SARS-CoV-2 coinfections with variant genomic lineages identified by multiplex fragment analysis

Lueking, Richard; Clark, Andrew E.; Narasimhan, Madhusudhanan; Mahimainathan, Lenin; Muthukumar, Alagarraju; Larsen, Christian; SoRelle, Jeffrey A.

doi:10.3389/fgene.2022.942713

Cited by 5 publications

(4 citation statements)

References 47 publications

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“…face with necrosis and release of exudates in the tumors after 30 days, therefore we did not measure virus titers after 30 dpi. However, if we find better tumor model, long-term replication in the mouse xenografts may continue much longer, as it does in human patients with SARS-CoV-2 infection (Avanzato et al, 2020;Borges et al, 2021;Clark et al, 2021;Lueking et al, 2022). We believe the selection of appropriate cells that do not suffer cytopathic effects due to SARS-CoV-2 infection was the most important factor in our model.…”

Section: Discussionmentioning

confidence: 94%

“…During the last 3 years, several SARS-CoV-2 variants have appeared and transmit around the globe. Several hypotheses were suggested to explain this emergence of SARS-CoV-2 variants, including persistent infection in immunocompromised patients (Avanzato et al, 2020;Choi et al, 2020;Borges et al, 2021), simultaneous infection and recombination of variants in unvaccinated or immunocompromised individuals (Lueking et al, 2022;Markov et al, 2023) and transmission between humans and animals resulting in accelerated evolution (Bashor et al, 2021). We are interested in the first hypothesis: persistent infection of SARS-CoV-2.…”

Section: Discussionmentioning

confidence: 99%

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Analysis of spike protein variants evolved in a novel in vivo long-term replication model for SARS-CoV-2

Kim,

Kim

et al. 2023

Front. Cell. Infect. Microbiol.

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IntroductionThe spectrum of SARS-CoV-2 mutations have increased over time, resulting in the emergence of several variants of concern. Persistent infection is assumed to be involved in the evolution of the variants. Calu-3 human lung cancer cells persistently grow without apoptosis and release low virus titers after infection.MethodsWe established a novel in vivo long-term replication model using xenografts of Calu-3 human lung cancer cells in immunodeficient mice. Virus replication in the tumor was monitored for 30 days and occurrence of mutations in the viral genome was determined by whole-genome deep sequencing. Viral isolates with mutations were selected after plaque forming assays and their properties were determined in cells and in K18-hACE2 mice.ResultsAfter infection with parental SARS-CoV-2, viruses were found in the tumor tissues for up to 30 days and acquired various mutations, predominantly in the spike (S) protein, some of which increased while others fluctuated for 30 days. Three viral isolates with different combination of mutations produced higher virus titers than the parental virus in Calu-3 cells without cytopathic effects. In K18-hACE2 mice, the variants were less lethal than the parental virus. Infection with each variant induced production of cross-reactive antibodies to the receptor binding domain of parental SARS-CoV-2 S protein and provided protective immunity against subsequent challenge with parental virus.DiscussionThese results suggest that most of the SARS-CoV-2 variants acquired mutations promoting host adaptation in the Calu-3 xenograft mice. This model can be used in the future to further study SARS-CoV-2 variants upon long-term replication in vivo.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Analysis of spike protein variants evolved in a novel in vivo long-term replication model for SARS-CoV-2

Kim,

Kim

et al. 2023

Front. Cell. Infect. Microbiol.

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“…Superinfections may have occurred when the incidence rates were highest during the pandemic, mainly in cases at high risk of overexposure (nosocomial outbreaks, HCWs, highly dependent cases) as was the case in our study [ 27 ]. Increased risk for co-infection involving different lineages (Delta, Omicron BA.1 or Omicron BA.2) has been reported for in immunocompromised patients elsewhere [ 28 ]. In five of our cases, one of the co-infecting strains was also identified circulating in the population close to the case diagnosis (data not shown), which would probably indicate superinfection.…”

Section: Discussionmentioning

confidence: 99%

Systematic genomic analysis of SARS-CoV-2 co-infections throughout the pandemic and segregation of the strains involved

et al. 2023

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Background SARS-CoV-2 recombinants involving the divergent Delta and Omicron lineages have been described, and one of them, “Kraken” (XBB.1.5), has recently been a matter of concern. Recombination requires the coexistence of two SARS-CoV-2 strains in the same individual. Only a limited number of studies have focused on the identification of co-infections and are restricted to co-infections involving the Delta/Omicron lineages. Methods We performed a systematic identification of SARS-CoV-2 co-infections throughout the pandemic (7609 different patients sequenced), not biassed towards the involvement of highly divergent lineages. Through a comprehensive set of validations based on the distribution of allelic frequencies, phylogenetic consistency, re-sequencing, host genetic analysis and contextual epidemiological analysis, these co-infections were robustly assigned. Results Fourteen (0.18%) co-infections with ≥ 8 heterozygous calls (8–85 HZs) were identified. Co-infections were identified throughout the pandemic and involved an equal proportion of strains from different lineages/sublineages (including pre-Alpha variants, Delta and Omicron) or strains from the same lineage. Co-infected cases were mainly unvaccinated, with mild or asymptomatic clinical presentation, and most were at risk of overexposure associated with the healthcare environment. Strain segregation enabled integration of sequences to clarify nosocomial outbreaks where analysis had been impaired due to co-infection. Conclusions Co-infection cases were identified throughout the pandemic, not just in the time periods when highly divergent lineages were co-circulating. Co-infections involving different lineages or strains from the same lineage were occurring in the same proportion. Most cases were mild, did not require medical assistance and were not vaccinated, and a large proportion were associated with the hospital environment.

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“…For recombination to occur, an individual has to be infected with two different lineages 13 , 15 which leads to the hypothesis that co-infection should take place frequently. This can happen in immunocompromised individuals, who have been described to be prolongedly infected with SARS-CoV-2 16 , but also in the general population 4 – 6 .…”

Section: Introductionmentioning

confidence: 99%

Systematic detection of co-infection and intra-host recombination in more than 2 million global SARS-CoV-2 samples

Pipek,

Medgyes-Horváth,

Stéger

et al. 2024

Nat Commun

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Systematic monitoring of SARS-CoV-2 co-infections between different lineages and assessing the risk of intra-host recombinant emergence are crucial for forecasting viral evolution. Here we present a comprehensive analysis of more than 2 million SARS-CoV-2 raw read datasets submitted to the European COVID-19 Data Portal to identify co-infections and intra-host recombination. Co-infection was observed in 0.35% of the investigated cases. Two independent procedures were implemented to detect intra-host recombination. We show that sensitivity is predominantly determined by the density of lineage-defining mutations along the genome, thus we used an expanded list of mutually exclusive defining mutations of specific variant combinations to increase statistical power. We call attention to multiple challenges rendering recombinant detection difficult and provide guidelines for the reduction of false positives arising from chimeric sequences produced during PCR amplification. Additionally, we identify three recombination hotspots of Delta – Omicron BA.1 intra-host recombinants.

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SARS-CoV-2 coinfections with variant genomic lineages identified by multiplex fragment analysis

Cited by 5 publications

References 47 publications

Analysis of spike protein variants evolved in a novel in vivo long-term replication model for SARS-CoV-2

Analysis of spike protein variants evolved in a novel in vivo long-term replication model for SARS-CoV-2

Systematic genomic analysis of SARS-CoV-2 co-infections throughout the pandemic and segregation of the strains involved

Systematic detection of co-infection and intra-host recombination in more than 2 million global SARS-CoV-2 samples

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