation. Given the complexity of disease expression, one major limitation in current animal models is the ability to capture this clinical heterogeneity due to technical limitations related to murinizing SARS-CoV2 or humanizing mice to render susceptible to infection. Here we describe a murine model of COVID-19 using respiratory infection with the native mouse betacoronavirus MHV-A59. We find that whereas high viral inoculums uniformly led to hypoxemic respiratory failure and death, lethal dose 50% (LD50) inoculums led to a recapitulation of most hallmark clinical features of COVID-19, including lymphocytopenias, heart and liver damage, and autonomic dysfunction. We find that extrapulmonary manifestations are due to viral metastasis and identify a critical role for type-I but not type-III interferons in preventing systemic viral dissemination. Early, but not late treatment with intrapulmonary type-I interferon, as well as convalescent serum, provided significant protection from lethality by limiting viral dissemination. We thus establish a Biosafety Level II model that may be a useful addition to the current pre-clinical animal models of COVID-19 for understanding disease pathogenesis and facilitating therapeutic development for human translation.

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Section: Discussionmentioning

confidence: 99%

Type I Interferon Limits Viral Dissemination-Driven Clinical Heterogeneity in a Native Murine Betacoronavirus Model of COVID-19

Qing

Sharma

Hilliard

et al. 2020

Preprint

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“…Biochemical characterization of MHV-JHM spike suggested that it is more labile than the spikes from other MHV strains, meaning that it undergoes conformational transitions spontaneously in the absence of the receptor (94,129,130). It is believed that MHV-JHM is able to infect neural cells where CEACAM1 expression level is very low, at least in part because its spike can mediate receptor-independent entry (131,132). Taken together, the membrane fusion mechanism of MHV spike depends on both proteolysis and receptor binding, and it may or may not depend on the low pH of endosomes; in addition, receptor-independent membrane fusion by MHV-JHM spike contributes to the neutral tropism of MHV-JHM.…”

Section: Triggers For Membrane Fusion By Coronavirus Spike Proteinsmentioning

confidence: 99%

Structure, Function, and Evolution of Coronavirus Spike Proteins

2016

Annu. Rev. Virol.

2,538

2,804

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The coronavirus spike protein is a multifunctional molecular machine that mediates coronavirus entry into host cells. It first binds to a receptor on the host cell surface through its S1 subunit and then fuses viral and host membranes through its S2 subunit. Two domains in S1 from different coronaviruses recognize a variety of host receptors, leading to viral attachment. The spike protein exists in two structurally distinct conformations, prefusion and postfusion. The transition from prefusion to postfusion conformation of the spike protein must be triggered, leading to membrane fusion. This article reviews current knowledge about the structures and functions of coronavirus spike proteins, illustrating how the two S1 domains recognize different receptors and how the spike proteins are regulated to undergo conformational transitions. I further discuss the evolution of these two critical functions of coronavirus spike proteins, receptor recognition and membrane fusion, in the context of the corresponding functions from other viruses and host cells.

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“…The MHVs, having CEACAM-binding sites on NTDs, readily delete CTD segments during passage in tissue culture [ 49 , 50 ]. These deletion-mutations have profound influences on CoV virulence, greatly decreasing the murine virus neurovirulence [ 51 ]. Another interesting example is with the porcine CoVs.…”

Section: Engaging the Cov Receptorsmentioning

confidence: 99%

Ready, Set, Fuse! The Coronavirus Spike Protein and Acquisition of Fusion Competence

Heald‐Sargent

Gallagher

2012

Viruses

318

295

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Coronavirus-cell entry programs involve virus-cell membrane fusions mediated by viral spike (S) proteins. Coronavirus S proteins acquire membrane fusion competence by receptor interactions, proteolysis, and acidification in endosomes. This review describes our current understanding of the S proteins, their interactions with and their responses to these entry triggers. We focus on receptors and proteases in prompting entry and highlight the type II transmembrane serine proteases (TTSPs) known to activate several virus fusion proteins. These and other proteases are essential cofactors permitting coronavirus infection, conceivably being in proximity to cell-surface receptors and thus poised to split entering spike proteins into the fragments that refold to mediate membrane fusion. The review concludes by noting how understanding of coronavirus entry informs antiviral therapies.

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Pathogenesis of neurotropic murine coronavirus is multifactorial

Cited by 7 publications

References 58 publications

Type I Interferon Limits Viral Dissemination-Driven Clinical Heterogeneity in a Native Murine Betacoronavirus Model of COVID-19

Type I Interferon Limits Viral Dissemination-Driven Clinical Heterogeneity in a Native Murine Betacoronavirus Model of COVID-19

Structure, Function, and Evolution of Coronavirus Spike Proteins

Ready, Set, Fuse! The Coronavirus Spike Protein and Acquisition of Fusion Competence

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