Viruses constitute a significant group of pathogens that have caused numerous fatalities and substantial economic losses in recent years,particularly with the emergence of coronaviruses.While the impact of SARS-CoV-2 ...Viruses constitute a significant group of pathogens that have caused numerous fatalities and substantial economic losses in recent years,particularly with the emergence of coronaviruses.While the impact of SARS-CoV-2 appears to be diminishing in daily life,only a limited number of drugs have received approval or emergency use authorization for its treatment.Given the high mutation rate of viral genomes,host-directed agents(HDAs)have emerged as a preferred choice due to their broad applicability and lasting effectiveness.In contrast to direct-acting antivirals(DAAs),HDAs offer several advantages,including broad-spectrum antiviral activities,potential efficacy against future emerging viruses,and a lower likelihood of inducing drug resistance.In our review article,we have synthesized known host-directed antiviral targets that span diverse cellular pathways and mechanisms,shedding light on the intricate interplay between host cells and viruses.Additionally,we have provided a brief overview of the development of HDAs based on these targets.We aim for this comprehensive analysis to offer valuable perspectives and insights that can guide future antiviral research and drug development efforts.展开更多
Host-directed therapy(HDT)is an emerging novel approach for treating multidrug-resistant Staphylococcus aureus(S.aureus)infection.Functioning as the indispensable specific cellular receptor for a-toxin(Hla),a-disinteg...Host-directed therapy(HDT)is an emerging novel approach for treating multidrug-resistant Staphylococcus aureus(S.aureus)infection.Functioning as the indispensable specific cellular receptor for a-toxin(Hla),a-disintegrin and metalloproteinase 10(ADAM10)is exploited to accelerate S.aureus infection through diverse mechanisms.The extraordinary contribution of ADAM10 to S.aureus pathogenesis renders it an attractive HDT target for combating S.aureus infection.Our study is the first to demonstrate the indispensable role of ADAM10 in S.aureus-induced necroptosis,and it enhances our knowledge of the role of ADAM10 in S.aureus infection.Using a fluorogenic substrate assay,we further identified kaempferol as a potent ADAM10 inhibitor that effectively protected mice from S.aureus infection by suppressing Hla-mediated barrier disruption and necroptosis.Collectively,our work presents a novel hostdirected therapeutic strategy for using the promising candidate kaempferol to treat S.aureus infection and other diseases relevant to the disordered upregulation of ADAM10.展开更多
The emergence of drug resistance to virus(i.e.,acyclovir(ACV)to herpesviruses)has been termed one of the common clinical issues,emphasizing the discovery of new antiviral agents.To address it,a genome-wide clustered r...The emergence of drug resistance to virus(i.e.,acyclovir(ACV)to herpesviruses)has been termed one of the common clinical issues,emphasizing the discovery of new antiviral agents.To address it,a genome-wide clustered regularly interspaced short palindromic repeats(CRISPR)screening was performed in mouse haploid embryonic stem cells infected with pseudorabies virus(PRV),anα-herpesvirus causing human and pig diseases.The results demonstrated that type 2 voltage-gated chloride channels(CLC-2)encoded by one of the identified genes,CLCN2,is a potential drug target for anti-herpesvirus therapy.CLC-2 inhibitors,omeprazole(OME)and 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid(DIDS),can efficiently inhibit infection of multiple herpesviruses in cellulo(i.e.,PRV,HSV and EBV),and effectively treat murine herpes simplex encephalitis(HSE).Additionally,DIDS was found to inhibit HSV-1 replication by blocking the PI3K/Akt pathway.Most importantly,both DIDS and OME were able to inhibit ACV-resistant HSV-1 strain infection.The study's findings suggest that targeting host-cell factors such as CLC-2 may be a promising approach to tackling herpesvirus drug resistance.The discovery of CLC-2 as a potential drug target for anti-herpesvirus therapy provides a new direction for the development of novel antiviral agents.展开更多
Tuberculosis(TB)has one of the highest mortality rates among infectious diseases worldwide.The immune response in the host after infection is proposed to contribute significantly to the progression of TB,but the speci...Tuberculosis(TB)has one of the highest mortality rates among infectious diseases worldwide.The immune response in the host after infection is proposed to contribute significantly to the progression of TB,but the specific mechanisms involved remain to be elucidated.Single-cell RNA sequencing(scRNA-seq)provides unbiased transcriptome sequencing of large quantities of individual cells,thereby defining biological comprehension of cellular heterogeneity and dynamic transcriptome state of cell populations in the field of immunology and is therefore increasingly applied to lung disease research.Here,we first briefly introduce the concept of scRNA-seq,followed by a summarization on the application of scRNA-seq to TB.Furthermore,we underscore the potential of scRNA-seq for clinical biomarker exploration,host-directed therapy,and precision therapy research in TB and discuss the bottlenecks that need to be overcome for the broad application of scRNA-seq to TB-related research.展开更多
The emergence of multidrug-resistant bacteria poses a significant challenge in the treatment of osteomyelitis,rendering traditional antibiotic treatment strategies inadequate in terms of achieving a complete cure.In r...The emergence of multidrug-resistant bacteria poses a significant challenge in the treatment of osteomyelitis,rendering traditional antibiotic treatment strategies inadequate in terms of achieving a complete cure.In recent years,triggerable biomaterial-based,antibiotic-free osteomyelitis treatment strategies have rapidly evolved,demonstrating excellent bactericidal effects.Triggerable biomaterials-based osteomyelitis theranostics encompass physical signal response strategies and host immune modulation approaches.These strategies can be effective against drug-resistant bacteria,circumventing the gradual acquisition of resistance that often accompanies traditional antibiotic treat-ment.Additionally,the inherent physical properties of the triggerable bio-materials facilitate the precise imaging of osteomyelitis.There is no doubt that triggerable biomaterial-mediated,antibiotic-free therapies are emerging as a trend,which is critically important in combating multidrug-resistant bacteria-induced osteomyelitis.In this review,we summarize the latest advances in osteomyelitis treatment strategies from both pathogen-directed and host-directed perspectives.The design regimens and specific action mechanisms of triggerable biomaterial-based nanoplatforms are also clarified.Finally,we outline the challenges faced by various antibiotic-free therapies and provide an outlook on the prospects for synergistic interactions.展开更多
基金supported by the National Program for Support of Top-notch Young Professionals(Grant No.0106514050 to Yonghui Zhang,China)the National Natural Science Foundation of China(Grant Nos.82273811 and U22A20380 to Yonghui Zhang)+1 种基金the National Key Research and Development Program of China(Grant No.2021YFA0910500 to Yonghui Zhang)TongjiRongcheng Center for Biomedicine,Huazhong University of Science and Technology。
文摘Viruses constitute a significant group of pathogens that have caused numerous fatalities and substantial economic losses in recent years,particularly with the emergence of coronaviruses.While the impact of SARS-CoV-2 appears to be diminishing in daily life,only a limited number of drugs have received approval or emergency use authorization for its treatment.Given the high mutation rate of viral genomes,host-directed agents(HDAs)have emerged as a preferred choice due to their broad applicability and lasting effectiveness.In contrast to direct-acting antivirals(DAAs),HDAs offer several advantages,including broad-spectrum antiviral activities,potential efficacy against future emerging viruses,and a lower likelihood of inducing drug resistance.In our review article,we have synthesized known host-directed antiviral targets that span diverse cellular pathways and mechanisms,shedding light on the intricate interplay between host cells and viruses.Additionally,we have provided a brief overview of the development of HDAs based on these targets.We aim for this comprehensive analysis to offer valuable perspectives and insights that can guide future antiviral research and drug development efforts.
基金supported by the National Natural Science Foundation of China(U22A20523,32172912,and 32102722)the Interdisciplinary Integration and Innovation Project of Jilin University(JLUXKJC2021QZ04)。
文摘Host-directed therapy(HDT)is an emerging novel approach for treating multidrug-resistant Staphylococcus aureus(S.aureus)infection.Functioning as the indispensable specific cellular receptor for a-toxin(Hla),a-disintegrin and metalloproteinase 10(ADAM10)is exploited to accelerate S.aureus infection through diverse mechanisms.The extraordinary contribution of ADAM10 to S.aureus pathogenesis renders it an attractive HDT target for combating S.aureus infection.Our study is the first to demonstrate the indispensable role of ADAM10 in S.aureus-induced necroptosis,and it enhances our knowledge of the role of ADAM10 in S.aureus infection.Using a fluorogenic substrate assay,we further identified kaempferol as a potent ADAM10 inhibitor that effectively protected mice from S.aureus infection by suppressing Hla-mediated barrier disruption and necroptosis.Collectively,our work presents a novel hostdirected therapeutic strategy for using the promising candidate kaempferol to treat S.aureus infection and other diseases relevant to the disordered upregulation of ADAM10.
基金supported by the National Natural Science Foundation of China(32071443)China Postdoctoral Science Foundation(2023M731465)the Natural Science Foundation of Gansu province(23JRRA1134)。
文摘The emergence of drug resistance to virus(i.e.,acyclovir(ACV)to herpesviruses)has been termed one of the common clinical issues,emphasizing the discovery of new antiviral agents.To address it,a genome-wide clustered regularly interspaced short palindromic repeats(CRISPR)screening was performed in mouse haploid embryonic stem cells infected with pseudorabies virus(PRV),anα-herpesvirus causing human and pig diseases.The results demonstrated that type 2 voltage-gated chloride channels(CLC-2)encoded by one of the identified genes,CLCN2,is a potential drug target for anti-herpesvirus therapy.CLC-2 inhibitors,omeprazole(OME)and 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid(DIDS),can efficiently inhibit infection of multiple herpesviruses in cellulo(i.e.,PRV,HSV and EBV),and effectively treat murine herpes simplex encephalitis(HSE).Additionally,DIDS was found to inhibit HSV-1 replication by blocking the PI3K/Akt pathway.Most importantly,both DIDS and OME were able to inhibit ACV-resistant HSV-1 strain infection.The study's findings suggest that targeting host-cell factors such as CLC-2 may be a promising approach to tackling herpesvirus drug resistance.The discovery of CLC-2 as a potential drug target for anti-herpesvirus therapy provides a new direction for the development of novel antiviral agents.
基金This research was supported by the National Natural Science Foundation of China(No.82100119)Science and Technology Project of Sichuan(Nos.2022ZDZX0018 and 2023NSFSC1889)+2 种基金Science and Technology Project of Chengdu(No.2023-YF09-00007-SN)the Sichuan University from“0”to“1”Innovation Project(No.2023SCUH0051)the 1.3.5 Project for Disciplines Excellence of West China Hospital,Sichuan University(No.ZYYC23027).
文摘Tuberculosis(TB)has one of the highest mortality rates among infectious diseases worldwide.The immune response in the host after infection is proposed to contribute significantly to the progression of TB,but the specific mechanisms involved remain to be elucidated.Single-cell RNA sequencing(scRNA-seq)provides unbiased transcriptome sequencing of large quantities of individual cells,thereby defining biological comprehension of cellular heterogeneity and dynamic transcriptome state of cell populations in the field of immunology and is therefore increasingly applied to lung disease research.Here,we first briefly introduce the concept of scRNA-seq,followed by a summarization on the application of scRNA-seq to TB.Furthermore,we underscore the potential of scRNA-seq for clinical biomarker exploration,host-directed therapy,and precision therapy research in TB and discuss the bottlenecks that need to be overcome for the broad application of scRNA-seq to TB-related research.
基金The authors sincerely acknowledge the financial support from the National Natural Science Foundation of China(52302343)Beijing Institute of Technology Teli Young Fellow Program(RCPT-20220029)the Beijing Institute of Technology Research Fund Program for Young Scholars(XSQD-6120220130,XSQD-202213001).
文摘The emergence of multidrug-resistant bacteria poses a significant challenge in the treatment of osteomyelitis,rendering traditional antibiotic treatment strategies inadequate in terms of achieving a complete cure.In recent years,triggerable biomaterial-based,antibiotic-free osteomyelitis treatment strategies have rapidly evolved,demonstrating excellent bactericidal effects.Triggerable biomaterials-based osteomyelitis theranostics encompass physical signal response strategies and host immune modulation approaches.These strategies can be effective against drug-resistant bacteria,circumventing the gradual acquisition of resistance that often accompanies traditional antibiotic treat-ment.Additionally,the inherent physical properties of the triggerable bio-materials facilitate the precise imaging of osteomyelitis.There is no doubt that triggerable biomaterial-mediated,antibiotic-free therapies are emerging as a trend,which is critically important in combating multidrug-resistant bacteria-induced osteomyelitis.In this review,we summarize the latest advances in osteomyelitis treatment strategies from both pathogen-directed and host-directed perspectives.The design regimens and specific action mechanisms of triggerable biomaterial-based nanoplatforms are also clarified.Finally,we outline the challenges faced by various antibiotic-free therapies and provide an outlook on the prospects for synergistic interactions.
