Repurposable drugs for SARS-CoV-2 and influenza sepsis with scRNA-seq data targeting post-transcription modifications

Coronavirus disease 2019(COVID-19)has impacted almost every part of human lifeworldwide,posing amassive threat to human health.The lack of time for new drug discovery and the urgent need for rapid disease control to reduce mortality have led to a search for quick and effective alternatives to novel therapeutics,for example drug repurposing.To identify potentially repurposable drugs,we employed a systematic approach to mine candidates from U.S.FDA-approved drugs and preclinical small-molecule compounds by integrating gene expression perturbation data for chemicals from the Library of Integrated Network-Based Cellular Signatures project with a publicly available single-cell RNA sequencing dataset from patients withmild and severe COVID-19(GEO:GSE145926,public data available and accessed on 22 April 2020).We identified 281 FDA-approved drugs that have the potential to be effective against severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection,16 of which are currently undergoing clinical trials to evaluate their efficacy against COVID-19.We experimentally tested and demonstrated the inhibitory effects of tyrphostin-AG-1478 and brefeldin-a,two chemical inhibitors of glycosylation(a post-translational modification)on the replication of the single-stranded ribonucleic acid(ssRNA)virus influenza A virus as well as on the transcription and translation of host cell cytokines and their regulators(IFNs and ISGs).In conclusion,we have identified and experimentally validated repurposable anti-SARS-CoV-2 and IAV drugs using a systems biology approach,which may have the potential for treating these viral infections and their complications(sepsis).

Pseudomonas aeruginosa:pathogenesis,virulence factors,antibiotic resistance,interaction with host,technology advances and emerging therapeutics

Pseudomonas aeruginosa(P.aeruginosa)is a Gram-negative opportunistic pathogen that infects patients with cystic fibrosis,burn wounds,immunodeficiency,chronic obstructive pulmonary disorder(COPD),cancer,and severe infection requiring ventilation,such as COVID-19.P.aeruginosa is also a widely-used model bacterium for all biological areas.In addition to continued,intense efforts in understanding bacterial pathogenesis of P.aeruginosa including virulence factors(LPS,quorum sensing,two-component systems,6 type secretion systems,outer membrane vesicles(OMVs),CRISPR-Cas and their regulation),rapid progress has been made in further studying host-pathogen interaction,particularly host immune networks involving autophagy,inflammasome,noncoding RNAs,cGAS,etc.Furthermore,numerous technologic advances,such as bioinformatics,metabolomics,scRNA-seq,nanoparticles,drug screening,and phage therapy,have been used to improve our understanding of P.aeruginosa pathogenesis and host defense.Nevertheless,much remains to be uncovered about interactions between P.aeruginosa and host immune responses,including mechanisms of drug resistance by known or unannotated bacterial virulence factors as well as mammalian cell signaling pathways.The widespread use of antibiotics and the slow development of effective antimicrobials present daunting challenges and necessitate new theoretical and practical platforms to screen and develop mechanism-tested novel drugs to treat intractable infections,especially those caused by multi-drug resistance strains.Benefited from has advancing in research tools and technology,dissecting this pathogen’s feature has entered into molecular and mechanistic details as well as dynamic and holistic views.Herein,we comprehensively review the progress and discuss the current status of P.aeruginosa biophysical traits,behaviors,virulence factors,invasive regulators,and host defense patterns against its infection,which point out new directions for future investigation and add to the design of novel and/or alternative therapeutics to combat this clinically significant pathogen.

Bitter receptor TAS2R138 facilitates lipid droplet degradation in neutrophils during Pseudomonas aeruginosa infection

Bitter receptors function primarily in sensing taste,but may also have other functions,such as detecting pathogenic organisms due to their agile response to foreign objects.The mouse taste receptor type-2 member 138(TAS2R138)is a member of the G-protein-coupled bitter receptor family,which is not only found in the tongue and nasal cavity,but also widely distributed in other organs,such as the respiratory tract,gut,and lungs.Despite its diverse functions,the role of TAS2R138 in host defense against bacterial infection is largely unknown.Here,we show that TAS2R138 facilitates the degradation of lipid droplets(LDs)in neutrophils during Pseudomonas aeruginosa infection through competitive binding with PPARG(peroxisome proliferator-activated receptor gamma)antagonist:A/-(3-oxododecanoyl)-L-homoserine lactone(AHL-12),which coincidently is a virulence-bound signal produced by this bacterium(P.aeruginosa).The released PPARG then migrates from nuclei to the cytoplasm to accelerate the degradation of LDs by binding PLIN2(perilipin-2).Subsequently,the TAS2R138-AHL-12 complex targets LDs to augment their degradation,and thereby facilitating the clearance of AHL-12 in neutrophils to maintain homeostasis in the local environment.These findings reveal a crucial role for TAS2R138 in neutrophil-mediated host immunity against P.aeruginosa infection.

Interaction among inflammasome,autophagy and non-coding RNAs:new horizons for drug

Autophagy and inflammasomes are shown to interact in various situations including infectious disease,cancer,diabetes and neurodegeneration.Since multiple layers of molecular regulators contribute to the interplay between autophagy and inflammasome activation,the detail of such interplay remains largely unknown.Non-coding RNAs(ncRNAs),which have been implicated in regulating an expanding list of cellular processes including immune defense against pathogens and inflammatory response in cancer and metabolic diseases,may join in the crosstalk between inflammasomes and autophagy in physiological or disease conditions.In this review,we summarize the latest research on the interlink among ncRNAs,inflammasomes and autophagy and discuss the emerging role of these three in multiple signaling transduction pathways involved in clinical conditions.By analyzing these intriguing interconnections,we hope to unveil the mechanism inter-regulating these multiple processes and ultimately discover potential drug targets for some refractory diseases.

Lyn prevents aberrant inflammatory responses to Pseudomonas infection in mammalian systems by repressing a SHIP-1-associated signaling cluster

The pleiotropic Src kinase Lyn has critical roles in host defense in alveolar macrophages against bacterial infection,but the underlying mechanism for Lyn-mediated inflammatory response remains largely elusive.Using mouse Pseudomonas aeruginosa infection models,we observed that Lyn^(−/−)mice manifest severe lung injury and enhanced inflammatory responses,compared with wild-type littermates.We demonstrate that Lyn exerts this immune function through interaction with IL-6 receptor and cytoskeletal protein Ezrin via its SH2 and SH3 domains.Depletion of Lyn results in excessive STAT3 activation,and enhanced the Src homology 2-containing inositol-5-phopsphatase 1(SHIP-1)expression.Deletion of SHIP-1 in Lyn^(−/−)mice(double knockout)promotes mouse survival and reduces inflammatory responses during P.aeruginosa infection,revealing the rescue of the deadly infectious phenotype in Lyn deficiency.Mechanistically,loss of SHIP-1 reduces NF-κB-dependent cytokine production and dampens MAP kinase activation through a TLR4-independent PI3K/Akt pathway.These findings reveal Lyn as a regulator for host immune response against P.aeruginosa infection through SHIP-1 and IL-6/STAT3 signaling pathway in alveolar macrophages.

Calling for a united action to defeat COVID-19

The widespread and lingering pandemic of COVID-19 is partly due to disjointed international countermeasures and policies enforced by different countries.We have been witnessing disparity in policies and measures in different countries and regions:some are in much better control than others.To effectively deal with this and future devastating pandemics,we as human beings must work together to coordinate a concerted,cooperative international policy to reduce or possibly avoid unnecessary health crises,and life and economic losses.