Figueiredo, L. T. M. | Search bioRxiv

bioRxiv2022

Airway epithelial cells and macrophages trigger IL-6-CD95/CD95L axis and mediate initial immunopathology of COVID-19

Airway epithelial cells (AEC) are the first in contact with SARS-CoV-2 and drive the interface with macrophage to generate inflammation. To elucidate how those initial events contribute to the immunopathology or to dysregulate the immune response observed in severe and critical COVID-19, we determined the direct and indirect interactions of these cells. AEC lineage (Calu-3) infected with SARS-CoV-2 and epithelial cells (CD45-EpCAM+) from intubated COVID-19 patients showed high expression of CD95L. Infected-Calu-3 cells secreted IL-6, and expressed annexin V and caspase-3, apoptosis markers. The direct interaction of macrophages with sorted apoptotic Calu-3 cells, driven by SARS-CoV-2 infection, resulted in macrophage death and increased expression of CD95, CD95L and CD163. Macrophages exposed to tracheal aspirate supernatants from intubated COVID-19 patients or to recombinant human IL-6 exhibited decreased HLA-DR and increased CD95 and CD163 expression. IL-6 effects on macrophages were prevented by tocilizumab (anti-IL-6 receptor mAb) and Kp7-6 (CD95/CD95L antagonist). Similarly, lung inflammation and death of AEC were decreased in CD95 and IL-6 knockout mice infected with SARS-CoV-2. Our results show that the AEC-macrophage interaction via CD95/CD95L signaling is an initial key step of immunopathology of severe COVID-19 and should be considered as a therapeutic target. O_FIG O_LINKSMALLFIG WIDTH=181 HEIGHT=200 SRC="FIGDIR/small/504760v1_ufig1.gif" ALT="Figure 1"> View larger version (88K): org.highwire.dtl.DTLVardef@aadef5org.highwire.dtl.DTLVardef@13d033org.highwire.dtl.DTLVardef@c9c555org.highwire.dtl.DTLVardef@ba821e_HPS_FORMAT_FIGEXP M_FIG C_FIG Highlights- SARS-CoV-2-infected airway epithelial cells (AEC) secrete IL-6, express Fas/FasL and undergo apoptosis; - SARS-CoV-2-infected apoptotic AEC induces Fas/FasL expression and death in macrophages; - IL-6 induces IL-1{beta} secretion, reduction of HLA-DR and increase of Fas and CD163 expression in macrophages; - Blockade of IL-6 signaling and Fas/FasL restores the expression of HLA-DR and reduces the expression of Fas and CD163, and secretion of IL-1{beta} on isolated macrophages; in vivo, the deficiency of Fas and IL-6 decreases acute pulmonary inflammation in SARS-CoV-2-infected mice.

immunology↗

bioRxiv2018

Whole-genome sequencing of parvoviruses from wild and domestic animals in Brazil provides new insights into parvovirus distribution and diversity

AbstractParvoviruses (family Parvoviridae) are small, single-stranded DNA viruses. Many parvoviral pathogens of medical, veterinary and ecological importance have been identified. In this study, we used high-throughput sequencing (HTS) to investigate the diversity of parvoviruses infecting wild and domestic animals in Brazil. We identified 21 parvovirus sequences (including twelve nearly complete genomes and nine partial genomes) in samples derived from rodents, bats, opossums, birds and cattle in Pernambuco, Sao Paulo, Parana and Rio Grande do Sul states. These sequences were investigated using phylogenetic and distance-based approaches, and were thereby classified into eight parvovirus species (six of which have not been described previously), representing six distinct genera in the subfamily Parvovirinae. Our findings extend the known biogeographic range of previously characterized parvovirus species, and the known host range of three parvovirus genera (Dependovirus, Aveparvovirus, and Tetraparvovirus). Moreover, our investigation provides a window into the ecological dynamics of parvovirus infections in vertebrates, revealing that many parvovirus genera contain well-defined sub-lineages that circulate widely throughout the world within particular taxonomic groups of hosts.

microbiology↗