Host and viral determinants for efficient SARS-CoV-2 infection of the human lung

Chu, Hin; Hu, Bingjie; Huang, Xiner; Chai, Yue; Zhou, Dongyan; Wang, Yixin; Shuai, Huiping; Yang, Dong; Hou, Yuxin; Zhang, Xi; Yuen, Terrence Tsz‐Tai; Cai, Jian‐Piao; Zhang, Anna Jinxia; Zhou, Jie; Yuan, Shuofeng; To, Kelvin Kai‐Wang; Chan, Iris Hiu-Shuen; Sit, Ko‐Yung; Foo, Chi Chung; Wong, Ian Yu‐Hong; Ng, Anthony Chin-Ki; Cheung, Tan To; Law, Simon; Au, Wing‐Kuk; Brindley, Melinda A.; Chen, Zhiwei; Kok, Kin‐Hang; Chan, Jasper Fuk‐Woo; Yuen, Kwok‐Yung

doi:10.1038/s41467-020-20457-w

Cited by 121 publications

(105 citation statements)

References 59 publications

Supporting

Mentioning

100

Contrasting

Order By: Relevance

“…Flow cytometry was performed according to standard protocols as we previously described [ 34 , 35 ]. In brief, MDMs and moDCs were infected with ZIKV PR or ZIKV U (MOI=0.1 or MOI=1.0) for 2 h at 37°C.…”

Section: Methodsmentioning

confidence: 99%

STAT2-dependent restriction of Zika virus by human macrophages but not dendritic cells

Yang

Chu

Lü

et al. 2021

Emerging Microbes & Infections

Self Cite

View full text Add to dashboard Cite

STAT2-dependent restriction of Zika virus by human macrophages but not dendritic cells ABSTRACTZika virus (ZIKV) is an emerging mosquito-borne flavivirus that poses significant threats to global public health. Macrophages and dendritic cells are both key sentinel cells in the host immune response and play critical roles in the pathogenesis of flavivirus infections. Recent studies showed that ZIKV could productively infect monocyte-derived dendritic cells (moDCs), but the role of macrophages in ZIKV infection remains incompletely understood. In this study, we first compared ZIKV infection in monocyte-derived macrophages (MDMs) and moDCs derived from the same donors. We demonstrated that while both MDMs and moDCs were susceptible to epidemic (Puerto Rico) and pre-epidemic (Uganda) strains of ZIKV, virus replication was largely restricted in MDMs but not in moDCs. ZIKV induced significant apoptosis in moDCs but not MDMs. The restricted virus replication in MDMs was not due to inefficient virus entry but was related to post-entry events in the viral replication cycle. In stark contrast with moDCs, ZIKV failed to inhibit STAT1 and STAT2 phosphorylation in MDMs. This resulted in the lack of efficient antagonism of the host type I interferon-mediated antiviral responses. Importantly, depletion of STAT2 but not STAT1 in MDMs significantly rescued the replication of ZIKV and the prototype flavivirus yellow fever virus. Overall, our findings revealed a differential interplay between macrophages and dendritic cells with ZIKV. While dendritic cells may be exploited by ZIKV to facilitate virus replication, macrophages restricted ZIKV infection.

show abstract

Section: Methodsmentioning

confidence: 99%

STAT2-dependent restriction of Zika virus by human macrophages but not dendritic cells

Yang

Chu

Lü

et al. 2021

Emerging Microbes & Infections

Self Cite

View full text Add to dashboard Cite

show abstract

“…Infection of Vero E6 cells by SARS-CoV-2 is dependent on endogenous levels of monkey ACE2 expression, as pretreatment with anti-ACE2 mAbs inhibits infection (Hoffmann et al, 2020). However, other host factors such as heparan sulfate also can mediate virus attachment to cells (Chu et al, 2021; Clausen et al, 2020). If binding to other cell surface ligands occurs prior to the RBD-ACE2 interaction, mAbs that block ACE2 binding may not efficiently inhibit SARS-CoV-2 attachment, but instead block a downstream ACE2-dependent entry step.…”

Section: Discussionmentioning

confidence: 99%

A potently neutralizing anti-SARS-CoV-2 antibody inhibits variants of concern by binding a highly conserved epitope

VanBlargan

Adams

et al. 2021

Preprint

View full text Add to dashboard Cite

SUMMARYWith the emergence of SARS-CoV-2 variants with increased transmissibility and potential resistance, antibodies and vaccines with broadly inhibitory activity are needed. Here we developed a panel of neutralizing anti-SARS-CoV-2 mAbs that bind the receptor binding domain of the spike protein at distinct epitopes and block virus attachment to cells and its receptor, human angiotensin converting enzyme-2 (hACE2). While several potently neutralizing mAbs protected K18-hACE2 transgenic mice against infection caused by historical SARS-CoV-2 strains, others induced escape variantsin vivoand lost activity against emerging strains. We identified one mAb, SARS2-38, that potently neutralizes all SARS-CoV-2 variants of concern tested and protects mice against challenge by multiple SARS-CoV-2 strains. Structural analysis showed that SARS2-38 engages a conserved epitope proximal to the receptor binding motif. Thus, treatment with or induction of inhibitory antibodies that bind conserved spike epitopes may limit the loss of potency of therapies or vaccines against emerging SARS-CoV-2 variants.

show abstract

“…In this study, we reveal caspase-6 as an essential host factor for efficient coronavirus replication. Caspase-6 inhibition limits the replication of all evaluated human-pathogenic The replication of coronaviruses including MERS-CoV and SARS-CoV-2 is known to depend on a host serine protease, transmembrane protease serine 2 (TMPRSS2), which cleavage activates the spike (S) protein of coronaviruses for efficient entry and replication 28,29 . In contrast, the role of host cysteine-aspartic protease on coronavirus replication has not been explored.…”

Section: Discussionmentioning

confidence: 99%

Coronaviruses exploit a host cysteine-aspartic protease for efficient replication

Yuen

Hin

Hou

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

Highly pathogenic coronaviruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1,2, Middle East respiratory syndrome coronavirus (MERS-CoV)3,4, and SARS-CoV-15 vary in their transmissibility and pathogenicity. However, infection by all three viruses result in substantial apoptosis in cell culture6-8 and in patient samples9-11, suggesting a potential link between apoptosis and the pathogenesis of coronaviruses. To date, the underlying mechanism of how apoptosis modulates coronavirus pathogenesis is unknown. Here we show that a cysteine-aspartic protease of the apoptosis cascade, caspase-6, serves as an essential host factor for efficient coronavirus replication. We demonstrate that caspase-6 cleaves coronavirus nucleocapsid (N) proteins, generating N fragments that serve as interferon (IFN) antagonists, thus facilitating virus replication. Inhibition of caspase-6 substantially attenuates the lung pathology and body weight loss of SARS-CoV-2-infected golden Syrian hamsters and improves the survival of mouse-adapted MERS-CoV (MERS-CoVMA)-infected human DPP4 knock-in (hDPP4 KI) mice. Overall, our study reveals how coronaviruses exploit a component of the host apoptosis cascade to facilitate their replication. These results further suggest caspase-6 as a potential target of intervention for the treatment of highly pathogenic coronavirus infections including COVID-19 and MERS.

show abstract

Host and viral determinants for efficient SARS-CoV-2 infection of the human lung

Cited by 121 publications

References 59 publications

STAT2-dependent restriction of Zika virus by human macrophages but not dendritic cells

STAT2-dependent restriction of Zika virus by human macrophages but not dendritic cells

A potently neutralizing anti-SARS-CoV-2 antibody inhibits variants of concern by binding a highly conserved epitope

Coronaviruses exploit a host cysteine-aspartic protease for efficient replication

Contact Info

Product

Resources

About