Immune transcriptome analysis of COVID-19 patients infected with SARS-CoV-2 variants carrying the E484K escape mutation identifies a distinct gene module

Abstract

Fast-spreading variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) energize the COVID-19 pandemic. While viral infections elicit a conserved immune response, it is not known whether SARS-CoV-2 variants, which display enhanced binding to the ACE2 receptor and reduced neutralizing activity by vaccine-elicited antibodies, prompt specific genomic immune responses. To test this, we generated and investigated the transcriptomes in BCs from hospitalized patients infected with either the Alpha variant (n = 36) or with the Alpha variant that had acquired the E484K escape mutation (Alpha+E484K) (n = 13). We identified a gene module preferentially activated in patients infected with the Alpha+E484K variant and in patients infected with the Beta (n = 9) and Gamma (n = 3) variants that also carry by the E484K escape mutation. The E484K signature was enriched for genes preferentially expressed in monocytes and linked to severe viral infection. However, both cohorts had undergone similar treatments and no differences in disease severity were reported suggesting that this signature reflects a variant response and does not necessarily associate with disease outcome. Additionally, longitudinal transcriptome analyses revealed a more persistent retention of immune signatures in Alpha+E484K patients throughout the entire course of COVID-19 disease and convalescence. While the OAS1 Neanderthal mutation has been linked to a milder COVID-19 pathology, we did not identify significant immune transcriptomes differences in the 25 patients homozygous for this mutation. Our study offers insights into distinct molecular immune responses elicited by SARS-CoV-2 variants carrying the E484K escape mutation throughout the COVID-19 disease.

Prior Vaccination Exceeds Prior Infection in Eliciting Innate and Humoral Immune Responses in Omicron Infected Outpatients

“…To understand the impact of prior vaccination or prior infection on the genomic immune response to Omicron infection, we investigated the immune transcriptome ( Figure 3 ; Table S1 ). These data sets were also compared to a naïve reference population (no previous SARS-CoV-2 infection and no vaccination) ( 10 ) and to hospitalized patients that had been infected with the Alpha variant ( 7 ). Bulk RNA-seq on buffy coats isolated within the first two days after validated Omicron infection was performed with an average sequencing depth of 200 million reads per sample.…”

“…Prior infection variant and number of days (mean and range) infected prior to Omicron infection for the vaccination/prior infection group are as follows: Delta (n=4, mean 55 days, range 34-64 days, D614G (n=2, mean 181 days, range 67-295 days, Alpha n=1, 303 days. The reference “Alpha” cohort consists of individuals (n=36, mean age 71 years) infected with the Alpha variant in the spring of 2021 that were hospitalized after developing COVID-19 ( 7 ). Blood samples were collected within 10 days of verified SARS-CoV-2 infection and the RNA was prepared by the same person, who isolated the RNA for the current Omicron study.…”

“…While Omicron infections generally result in a more moderate symptomology compared to other variants, the genomic immune response in this patient population has not been investigated. Transcriptome studies on hospitalized patients infected with the Alpha ( 7 ) or Beta ( 8 ) variants have revealed the activation of interferon pathway genes with an emphasis of the JAK/STAT pathway. While the interferon response in severely ill patients has been reported, it is not clear if Omicron patients with a generally lighter symptomology have a different immune transcriptome which can be further modulated by vaccination and prior infection.…”

Differences in transcriptional response underlie why prior vaccination exceeds prior infection in eliciting robust immune responses in Omicron infected outpatients

“…2a). Similarly to the immune transcriptome of Omicron infected individuals, a strong enrichment of innate immune genes is also observed in hospitalized patients infected with Alpha variant 3 (Fig. 2a).…”

“…These data sets were compared to reference populations that were naïve (no previous SARS-CoV-2 infection and no vaccination) (Lee et. al, Cell Reports, in press ) and to patients that had been infected with the Alpha variant 3 . Bulk RNA-seq on buffy coats isolated within the first two days after validated Omicron infection was performed with an average sequencing depth of 200 million reads per sample (Supplementary Table 2).…”