tetano
Editor, Senior Moderator
Emerg Microbes Infect
. 2021 Jan 5;1-56.
doi: 10.1080/22221751.2021.1872351. Online ahead of print.
Characterization of SARS-CoV-2 ORF6 deletion variants detected in a nosocomial cluster during routine genomic surveillance, Lyon, France
Gr?gory Qu?rom?s[SUP] 1 [/SUP], Gr?gory Destras[SUP] 1 2 [/SUP], Antonin Bal[SUP] 1 2 [/SUP], Hadrien Regue[SUP] 2 [/SUP], Gwendolyne Burfin[SUP] 2 3 [/SUP], Solenne Brun[SUP] 2 3 [/SUP], R?mi Fanget[SUP] 2 3 [/SUP], Florence Morfin[SUP] 1 2 [/SUP], Martine Valette[SUP] 1 2 3 [/SUP], Sophie Trouillet-Assant[SUP] 1 [/SUP], Bruno Lina[SUP] 1 2 3 [/SUP], Emilie Frobert[SUP] 1 2 [/SUP], Laurence Josset[SUP] 1 2 [/SUP]
Affiliations
Abstract
While the SARS-CoV-2 genome has remained relatively stable since its emergence, genomic deletions are a frequently described evolutionary pattern of previous coronaviruses with significant impacts on outbreaks. During routine molecular surveillance of SARS-CoV-2 performed at the National Reference Center of Respiratory Viruses (Lyon, France) (n=229 sequences collected Feb-April 2020), two frameshifting deletions were detected in the open reading frame 6, starting at the same position (27267). While a 26-nucleotide deletion variant (D26) was only found in one nasopharyngeal sample in March 2020, the 34-nucleotide deletion variant (D34) was found within a single geriatric hospital unit in 5/9 patients and one health care worker in April 2020. Phylogeny analysis strongly suggested a nosocomial transmission between patients for D34, with potential fecal transmission, as D34 was also identified in a stool sample. No difference in disease severity was observed within the patients hospitalized in the geriatric unit and infected with WT (n=4) or D34 (n=5). In vitro characterization of D26 and D34 revealed comparable replication kinetics with the wild-type (WT), but differential host immune responses. While interferon-stimulated genes were similarly upregulated after infection with WT and ORF6 deletion variants, the latter specifically induced overexpression of 9 genes coding for inflammatory cytokines in the NF-kB pathway, including CCL2/MCP1, PTX3, and TNFα, for which high plasma levels of these cytokines have been associated with severe COVID-19. Given the heterogeneous clinical manifestations of COVID-19, our findings emphasize the need to monitor the occurrence of ORF6 deletions and assess their impact on the host immune response.
Keywords: ORF6; SARS-CoV-2; deletion; genomic surveillance; inflammation; nosocomial cluster.
. 2021 Jan 5;1-56.
doi: 10.1080/22221751.2021.1872351. Online ahead of print.
Characterization of SARS-CoV-2 ORF6 deletion variants detected in a nosocomial cluster during routine genomic surveillance, Lyon, France
Gr?gory Qu?rom?s[SUP] 1 [/SUP], Gr?gory Destras[SUP] 1 2 [/SUP], Antonin Bal[SUP] 1 2 [/SUP], Hadrien Regue[SUP] 2 [/SUP], Gwendolyne Burfin[SUP] 2 3 [/SUP], Solenne Brun[SUP] 2 3 [/SUP], R?mi Fanget[SUP] 2 3 [/SUP], Florence Morfin[SUP] 1 2 [/SUP], Martine Valette[SUP] 1 2 3 [/SUP], Sophie Trouillet-Assant[SUP] 1 [/SUP], Bruno Lina[SUP] 1 2 3 [/SUP], Emilie Frobert[SUP] 1 2 [/SUP], Laurence Josset[SUP] 1 2 [/SUP]
Affiliations
- PMID: 33399033
- DOI: 10.1080/22221751.2021.1872351
Abstract
While the SARS-CoV-2 genome has remained relatively stable since its emergence, genomic deletions are a frequently described evolutionary pattern of previous coronaviruses with significant impacts on outbreaks. During routine molecular surveillance of SARS-CoV-2 performed at the National Reference Center of Respiratory Viruses (Lyon, France) (n=229 sequences collected Feb-April 2020), two frameshifting deletions were detected in the open reading frame 6, starting at the same position (27267). While a 26-nucleotide deletion variant (D26) was only found in one nasopharyngeal sample in March 2020, the 34-nucleotide deletion variant (D34) was found within a single geriatric hospital unit in 5/9 patients and one health care worker in April 2020. Phylogeny analysis strongly suggested a nosocomial transmission between patients for D34, with potential fecal transmission, as D34 was also identified in a stool sample. No difference in disease severity was observed within the patients hospitalized in the geriatric unit and infected with WT (n=4) or D34 (n=5). In vitro characterization of D26 and D34 revealed comparable replication kinetics with the wild-type (WT), but differential host immune responses. While interferon-stimulated genes were similarly upregulated after infection with WT and ORF6 deletion variants, the latter specifically induced overexpression of 9 genes coding for inflammatory cytokines in the NF-kB pathway, including CCL2/MCP1, PTX3, and TNFα, for which high plasma levels of these cytokines have been associated with severe COVID-19. Given the heterogeneous clinical manifestations of COVID-19, our findings emphasize the need to monitor the occurrence of ORF6 deletions and assess their impact on the host immune response.
Keywords: ORF6; SARS-CoV-2; deletion; genomic surveillance; inflammation; nosocomial cluster.