Characteristics of replication and pathogenicity of SARS-CoV-2 Alpha and Delta isolates

Feng, Xiaoli; Yu, Dandan; Zhang, Mi; Li, Xiaohong; Zou, Qing-Cui; Ma, Wenping; Han, Jian; Xu, Ling; Yang, Cuixian; Wang, Qu; Deng, Zhonghua; Long, Junyi; Long, Yanghaopeng; Li, Mingkun; Yao, Yong-Gang; Dong, Xingqi; Zeng, Jianxiong; Li, Minghua

doi:10.1016/j.virs.2022.09.007

Cited by 5 publications

(8 citation statements)

References 59 publications

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“…However, when using epithelial cell lines derived from human lung (Calu-3) and intestine (Caco-2), we found no evidence of SARS-CoV-2 infection enhancement by NTD-binding mAbs. Both Caco-2 and Calu-3 cells express ACE2 and are widely used to characterize SARS-CoV-2 infection in vitro (35–39). The relative absence of infection enhancement with NTD-binding antibodies in these cells may result from lower ACE2 expression, a possibility that aligns with the observed impact of ACE2 expression levels on experimental measures of antibody neutralization of SARS-CoV-2 (40).…”

Section: Discussionmentioning

confidence: 99%

Characteristics and functions of infection-enhancing antibodies to the N-terminal domain of SARS-CoV-2

Connor,

Sakharkar,

Rappazzo

et al. 2023

Preprint

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Characterization of functional antibody responses to the N-terminal domain (NTD) of the SARS-CoV-2 spike (S) protein has included identification of both potent neutralizing activity and putative enhancement of infection. Fcγ-receptor (FcγR)-independent enhancement of SARS-CoV-2 infection mediated by NTD-binding monoclonal antibodies (mAbs) has been observed in vitro, but the functional significance of these antibodies in vivo is not clear. Here we studied 1,213 S-binding mAbs derived from longitudinal sampling of B-cells collected from eight COVID-19 convalescent patients and identified 72 (5.9%) mAbs that enhanced infection in a VSV-SARS-CoV-2-S-Wuhan pseudovirus (PV) assay. The majority (68%) of these mAbs recognized the NTD, were identified in patients with mild and severe disease, and persisted for at least five months post-infection. Enhancement of PV infection by NTD-binding mAbs was not observed using intestinal (Caco-2) and respiratory (Calu-3) epithelial cells as infection targets and was diminished or lost against SARS-CoV-2 variants of concern (VOC). Proteomic deconvolution of the serum antibody repertoire from two of the convalescent subjects identified, for the first time, NTD-binding, infection-enhancing mAbs among the circulating immunoglobulins directly isolated from serum (i.e., functionally secreted antibody). Functional analysis of these mAbs demonstrated robust activation of FcγRIIIa associated with antibody binding to recombinant S proteins. Taken together, these findings suggest functionally active NTD-specific mAbs arise frequently during natural infection and can last as major serum clonotypes during convalescence. These antibodies display diverse attributes that include FcγR activation, and may be selected against by mutations in NTD associated with SARS-CoV-2 VOC.

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Section: Discussionmentioning

confidence: 99%

Characteristics and functions of infection-enhancing antibodies to the N-terminal domain of SARS-CoV-2

Connor,

Sakharkar,

Rappazzo

et al. 2023

Preprint

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“…The SARS‐CoV‐2 variants, Delta (B.1.617.2), BA.2.75, and BA.5.2, were provided by the Kunming National High‐level Biosafety Research Center for Non‐Human Primates in the KIZ. The isolation and identification of the Delta strain have been described 54 . In brief, the variants were isolated from clinical specimens (nasopharyngeal swabs) containing SARS‐CoV‐2, propagated, and titrated in Vero E6 cells.…”

Section: Methodsmentioning

confidence: 99%

“…The isolation and identification of the Delta strain have been described. 54 In brief, the variants were isolated from clinical specimens (nasopharyngeal swabs) containing SARS-CoV-2, propagated, and titrated in Vero E6 cells. The viral genome was then extracted and subjected to wholegenome sequencing, and the variant was identified by comparing and analyzing the viral genome using Nextstrain (https://nextstrain.org/).…”

Section: Sars-cov-2 Variantsmentioning

confidence: 99%

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Differential pathogenic and molecular features in neurological infection of SARS‐CoV‐2 Omicron BA.5.2 and BA.2.75 and Delta

Wang,

Yang,

et al. 2024

Journal of Medical Virology

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The Coronavirus disease 2019 (COVID‐19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) remains a global threat, exacerbated by the emergence of viral variants. Two variants of SARS‐CoV‐2, Omicron BA.2.75 and BA.5, led to global infection peaks between May 2022 and May 2023, yet their precise characteristics in pathogenesis are not well understood. In this study, we compared these two Omicron sublineages with the previously dominant Delta variant using a human angiotensin‐converting enzyme 2 knock‐in mouse model. As expected, Delta exhibited higher viral replication in the lung and brain than both Omicron sublineages which induced less severe lung damage and immune activation. In contrast, the Omicron variants especially BA.5.2 showed a propensity for cellular proliferation and developmental pathways. Both Delta and BA.5.2 variants, but not BA.2.75, led to decreased pulmonary lymphocytes, indicating differential adaptive immune response. Neuroinvasiveness was shared with all strains, accompanied by vascular abnormalities, synaptic injury, and loss of astrocytes. However, Immunostaining assays and transcriptomic analysis showed that BA.5.2 displayed stronger immune suppression and neurodegeneration, while BA.2.75 exhibited more similar characteristics to Delta in the cortex. Such differentially infectious features could be partially attributed to the weakened interaction between Omicron Spike protein and host proteomes decoded via co‐immunoprecipitation followed by mass spectrometry in neuronal cells. Our present study supports attenuated replication and pathogenicity of Omicron variants but also highlights their newly infectious characteristics in the lung and brain, especially with BA.5.2 demonstrating enhanced immune evasion and neural damage that could exacerbate neurological sequelae.

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“…The SARS-CoV-2 prototype was kindly provided by the Guangdong Provincial Center for Disease Control and Prevention (Guangdong, China), as described in our previous studies (60)(61)(62) Gibco, USA) supplemented with 10% FBS (Gibco, USA), 1% MEM non-essential acids (Gibco, USA), 1% sodium pyruvate (100 mM, Gibco, USA), and 1% antibiotics.…”

Section: Viral Strains and Cellsmentioning

confidence: 99%

Primate-specific BTN3A2 protects against SARS-CoV-2 infection by interacting with and reducing ACE2

Xu,

Yu,

et al. 2024

Preprint

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Coronavirus disease 2019 (COVID-19) is an immune-related disorder caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 invades cells via the entry receptor angiotensin-converting enzyme 2 (ACE2). While several attachment factors and co-receptors for SARS-CoV-2 have been identified, the complete pathogenesis of the virus remains to be determined. Unraveling the molecular mechanisms governing SARS-CoV-2 interactions with host cells is crucial for the formulation of effective prophylactic measures and the advancement of COVID-19 therapeutics. Here, we identified butyrophilin subfamily 3 member A2 (BTN3A2) as a potent inhibitor of SARS-CoV-2 infection. The mRNA level of BTN3A2 was correlated with COVID-19 severity. Upon re-analysis of a human lung single-cell RNA sequencing dataset, BTN3A2 expression was predominantly identified in epithelial cells. Moreover, this expression was elevated in pathological epithelial cells from COVID-19 patients and co-occurred with ACE2 expression in the same cellular subtypes in the lung. Additionally, BTN3A2 primarily targeted the early stage of the viral life cycle by inhibiting SARS-CoV-2 attachment through direct interactions with the receptor-binding domain (RBD) of the Spike protein and ACE2. Furthermore, BTN3A2 inhibited ACE2-mediated SARS-CoV-2 infection by reducing ACE2 in vitro and in a BTN3A2 transgenic mouse model. These results reveal a key role of BTN3A2 in the fight against COVID-19 and broaden our understanding of the pathobiology of SARS-CoV-2 infection. Identifying potential monoclonal antibodies that target BTN3A2 may facilitate disruption of SARS-CoV-2 infection, providing a therapeutic avenue for COVID-19.

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Characteristics of replication and pathogenicity of SARS-CoV-2 Alpha and Delta isolates

Cited by 5 publications

References 59 publications

Characteristics and functions of infection-enhancing antibodies to the N-terminal domain of SARS-CoV-2

Characteristics and functions of infection-enhancing antibodies to the N-terminal domain of SARS-CoV-2

Differential pathogenic and molecular features in neurological infection of SARS‐CoV‐2 Omicron BA.5.2 and BA.2.75 and Delta

Primate-specific BTN3A2 protects against SARS-CoV-2 infection by interacting with and reducing ACE2

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