Comparison of nonhuman primates identified the suitable model for COVID-19

Identification of a suitable nonhuman primate(NHP)model of COVID-19 remains challenging.Here,we characterized severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection in three NHP species:Old World monkeys Macaca mulatta(M.mulatta)and Macaca fascicularis(M.fascicularis)and New World monkey Callithrix jacchus(C.jacchus).Infected M.mulatta and M.fascicularis showed abnormal chest radiographs,an increased body temperature and a decreased body weight.Viral genomes were detected in swab and blood samples from all animals.Viral load was detected in the pulmonary tissues of M.mulatta and M.fascicularis but not C.jacchus.Furthermore,among the three animal species,M.mulatta showed the strongest response to SARS-CoV-2,including increased inflammatory cytokine expression and pathological changes in the pulmonary tissues.Collectively,these data revealed the different susceptibilities of Old World and New World monkeys to SARS-CoV-2 and identified M.mulatta as the most suitable for modeling COVID-19.

Histones released by NETosis enhance the infectivity of SARS-CoV-2 by bridging the spike protein subunit 2 and sialic acid on host cells

Neutrophil extracellular traps(NETs)can capture and kill viruses,such as influenza viruses,human immunodeficiency virus(HIV),and respiratory syncytial virus(RSV),thus contributing to host defense.Contrary to our expectation,we show here that the histones released by NETosis enhance the infectivity of SARS-CoV-2,as found by using live SARS-CoV-2 and two pseudovirus systems as well as a mouse model.The histone H3 or H4 selectively binds to subunit 2 of the spike(S)protein,as shown by a biochemical binding assay,surface plasmon resonance and binding energy calculation as well as the construction of a mutant S protein by replacing four acidic amino acids.Sialic acid on the host cell surface is the key molecule to which histones bridge subunit 2 of the S protein.Moreover,histones enhance cell-cell fusion.Finally,treatment with an inhibitor of NETosis,histone H3 or H4,or sialic acid notably affected the levels of sgRNA copies and the number of apoptotic cells in a mouse model.These findings suggest that SARS-CoV-2 could hijack histones from neutrophil NETosis to promote its host cell attachment and entry process and may be important in exploring pathogenesis and possible strategies to develop new effective therapies for COVID-19.

Three doses of prototypic SARS-CoV-2 inactivated vaccine induce cross-protection against its variants of concern

Variants are globally emerging very quickly following pandemic prototypic SARS-CoV-2.To evaluate the cross-protection of prototypic SARS-CoV-2 vaccine against its variants,we vaccinated rhesus monkeys with three doses of prototypic SARS-CoV-2 inactivated vaccine,followed by challenging with emerging SARS-CoV-2 variants of concern(VOCs).

The olfactory route is a potential way for SARS-CoV-2 to invade the central nervous system of rhesus monkeys

Neurological manifestations are frequently reported in the COVID-19 patients.Neuromechanism of SARS-CoV-2 remains to be elucidated.In this study,we explored the mechanisms of SARS-CoV-2 neurotropism via our established non-human primate model of COVID-19.In rhesus monkey,SARS-CoV-2 invades the CNS primarily via the olfactory bulb.Thereafter,viruses rapidly spread to functional areas of the central nervous system,such as hippocampus,thalamus,and medulla oblongata.The infection of SARS-CoV-2 induces the inflammation possibly by targeting neurons,microglia,and astrocytes in the CNS.Consistently,SARS-CoV-2 infects neuro-derived SK-N-SH,glial-derived U251,and brain microvascular endothelial cells in vitro.To our knowledge,this is the first experimental evidence of SARS-CoV-2 neuroinvasion in the NHP model,which provides important insights into the CNS-related pathogenesis of SARS-CoV-2.