Mutations in SARS-CoV-2 variant nsp6 enhance type-I interferon antagonism

Bills, Cody J.; Xia, Hongjie; Chen, John Yun-Chung; Yeung, Jason; Kalveram, Birte; Walker, David H.; Xie, Xuping; Shi, Pei–Yong

doi:10.1080/22221751.2023.2209208

Cited by 10 publications

(5 citation statements)

References 52 publications

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“…We show that these two variants differ in their ability to inhibit the interferon response in individuals infected with SARS-CoV-2. This is supported by gene expression and interactome analyses, which corroborate the findings of previous researchers that studied the interferon response in tissue culture samples and animal models [43].…”

Section: Discussionsupporting

confidence: 89%

Differential Type-I Interferon Response in Buffy Coat Transcriptome of Individuals Infected with SARS-CoV-2 Gamma and Delta Variants

da Fonseca,

Cavalcante,

Brustolini

et al. 2023

IJMS

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The innate immune system is the first line of defense against pathogens such as the acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The type I-interferon (IFN) response activation during the initial steps of infection is essential to prevent viral replication and tissue damage. SARS-CoV and SARS-CoV-2 can inhibit this activation, and individuals with a dysregulated IFN-I response are more likely to develop severe disease. Several mutations in different variants of SARS-CoV-2 have shown the potential to interfere with the immune system. Here, we evaluated the buffy coat transcriptome of individuals infected with Gamma or Delta variants of SARS-CoV-2. The Delta transcriptome presents more genes enriched in the innate immune response and Gamma in the adaptive immune response. Interactome and enriched promoter analysis showed that Delta could activate the INF-I response more effectively than Gamma. Two mutations in the N protein and one in the nsp6 protein found exclusively in Gamma have already been described as inhibitors of the interferon response pathway. This indicates that the Gamma variant evolved to evade the IFN-I response. Accordingly, in this work, we showed one of the mechanisms that variants of SARS-CoV-2 can use to avoid or interfere with the host Immune system.

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Section: Discussionsupporting

confidence: 89%

Differential Type-I Interferon Response in Buffy Coat Transcriptome of Individuals Infected with SARS-CoV-2 Gamma and Delta Variants

da Fonseca,

Cavalcante,

Brustolini

et al. 2023

IJMS

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“…CD63, as a tetraspanin protein, mainly distributes on the cell membrane and endosome membrane ( 37 , 57 ). In contrast, NSP6 is a multi-transmembrane protein that localizes on the ER membrane and in the perinuclear space ( 24 , 58 ). After co-transfecting GFP-tagged NSP6 (NSP6-GFP) with CD63-RFP, we found that most CD63 proteins were redistributed from the membrane surface into the cytoplasm and significantly co-localized with NSP6 proteins ( Fig.…”

Section: Resultsmentioning

confidence: 99%

NSP6 inhibits the production of ACE2-containing exosomes to promote SARS-CoV-2 infectivity

Lv,

Chen,

Liang

et al. 2024

mBio

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The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has triggered a global pandemic, which severely endangers public health. Our and others’ works have shown that the angiotensin-converting enzyme 2 (ACE2)-containing exosomes (ACE2-exos) have superior antiviral efficacies, especially in response to emerging variants. However, the mechanisms of how the virus counteracts the host and regulates ACE2-exos remain unclear. Here, we identified that SARS-CoV-2 nonstructural protein 6 (NSP6) inhibits the production of ACE2-exos by affecting the protein level of ACE2 as well as tetraspanin-CD63 which is a key factor for exosome biogenesis. We further found that the protein stability of CD63 and ACE2 is maintained by the deubiquitination of proteasome 26S subunit, non-ATPase 12 (PSMD12). NSP6 interacts with PSMD12 and counteracts its function, consequently promoting the degradation of CD63 and ACE2. As a result, NSP6 diminishes the antiviral efficacy of ACE2-exos and facilitates the virus to infect healthy bystander cells. Overall, our study provides a valuable target for the discovery of promising drugs for the treatment of coronavirus disease 2019. IMPORTANCE The outbreak of coronavirus disease 2019 (COVID-19) severely endangers global public health. The efficacy of vaccines and antibodies declined with the rapid emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutants. Angiotensin-converting enzyme 2-containing exosomes (ACE2-exos) therapy exhibits a broad neutralizing activity, which could be used against various viral mutations. Our study here revealed that SARS-CoV-2 nonstructural protein 6 inhibited the production of ACE2-exos, thereby promoting viral infection to the adjacent bystander cells. The identification of a new target for blocking SARS-CoV-2 depends on fully understanding the virus-host interaction networks. Our study sheds light on the mechanism by which the virus resists the host exosome defenses, which would facilitate the study and design of ACE2-exos-based therapeutics for COVID-19.

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“…Notably, the T429I substitution in non-structural protein-4 (NSP4) enhances replication capacity, improves evasion mechanisms against host immune responses, and augments the infectivity of SARS-CoV-2 [ 75 ]. Similarly, the triple deletion ΔSGF in non-structural protein-6 (NSP6) significantly impacts host-pathogen interactions, resulting in discernible alterations in the virulence profile of SARS-CoV-2 [ 76 ].…”

Section: Discussionmentioning

confidence: 99%

Unraveling the genetic variations underlying virulence disparities among SARS-CoV-2 strains across global regions: insights from Pakistan

Jabeen,

Shoukat,

Shireen

et al. 2024

Virol J

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Over the course of the COVID-19 pandemic, several SARS-CoV-2 variants have emerged that may exhibit different etiological effects such as enhanced transmissibility and infectivity. However, genetic variations that reduce virulence and deteriorate viral fitness have not yet been thoroughly investigated. The present study sought to evaluate the effects of viral genetic makeup on COVID-19 epidemiology in Pakistan, where the infectivity and mortality rate was comparatively lower than other countries during the first pandemic wave. For this purpose, we focused on the comparative analyses of 7096 amino-acid long polyprotein pp1ab. Comparative sequence analysis of 203 SARS-CoV-2 genomes, sampled from Pakistan during the first wave of the pandemic revealed 179 amino acid substitutions in pp1ab. Within this set, 38 substitutions were identified within the Nsp3 region of the pp1ab polyprotein. Structural and biophysical analysis of proteins revealed that amino acid variations within Nsp3’s macrodomains induced conformational changes and modified protein-ligand interactions, consequently diminishing the virulence and fitness of SARS-CoV-2. Additionally, the epistatic effects resulting from evolutionary substitutions in SARS-CoV-2 proteins may have unnoticed implications for reducing disease burden. In light of these findings, further characterization of such deleterious SARS-CoV-2 mutations will not only aid in identifying potential therapeutic targets but will also provide a roadmap for maintaining vigilance against the genetic variability of diverse SARS-CoV-2 strains circulating globally. Furthermore, these insights empower us to more effectively manage and respond to potential viral-based pandemic outbreaks of a similar nature in the future.

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Mutations in SARS-CoV-2 variant nsp6 enhance type-I interferon antagonism

Cited by 10 publications

References 52 publications

Differential Type-I Interferon Response in Buffy Coat Transcriptome of Individuals Infected with SARS-CoV-2 Gamma and Delta Variants

Differential Type-I Interferon Response in Buffy Coat Transcriptome of Individuals Infected with SARS-CoV-2 Gamma and Delta Variants

NSP6 inhibits the production of ACE2-containing exosomes to promote SARS-CoV-2 infectivity

Unraveling the genetic variations underlying virulence disparities among SARS-CoV-2 strains across global regions: insights from Pakistan

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