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

Abstract

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. Single cell RNAseq (scRNAseq) allows for the study of individual cells, uncovering heterogeneous and variable responses to environment, infection and inflammation. While studies have reported immune profiling using scRNAseq 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. Our longitudinal scRNAseq of bronchoalveolar lavage (BAL) cell suspensions from young rhesus macaques infected with SARS-CoV-2 (n = 6) demonstrates 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) showing accumulation of distinct populations of both macrophages and T-lymphocytes expressing strong interferon-driven inflammatory gene signature at 3dpi. Type I interferon response is induced in the plasmacytoid dendritic cells with appearance of a distinct HLADR+CD68+CD163+SIGLEC1+ macrophage population exhibiting higher angiotensin-converting enzyme 2 (ACE2) expression. These macrophages are significantly enriched in the lungs of macaques at 3dpi and harbor 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.

Isoniazid and rifapentine treatment effectively reduces persistent M. tuberculosis infection in macaque lungs

“…Briefly, the region of interest (ROI) ( 29 ) was drawn using connected thresholding referencing Hounsfield units for the lung, while also drawn manually, to identify lung lesions as previously described ( 30 ). Subsequently, image-derived mean SUVs were calculated for the complete lung ROI and represented as total lung activity, while the mean SUV for the lung lesion ROI are represented as lung lesion activity ( 31 ).…”

“…tuberculosis CDC1551, and of the 12 animals that developed latent tuberculosis infection, 6 were left untreated, while 6 were treated weekly with isoniazid and rifapentine for 3 months (3HP) and rested for 1 month before coinfection with SIV. ( 30 ) Animals were monitored for signs of disease such as ( B ) C-reactive protein (CRP), ( C ) pyrexia, and ( D ) wasting throughout the study. The thin dotted lines represent the treatment period and the thick dotted line represents SIV coinfection.…”

Bioinformatics approach to identify the influences of SARS-COV2 infections on atherosclerosis

“…Among plasmacytoid dendritic cells, type I interferon is induced with the appearance of CD163+ SIGLEC1+ macrophages with increased angiotensin converting enzyme 2 (ACE2) levels ( 24 ). Macrophages are highly enriched in the lungs of macaques at peak viremia and harbor the SARS-CoV-2 virus while also expressing an interferon-driven innate antiviral gene signature ( 25 ). CD163(+) macrophages promote angiogenesis, vascular permeability and inflammation in atherosclerosis via the CD163/HIF1α/VEGF-A pathway.…”

Oxysterols drive inflammation via GPR183 during influenza virus and SARS-CoV-2 infection

“…In non-human primates, influenza virus infection leads to infiltration of myeloid cells into the lungs (30). Similarly, in several animal models of acute infection with SARS-CoV-2, macrophages rapidly infiltrate the lungs (4–6). Patients with severe COVID-19 infection had higher proportions of macrophages and neutrophils in BALF, with the macrophage phenotype from deceased COVID-19 patients being more activated (28).…”

“…A study of >600 hospitalised patients found that in severe cases resident alveolar macrophages were depleted and replaced by large numbers of inflammatory monocytes and monocyte- derived macrophages (3). Rapid monocyte infiltration of the lung during the acute phase of severe acute respiratory coronavirus 2 (SARS-CoV-2) infection is replicated in several animal models (4–6). On the other hand, monocyte recruitment is also an essential component of repair following lung injury (7).…”