Myeloid cell interferon responses correlate with clearance of SARS-CoV-2

Abstract

The emergence of mutant SARS-CoV-2 strains associated with an increased risk of COVID-19-related death necessitates better understanding of the early viral dynamics, host responses and immunopathology. While studies have reported immune profiling using single cell RNA sequencing in terminal human COVID-19 patients, performing longitudinal immune cell dynamics in humans is challenging. Macaques are a suitable model of SARS-CoV-2 infection. We performed longitudinal single-cell RNA sequencing of bronchoalveolar lavage (BAL) cell suspensions from adult rhesus macaques infected with SARS-CoV-2 (n=6) to delineate the early dynamics of immune cells changes. The bronchoalveolar compartment exhibited dynamic changes in transcriptional landscape 3 days post- SARS-CoV-2-infection (3dpi) (peak viremia), relative to 14-17dpi (recovery phase) and pre-infection (baseline). We observed the accumulation of distinct populations of both macrophages and T-lymphocytes expressing strong interferon-driven inflammatory gene signature at 3dpi. Type I IFN response was highly induced in the plasmacytoid dendritic cells. The presence of a distinct HLADR+CD68+CD163+SIGLEC1+ macrophage population exhibiting higher angiotensin converting enzyme 2 (ACE2) expression was also observed. These macrophages were significantly recruited to the lungs of macaques at 3dpi and harbored SARS-CoV-2, while expressing a strong interferon-driven innate anti-viral gene signature. The accumulation of these responses correlated with decline in viremia and recovery. The recruitment of a myeloid cell-mediated Type I IFN response is associated with the rapid clearance of SARS-CoV-2 infection in macaques.

Delineating COVID-19 immunological features using single-cell RNA sequencing

“…In addition to using samples from COVID-19 patients for research, developing animal models for COVID-19 and subjecting them to scRNA-seq could facilitate preclinical analysis of vaccines and therapeutic agents. Although there are many studies using infected animals for COVID-19 research, 87,88 only a few studies performed scRNA-seq on COVID-19-infected animals like monkeys, 89 hamsters, 90 macaques, 91 ferrets, 92 and K18-hACE2 transgenic mice. 93 Several studies demonstrated the antiviral immune responses of animal models after receiving newly developed vaccines with scRNA-seq, [94][95][96][97] revealing induced gene modules of different immune cell populations.…”

Understanding COVID-19: From Dysregulated Immunity to Vaccination Status Quo

“…This study gives additional mechanistic insights into how SARS-CoV-2 can hamper innate immune responses ( 39 ). Extensive work performed in the NHP model of SARS-CoV-2 infection indicates that these animals mount robust, early IFN responses, and simultaneously clear the infection ( 18 , 19 , 40 ). On the other hand, many humans with late to end-stage COVID-19 are characterized by a “cytokine storm” with IFN as the key cytokine.…”

“…In addition to interfering with the IFN system, SARS-CoV-2 has also been shown to infect antigen-presenting cells (APCs) including dendritic cells, macrophages and monocytes, disrupting their primitive function of activating adaptive immunity ( 24 , 25 , 40 , 42 ). While these cells did not support viral production, their attenuated functions averted strong antibody but weak CD8 T cell responses ( 24 , 25 ).…”