The phylogenomics of evolving virus virulence

Geoghegan, Jemma L.; Holmes, Edward C.

doi:10.1038/s41576-018-0055-5

Cited by 173 publications

(153 citation statements)

References 159 publications

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“…The current pandemic and its pleotropic effects can be explained in part by interaction between SARS-CoV-2 spike protein S, the ACE2/L-SIGN/CD209 receptor on the type II alveolar cell of the lung, and the DC-SIGN receptor on the respiratory dendritic cell (DC) and associated endothelial cells. Infection of the DC by SARS-CoV-2 can potentially explain the exuberant distal immunopathology seen in COVID- 19.…”

Section: Conflict Of Interest: Nonementioning

confidence: 99%

“…SARS-CoV-2 strains with various mutations in the viral spike can vary as much as 270fold in virulence in Vero E6 culture 18 . Viral evolutionary theory suggests that one option for a viral strain introduced to a novel host is to maintain fitness through reduction in virulence 19 , and these various glycosylation mutations in the spike protein can plausibly provide one such mechanism for attenuation.…”

Section: Conflict Of Interest: Nonementioning

confidence: 99%

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DC/L‐SIGNs of hope in the COVID‐19 pandemic

Brufsky

Lotze

2020

Journal of Medical Virology

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In a rapidly evolving pandemic such as COVID-19, theories which help unify disparate pre-clinical and clinical observations would be useful. The current pandemic and its pleotropic effects can be explained in part by interaction between SARS-CoV-2 spike protein S, the ACE2/L-SIGN/CD209 receptor on the type II alveolar cell of the lung, and the DC-SIGN receptor on the respiratory dendritic cell (DC) and associated endothelial cells. Infection of the DC by SARS-CoV-2 can potentially explain the exuberant distal immunopathology seen in In a mouse model of severe acute respiratory distress syndrome (SARS), the human disease most related to COVID-19 in clinical course, severe disease is correlated with slow kinetics of SARS-CoV viral clearance 1 . This is accompanied by delayed activation and transit of respiratory DCs to the draining lymph nodes with a deficient virus-specific T cell response 1 . In the SARS-CoV-2 infection, there is initial lymphopenia, and the lymphocyte count is predictive of disease severity and mortality 2 . Lymphocyte counts recover with viral clearance and disease resolution, with adaptive immune cells (CD3+ T cells) being especially important 2 . Such immune deficiency can in part be explained by viral infection and T-cell interaction with the respiratory DC.Early and central infection of tissue resident dendritic cells (DC) by the SARS-CoV-2 coronavirus explain some of the immunopathology of the COVID-19 pandemic. DC are richly abundant in the lung and responsive to viral infection 3 . RNA expression profiling studies demonstrate that human DC express the ACE2 receptor for SARS-CoV-2 4 . In COVID-19, T cell receptor (TCR) repertoires are dramatically reduced during the early onset of severe SARS-CoV-2 infection but recover during the convalescent stage 5 . Such reduction of T cells suggest acute wholesale apoptotic death with engagement of the TCR in the absence of costimulatory molecules, normally provided by DC 6 .DC also express DC-SIGN. DC-SIGN (dendritic cell-specific ICAM-3-grabbing nonintegrin) is a membrane receptor of a C-type lectin family expressed on DCs with a primary function of recognizing high mannose glycans present on other cellular receptors or pathogens 7 . With L-SIGN (CD209L, DC-SIGNR, or liver/lymph specific SIGN) expression, the other SIGN found in humans 8 , these mannose receptors are involved in virus capture and entry into cells 9 . L-SIGN is expressed on human type II alveolar cells, is associated with ACE2 10 , and can enhance ACE2 mediated binding and cellular entry of viral pseudotypes expressing the spike protein S of SARS-CoV 9 .Lentiviral pseudotyped viruses expressing SARS-CoV S protein require acidification of the endosome for viral entry 11 . DC-SIGN mediates binding of these pseudotyped vectors to human DC with uptake into the endosome, followed by polarization of the endosome and delivery of the virus in an "infectious synapse" 11 . This appears similar to an infectious synapse between infected DC and T cells that facilitates HIV infection mediated by...

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Section: Conflict Of Interest: Nonementioning

confidence: 99%

Section: Conflict Of Interest: Nonementioning

confidence: 99%

DC/L‐SIGNs of hope in the COVID‐19 pandemic

Brufsky

Lotze

2020

Journal of Medical Virology

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“…Microbial pathogens have evolved varied virulence strategies to modulate host cell function (Geoghegan and Holmes, 2018; Ribet and Cossart, 2015). A common mechanism, employed by all viral and some bacterial pathogens, is to enter host cells, where they co-opt cellular functions while simultaneously evading extracellular threats such as innate and adaptive immune mechanisms (Hybiske and Stephens, 2008; Lee et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Functional remodeling of lysosomes by type I interferon modifies host defense

Zhang

Zoued

Liu

et al. 2020

Preprint

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SUMMARYOrganelle remodeling is critical for cellular homeostasis, but host factors that control organelle function during microbial infection remain largely uncharacterized. Here, a genome-scale CRISPR/Cas9 screen in intestinal epithelial cells with the prototypical intracellular bacterial pathogen Salmonella led us to discover that type I interferon (IFN-I) remodels lysosomes. Even in the absence of infection, IFN-I signaling modified the localization, acidification, protease activity and proteomic profile of lysosomes. Proteomic and genetic analyses revealed that multiple IFN-I-stimulated genes including Ifitm3, Slc15a3, and Cnp contribute to lysosome acidification. IFN-I-dependent lysosome acidification stimulated intracellular Salmonella virulence gene expression, leading to rupture of the Salmonella-containing vacuole and host cell death. Moreover, IFN-I signaling promoted in vivo Salmonella pathogenesis in the intestinal epithelium, where Salmonella initiates infection. Our findings explain how an intracellular bacterial pathogen co-opts epithelial IFN-I signaling. We propose that IFN-I control of lysosome function broadly impacts host defense against diverse viral and microbial pathogens.

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“…This residue is highly conserved in coronaviruses 8 . There are many examples of mutation in this spike protein region resulting in changes in virulence 9,10 , and in particular a single serine to glycine change at residue 310 in a murine coronavirus spike protein resulted in increased virulence 11 through decreased stability of the viral fusion machinery.…”

mentioning

confidence: 99%

Distinct viral clades of SARS‐CoV‐2: Implications for modeling of viral spread

Brufsky

2020

Journal of Medical Virology

141

151

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Distinct viral clades have a likely impact on COVID-19 pathogenesis and spread. Sequence analysis from 2310 viral isolates from Nexstrain reveals that residue at 614 of the viral spike protein is changed from a putative ancestral aspartic acid (D) to a glycine (G) between two viral clades. The G strain is predominantly on the East Coast of the United States, and the D strain is predominantly on the West Coast. This mutation of the SARS-CoV-2 S protein spike is conserved in coronaviruses. Point mutations in a murine coronavirus spike protein can result in increased virulence through instability of the viral machinery and altered viral to cell membrane fusion. This observation may partially explain the discrepancy in predicted deaths from COVID-19 between the East Coast and West Coast,

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The phylogenomics of evolving virus virulence

Cited by 173 publications

References 159 publications

DC/L‐SIGNs of hope in the COVID‐19 pandemic

DC/L‐SIGNs of hope in the COVID‐19 pandemic

Functional remodeling of lysosomes by type I interferon modifies host defense

Distinct viral clades of SARS‐CoV‐2: Implications for modeling of viral spread

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