Mutations in viral nucleocapsid protein and endoRNase are discovered to associate with COVID19 hospitalization risk

Abstract

SARS-CoV-2 is spreading worldwide with continuously evolving variants, some of which occur in the Spike protein and appear to increase viral transmissibility. However, variants that cause severe COVID-19 or lead to other breakthroughs have not been well characterized. To discover such viral variants, we assembled a cohort of 683 COVID-19 patients; 388 inpatients (“cases”) and 295 outpatients (“controls”) from April to August 2020 using electronically captured COVID test request forms and sequenced their viral genomes. To improve the analytical power, we accessed 7137 viral sequences in Washington State to filter out viral single nucleotide variants (SNVs) that did not have significant expansions over the collection period. Applying this filter led to the identification of 53 SNVs that were statistically significant, of which 13 SNVs each had 3 or more variant copies in the discovery cohort. Correlating these selected SNVs with case/control status, eight SNVs were found to significantly associate with inpatient status (q-values < 0.01). Using temporal synchrony, we identified a four SNV-haplotype (t19839-g28881-g28882-g28883) that was significantly associated with case/control status (Fisher’s exact p = 2.84 × 10–11). This haplotype appeared in April 2020, peaked in June, and persisted into January 2021. The association was replicated (OR = 5.46, p-value = 4.71 × 10−12) in an independent cohort of 964 COVID-19 patients (June 1, 2020 to March 31, 2021). The haplotype included a synonymous change N73N in endoRNase, and three non-synonymous changes coding residues R203K, R203S and G204R in the nucleocapsid protein. This discovery points to the potential functional role of the nucleocapsid protein in triggering “cytokine storms” and severe COVID-19 that led to hospitalization. The study further emphasizes a need for tracking and analyzing viral sequences in correlations with clinical status.

Clinical Severity of SARS-CoV-2 Omicron Variant Compared with Delta among Hospitalized COVID-19 Patients in Belgium during Autumn and Winter Season 2021–2022

“…9 C-reactive protein. 10 Defined as a combination of three binary severity indicators: having been admitted to ICU and/or developed acute respiratory distress syndrome (ARDS) and/or died in the hospital. 11 Extracorporeal life support.…”

“…Moreover, the risk for severe outcomes has been evolving over time as successive COVID-19 waves have been triggered by emerging SARS-CoV-2 variants with varying epidemiological characteristics [7]. These new variants accumulate mutations impacting their transmissibility, immune escape, and/or virulence [8][9][10].…”

Investigation of a SARS-CoV-2 outbreak in a Texas summer camp resulting from a single introduction

“…The results were aligned with 3 additional genomes that were isolated from an Arlington, TX family that tested positive following contact with asymptomatic attendees after the camp concluded. The Arlington genomes were sequenced using similar methods (35). All genomes are available on GSAID EPI_ISL_12486186-213 (Table 1).…”

GenomeBits insight into omicron and delta variants of coronavirus pathogen

“…This debate, however, highlights the need for a global network of real-time surveillance systems, with the capacity to rapidly deploy genomic tools and statistical studies for pathogen identification and characterization of the evolution of potential lineages and mutations. SARS-CoV-2 is still spreading worldwide with evolving variants, some of which occur in the Spike protein and appear to increase viral infection [ 4 ]. The recent study in Ref [ 4 ], emphasizes the need to track and analyze viral sequences also in relation to clinical status.…”

“…SARS-CoV-2 is still spreading worldwide with evolving variants, some of which occur in the Spike protein and appear to increase viral infection [ 4 ]. The recent study in Ref [ 4 ], emphasizes the need to track and analyze viral sequences also in relation to clinical status.…”