Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused millions of deaths and substantial morbidity worldwide. Intense scientific effort to understand the biology of SARS-CoV-2 has resulted in daunting numbers of genomic sequences. We witnessed evolutionary events that could mostly be inferred indirectly before, such as the emergence of variants with distinct phenotypes, for example transmissibility, severity and immune evasion. This Review explores the mechanisms that generate genetic variation in SARS-CoV-2, underlying the within-host and population-level processes that underpin these events. We examine the selective forces that likely drove the evolution of higher transmissibility and, in some cases, higher severity during the first year of the pandemic and the role of antigenic evolution during the second and third years, together with the implications of immune escape and reinfections, and the increasing evidence for and potential relevance of recombination. In order to understand how major lineages, such as variants of concern (VOCs), are generated, we contrast the evidence for the chronic infection model underlying the emergence of VOCs with the possibility of an animal reservoir playing a role in SARS-CoV-2 evolution, and conclude that the Nature Reviews Microbiology Review articlevirus (HIV; ~10 -4 × 10 -6 mutations per nucleotide per replication cycle), which, unlike coronaviruses, lack a 3′ exonuclease proofreading mechanism in their replication machinery 8,[10][11][12] . Insertions and deletions result from replication errors and can also generate diversity, such as the deletion at position 69-70 of the spike gene responsible for the S-gene dropout that was instrumental in detecting the SARS-CoV-2 Alpha variant, and has been reported to be associated with increased infectivity 13 .In addition to RNA replication errors, host-mediated genome editing by innate cell defence mechanisms may introduce substantial numbers of directed mutations into the SARS-CoV-2 genome, and thus may influence its evolutionary rate. Cellular mutational drivers include members of the apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) family [14][15][16] , including APOBEC1, APOBEC3A and APOBEC3G that demonstrate editing activity for numerous DNA and RNA virus and retroviral genomes 17,18 , including SARS- . APOBEC activity has been inferred bioinformatically through observations of a substantial excess of C → U transitions over all other mutations 18,20,21 . SARS-CoV-2 genomes may also be edited by different cellular antiviral proteins (adenosine deaminases that act on RNA 1 (ADAR1)), leading to A → G mutations (and U → C mutations in opposite genomic strands) 21,22 .The potential editing-associated C → U mutations in the SARS-CoV-2 genome sequences introduce complexities to SARS-CoV-2 evolutionary genomic analysis. C → U mutations account, in part, for the strikingly high ratio of non-synonymous changes in SARS-CoV-2 genomes compared with those at synonymous sites; the mean dN/dS ratio ...
The comparatively milder infections with the Omicron variant and higher levels of population immunity have raised hopes for a weakening of the pandemic. We argue that the lower severity of Omicron is a coincidence and that ongoing rapid antigenic evolution is likely to produce new variants that may escape immunity and be more severe.
Background: In previous studies we have shown that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replicates in vitro in bacterial growth medium, that the viral replication follows bacterial growth, and it is influenced by the administration of specific antibiotics. These observations are compatible with a ‘bacteriophage-like’ behaviour of SARS-CoV-2. Methods: We have further elaborated on these unusual findings and here we present the results of three different supplementary experiments: (1) an electron-microscope analysis of samples of bacteria obtained from a faecal sample of a subject positive to SARS-CoV-2; (2) mass spectrometric analysis of these cultures to assess the eventual de novo synthesis of SARS-CoV-2 spike protein; (3) sequencing of SARS-CoV-2 collected from plaques obtained from two different gut microbial bacteria inoculated with supernatant from faecal microbiota of an individual positive to SARS-CoV-2. Results: Immuno-labelling with Anti-SARS-CoV-2 nucleocapsid protein antibody confirmed presence of SARS-CoV-2 both outside and inside bacteria. De novo synthesis of SARS-CoV-2 spike protein was observed, as evidence that SARS-CoV-2 RNA is translated in the bacterial cultures. In addition, phage-like plaques were spotted on faecal bacteria cultures after inoculation with supernatant from faecal microbiota of an individual positive to SARS-CoV-2. Bioinformatic analyses on the reads obtained by sequencing RNA extracted from the plaques revealed nucleic acid polymorphisms, suggesting different replication environment in the two bacterial cultures. Conclusions: Based on these results we conclude that, in addition to its well-documented interactions with eukaryotic cells, SARS-CoV-2 may act as a bacteriophage when interacting with at least two bacterial species known to be present in the human microbiota. If the hypothesis proposed, i.e., that under certain conditions SARS-CoV-2 may multiply at the expense of human gut bacteria, is further substantiated, it would drastically change the model of acting and infecting of SARS-CoV-2, and most likely that of other human pathogenic viruses.
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