Visualization of perforin/gasdermin/complement-formed pores in real cell membranes using atomic force microscopy

Different types of pores ubiquitously form in cell membranes,leading to various types of cell death that profoundly influence the fate of inflammation and the disease status.However,these pores have never truly been visualized to date.Atomic force microscopy(AFM),which is emerging as a powerful tool to analyze the mechanical properties of biomolecules and cells,is actually an excellent imaging platform that allows biological samples to be visualized by probing surface roughness at the level of atomic resolution.Here,membrane pore structures were clearly visualized using AFM.This visualization not only describes the aperture and depth of the pore complexes but also highlights differences among the pores formed by perforin and gasdermins in tumor cell membranes and by complement in immune cell membranes.Additionally,this type of visualization also reveals the dynamic process of pore formation,fusion,and repair.

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.

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.

YAP Inactivation by Soft Mechanotransduction Relieves MAFG for Tumor Cell Dedifferentiation

Solid tumor cells live in a highly dynamic mechanical microenvironment.How the extracellular-matrix-generated mechanotransduction regulates tumor cell development and differentiation remains an enigma.Here,we show that a low mechanical force generated from the soft matrix induces dedifferentiation of moderately stiff tumor cells to soft stem-cell-like cells.Mechanistically,integrin?was identified to transduce mechano-signaling to trigger tumor cell dedifferentiation by recruiting RhoGDI1 to inactivate RhoA and subsequently Yes-associated protein(YAP).YAP inactivation relieved the inhibition of v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog G(MAFG),allowing MAFG to transactivate the stemness genes NANOG,SOX2,and NESTIN.Inactivation also restoredβ8 expression,thereby forming a closed mechanical loop.Importantly,MAFG expression is correlated with worse prognosis.Our findings provide mechanical insights into the regulation of tumor cell dedifferentiation,which has therapeutic implications for exploring innovative strategies to attack malignancies.