HIV encephalopathy is contributed by macrophages and microglia

Dear Editor,Acquired immunodeficiency syndrome(AIDS),characterized by a significant decrease in the number of CD4^(+)T cells,causes a defective T cell immune response,which subsequently leads to various conditional pathogenic infections and tumors(Calmy et al.,2018;Seligmann et al.,1987).Neurological disorders have been reported in 70%–80%of patients with AIDS(Saylor et al.,2016)。

Differential transcriptomic landscapes of multiple organs from SARS-CoV-2 early infected rhesus macaques

SARS-CoV-2 infection causes complicated clinical manifestations with variable multi-organ injuries,how-ever,the underlying mechanism,in particular immune responses in different organs,remains elusive.In this study,comprehensive transcriptomic alterations of 14 tissues from rhesus macaque infected with SARS-CoV-2 were analyzed.Compared to normal controls,SARS-CoV-2 infection resulted in dysregulation of genes involving diverse functions in various examined tissues/organs,with drastic transcriptomic changes in cerebral cortex and right ventricle.Intriguingly,cerebral cortex exhibited a hyperinflammatory state evidenced by sig-nificant upregulation of inflammation response-related genes.Meanwhile,expressions of coagulation,angio-genesis and fibrosis factors were also up-regulated in cerebral cortex.Based on our findings,neuropilin 1(NRP1),a receptor of SARS-CoV-2,was significantly elevated in cerebral cortex post infection,accompanied by active immune response releasing inflammatory factors and signal transmission among tissues,which enhanced infection of the central nervous system(CNS)in a positive feedback way,leading to viral encephalitis.Overall,our study depicts a multi-tissue/organ tran-scriptomic landscapes of rhesus macaque with early infection of SARS-CoV-2,and provides important insights into the mechanistic basis for COVID-19-asso-ciated clinical complications.

SARS-CoV-2 treatment effects induced by ACE2-expressing microparticles are explained by the oxidized cholesterolincreased endosomal pH of alveolar macrophages

Exploring the cross-talk between the immune system and advanced biomaterials to treat SARS-CoV-2 infection is a promising strategy.Here,we show that ACE2-overexpressing A549 cell-derived microparticles(AO-MPs)are a potential therapeutic agent against SARS-CoV-2 infection.Intranasally administered AO-MPs dexterously navigate the anatomical and biological features of the lungs to enter the alveoli and are taken up by alveolar macrophages(AMs).Then,AO-MPs increase the endosomal pH but decrease the lysosomal pH in AMs,thus escorting bound SARS-CoV-2 from phago-endosomes to lysosomes for degradation.This pH regulation is attributable to oxidized cholesterol,which is enriched in AO-MPs and translocated to endosomal membranes,thus interfering with proton pumps and impairing endosomal acidification.In addition to promoting viral degradation,AO-MPs also inhibit the proinflammatory phenotype of AMs,leading to increased treatment efficacy in a SARS-CoV-2-infected mouse model without side effects.These findings highlight the potential use of AO-MPs to treat SARS-CoV-2-infected patients and showcase the feasibility of MP therapies for combatting emerging respiratory viruses in the future.

Genome-wide 5-Hydroxymethylcytosine Profiling Analysis Identifies MAP7D1 as A Novel Regulator of Lymph Node Metastasis in Breast Cancer

Although DNA 5-hydroxymethylcytosine(5 hmC)is recognized as an important epigenetic mark in cancer,its precise role in lymph node metastasis remains elusive.In this study,we investigated how 5 hmC associates with lymph node metastasis in breast cancer.Accompanying with high expression of TET1 and TET2 proteins,large numbers of genes in the metastasis-positive primary tumors exhibit higher 5 hmC levels than those in the metastasis-negative primary tumors.In contrast,the TET protein expression and DNA 5 hmC decrease significantly within the metastatic lesions in the lymph nodes compared to those in their matched primary tumors.Through genomewide analysis of 8 sets of primary tumors,we identified 100 high-confidence metastasis-associated5 hmC signatures,and it is found that increased levels of DNA 5 hmC and gene expression of MAP7 D1 associate with high risk of lymph node metastasis.Furthermore,we demonstrate that MAP7 D1,regulated by TET1,promotes tumor growth and metastasis.In conclusion,the dynamic5 hmC profiles during lymph node metastasis suggest a link between DNA 5 hmC and lymph node metastasis.Meanwhile,the role of MAP7 D1 in breast cancer progression suggests that the metastasis-associated 5 hmC signatures are potential biomarkers to predict the risk for lymph node metastasis,which may serve as diagnostic and therapeutic targets for metastatic breast cancer.

ACE2 expression is regulated by AhR in SARS-CoV-2-infected macaques

During the current outbreak of coronavirus disease 2019(COVID-19)caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),more than 115 million people have been infected,and 2.5 million have died.1,2 Despite such great harm to human health,the pathogenesis of COVID-19 remains unclear.As the first step in the pathogenetic process,viral entry is mediated by the binding of the SARS-CoV-2 surface spike(S)protein to angiotensin-converting enzyme 2(ACE2)on host cells,such as lung epithelial cells.As an alternative to S protein-blocking strategies,manipulating host cell ACE2 expression may exert an inhibitory effect on SARS-CoV-2 infection.However,the molecular mechanism regulating ACE2 expression remains unclear.

Escaping alveolar macrophage endosomal retention explains massive expansion of SARS-CoV-2 delta variant

Dear Editor,Genetic variant Delta(B.1.617.2)of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),which possesses a remarkable ability to transmit and spread,is currently becoming predominant worldwide.Despite its great harm to human beings,how the Delta variant with T478K,P681R and L452R mutations achieves its ultrafast spread remains elusive.Entry of SARS-CoV-2 into host cells is mediated by a rapid enzymatic hydrolysis.

Airway administration of bisphosphate and dexamethasone inhibits SARS-CoV-2 variant infection by targeting alveolar macrophages

Dear Editor,Alveolar macrophages(AMs)are among the first immune cells to encounter SARS-CoV-2 during an infection due to their abundant numbers and physical location in the lungs.Thus,the reaction of AMs to SARS-CoV-2 has a profound impact on the outcome of the infection.In most cases,AMs can release cytokines and prime adaptive T-and B-cell immune responses to resolve the infection.

SARS-CoV-2 leads to myocardial injury in rhesus macaque

Dear Editor,Coronavirus disease 2019(COVID-19)is caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection,which induces multiple cardiovascular complications including acute myocardial injury resulting from acute coronary syndrome,myocarditis,stress-cardiomyopathy,arrhythmias,cardiogenic shock,and cardiac arrest.The incidence of myocardial injury in COVID-19 patients was up to 20%or higher in the subpopulation with existing cardiovascular diseases,accounting for 69.4%of mortality.1 Although the presence of angiotensin-converting enzyme 2(ACE2)in cardiomyocytes could result in viral myocarditis in COVID-19 patients,the cardiopathology involved in COVID-19 is still unclear.