Gut microbial dysbiosis has been linked to many noncommunicable diseases.However,little is known about specific gut microbiota composition and its correlated metabolites associated with molecular signatures underlying...Gut microbial dysbiosis has been linked to many noncommunicable diseases.However,little is known about specific gut microbiota composition and its correlated metabolites associated with molecular signatures underlying host response to infection.Here,we describe the construction of a proteomic risk score based on 20 blood proteomic biomarkers,which have recently been identified as molecular signatures predicting the progression of the COVID-19.We demonstrate that in our cohort of 990 healthy individuals without infection,this proteomic risk score is positively associated with proinflammatory cytokines mainly among older,but not younger,individuals.We further discover that a core set of gut microbiota can accurately predict the above proteomic biomarkers among 301 individuals using a machine learning model and that these gut microbiota features are highly correlated with proinflammatory cytokines in another independent set of 366 individuals.Fecal metabolomics analysis suggests potential amino acid-related pathways linking gut microbiota to host metabolism and inflammation.Overall,our multi-omics analyses suggest that gut microbiota composition and function are closely related to inflammation and molecular signatures of host response to infection among healthy individuals.These results may provide novel insights into the cross-talk between gut microbiota and host immune system.展开更多
Crown rot(CR),caused by Fusarium pseudograminearum and related species,is a soil-borne disease threatening global wheat(Triticum aestivum)production,with yield losses exceeding 50%under severe infections.The rapid spr...Crown rot(CR),caused by Fusarium pseudograminearum and related species,is a soil-borne disease threatening global wheat(Triticum aestivum)production,with yield losses exceeding 50%under severe infections.The rapid spread of CR in China,driven by straw retention policies and warming climates,highlights the need for interdisciplinary solutions.This review systematically integrates advances in CR research and addresses pathogen biology,host resistance,and sustainable management.Research on pathogen biology has clarified the distribution of major Fusarium species,the infection process,toxin profiles,mating types,and virulence factors.Host resistance to CR is quantitatively controlled,and through quantitative trait locus(QTL)mapping and omics-based approaches,several genes encoding transcription factors,receptor-like kinases and enzymes,signaling pathways and secondary metabolites involved in resistance have been identified.Advances in control strategies,including chemical and biological methods,as well as the application of nanotechnology,have shown promising results.The review also highlights future research directions,such as investigating the molecular mechanisms of pathogen-host interactions,identifying effectors and susceptibility genes for CR in wheat,and integrating multi-omics studies with high-resolution genetic maps to pinpoint CR resistance genes.These efforts are crucial for improving our understanding of the disease and developing effective management strategies.展开更多
Bacterial biofilms have emerged as potential critical triggers in the pathogenesis of bisphosphonate（BP）-related osteonecrosis of the jaw（ONJ） or BRONJ. BRONJ lesions have shown to be heavily colonized by oral bac...Bacterial biofilms have emerged as potential critical triggers in the pathogenesis of bisphosphonate（BP）-related osteonecrosis of the jaw（ONJ） or BRONJ. BRONJ lesions have shown to be heavily colonized by oral bacteria, most of these difficult to cultivate and presents many clinical challenges. The purpose of this study was to characterize the bacterial diversity in BRONJ lesions and to determine host immune response. We examined tissue specimens from three cohorts（n530）; patients with periodontal disease without a history of BP therapy（Control, n510）, patients with periodontal disease having history of BP therapy but without ONJ（BP, n55） and patients with BRONJ（BRONJ, n515）. Denaturing gradient gel electrophoresis of polymerase chain reaction（PCR）-amplified 16 S r RNA gene fragments revealed less bacterial diversity in BRONJ than BP and Control cohorts. Sequence analysis detected six phyla with predominant affiliation to Firmicutes in BRONJ（71.6%）, BP（70.3%） and Control（59.1%）. Significant differences（P,0.05） in genera were observed, between Control/BP, Control/BRONJ and BP/BRONJ cohorts. Enzyme-linked immunosorbent assay（ELISA）results indicated that the levels of myeloperoxidase were significantly lower, whereas interleukin-6 and tumor necrosis factor-alpha levels were moderately elevated in BRONJ patients as compared to Controls. PCR array showed significant changes in BRONJ patients with downregulation of host genes, such as nucleotide-binding oligomerization domain containing protein 2, and cathepsin G, the key modulators for antibacterial response and upregulation of secretory leukocyte protease inhibitor, proteinase 3 and conserved helix–loop–helix ubiquitous kinase. The results suggest that colonization of unique bacterial communities coupled with deficient innate immune response is likely to impact the pathogenesis of ONJ.展开更多
Dental-derived stem cells(DSCs)are attractive cell sources due to their easy access,superior growth capacity and low immunogenicity.They can respond to multiple extracellular matrix signals,which provide biophysical a...Dental-derived stem cells(DSCs)are attractive cell sources due to their easy access,superior growth capacity and low immunogenicity.They can respond to multiple extracellular matrix signals,which provide biophysical and biochemical cues to regulate the fate of residing cells.However,the direct transplantation of DSCs suffers from poor proliferation and differentiation toward functional cells and low survival rates due to local inflammation.Recently,elegant advances in the design of novel biomaterials have been made to give promise to the use of biomimetic biomaterials to regulate various cell behaviors,including proliferation,differentiation and migration.Biomaterials could be tailored with multiple functionalities,e.g.,stimuli-responsiveness.There is an emerging need to summarize recent advances in engineered biomaterials-mediated delivery and therapy of DSCs and their potential applications.Herein,we outlined the design of biomaterials for supporting DSCs and the host response to the transplantation.展开更多
Background： The community-based Ontology of Biological and Clinical Statistics （OBCS） represents and standardizes biological and clinical data and statistical methods. Methods： Both OBCS and the Vaccine Ontology ...Background： The community-based Ontology of Biological and Clinical Statistics （OBCS） represents and standardizes biological and clinical data and statistical methods. Methods： Both OBCS and the Vaccine Ontology （VO） were used to ontologically model various components and relations in a typical host response to vaccination study. Such a model was then applied to represent and compare three microarray studies of host responses to the yellow fever vaccine YF-17D. A literature meta-analysis was then conducted to survey yellow fever vaccine response papers and summarize statistical methods, using OBCS. Results： A general ontological model was developed to identify major components in a typical host response to vaccination. Our ontology modeling of three similar studies identified common and different components which may contribute to varying conclusions. Although these three studies all used the same vaccine, human blood samples, similar sample collection time post vaccination, and microarray assays, statistically differentially expressed genes and associated gene functions differed, likely due to the differences in specific variables （e.g., microarray type and human variations）. Our manual annotation of 95 papers in human responses to yellow fever vaccines identified 38 data analysis methods. These statistical methods were consistently represented and classified with OBCS. Eight statistical methods not available in existing ontologies were added to OBCS. Conclusions： The study represents the first single use case of applying OBCS ontology to standardize, integrate, and use biomedical data and statistical methods. Our ontology-based meta-analysis showed that different experimental results might be due to different experimental assays and conditions, sample variations, and data analysis methods.展开更多
Gastric cancer(GC)is the result of a multifactorial process whose main components are infection by Helicobacter pylori(H.pylori),bacterial virulence factors,host immune response and environmental factors.The developme...Gastric cancer(GC)is the result of a multifactorial process whose main components are infection by Helicobacter pylori(H.pylori),bacterial virulence factors,host immune response and environmental factors.The development of the neoplastic microenvironment also depends on genetic and epigenetic changes in oncogenes and tumor suppressor genes,which results in deregulation of cell signaling pathways and apoptosis process.This review summarizes the main aspects of the pathogenesis of GC and the immune response involved in chronic inflammation generated by H.pylori.展开更多
Sepsis is a life-threatening syndrome caused by a dysregulated host response to infection,resulting in very high mortality.Dysfunction of the tightly regulated immune response occurs when the body exerts an exacerbate...Sepsis is a life-threatening syndrome caused by a dysregulated host response to infection,resulting in very high mortality.Dysfunction of the tightly regulated immune response occurs when the body exerts an exacerbated hyperinflammatory response that is counteracted by an anti-inflammatory response,which results in immune paralysis if it is sustained for long.Innate lymphoid cells(ILCs)are immune effector cells of lymphoid origin that are devoid of recombination-activating gene-dependent rearranged antigen receptors,as in T and B cells.1 This evolutionary adaptation eliminates the necessity for antigen presentation to activate these cells,and therefore,these cells can rapidly sense and respond to infection and inflammation.ILCs sense tissue injury and pathogen infiltration through numerous cytokine,chemokine,and pattern recognition receptors.ILCs are of lymphoid origin and arise from a common lymphoid progenitor(CLP).展开更多
Infection with hepatitis B virus (HBV) leads to a wide spectrum of clinical presentations ranging from an asymptomatic carrier state to self-limited acute or fulminant hepatitis to chronic hepatitis with progression t...Infection with hepatitis B virus (HBV) leads to a wide spectrum of clinical presentations ranging from an asymptomatic carrier state to self-limited acute or fulminant hepatitis to chronic hepatitis with progression to cirrhosis and hepatocellular carcinoma. Infection with HBV is one of the most common viral diseases affecting man. Both viral factors as well as the host immune response have been implicated in the pathogenesis and clinical outcome of HBV infection. In this review, we will discuss the impact of virus-host interactions for the pathogenesis of HBV infection and liver disease. These interactions include the relevance of naturally occurring viral variants for clinical disease, the role of virus-induced apoptosis for HBV-induced liver cell injury and the impact of antiviral immune responses for outcome of infection.展开更多
Sepsis is a life-threatening condition that is characterized by multiple organ dysfunction due to abnormal host response to various pathogens,like bacteria,fungi and virus.The differences between viral and bacterial s...Sepsis is a life-threatening condition that is characterized by multiple organ dysfunction due to abnormal host response to various pathogens,like bacteria,fungi and virus.The differences between viral and bacterial sepsis are indeed of great significance to deepen the understanding of the pathogenesis of sepsis,especially under pandemics of SARS-CoV-2 infection.展开更多
Neospora caninum (N. caninum), a cyst-forming protozoan parasite, is a major cause of bovine abortions and neonatal mortality worldwide. N. caninum has a broad intermediate host range, and its sexual cycle occurs excl...Neospora caninum (N. caninum), a cyst-forming protozoan parasite, is a major cause of bovine abortions and neonatal mortality worldwide. N. caninum has a broad intermediate host range, and its sexual cycle occurs exclusively in canids. Another species of Neospora, Neospora hughesi (N. hughesi), has been identified and causes myeloencephalitis in horses. Although molecular epidemiology studies are in their infancy, the 18S ribosomal RNA (rRNA) and ITS1 regions within the small subunit ribosomal RNA (ssuRNA) and an N. caninum species-specific DNA probe (pNc5) have been used extensively to differentiate Neospora from other closely related apicomplexan parasites. While these repetitive regions have higher sensitivity and specificity than housekeeping or antigen genes, they suffer from low discriminatory power and fail to capture intra-species diversity. Similarly, although multiple minisatellite or microsatellite marker studies have shown clear geographic substructures within Neospora, strains are often misclassified due to a convergence in the size of different alleles at microsatellite loci, known as homoplasy. Only one strain, N. caninum Liverpool (Nc-Liv), has been genome sequenced and compared with its closest relative, Toxoplasma gondii (T. gondii). Hence, detailed population genomics studies based on whole-genome sequences from multiple strains worldwide are needed in order to better understand the current population genetic structure of Neospora, and ultimately to determine more effective vaccine candidates against bovine neosporosis. The aim of this review is to outline our current understanding of the molecular epidemiology and genomics of Neospora in juxtaposition with the closely related apicomplexan parasites Hammondia hammondi and T. gondii.展开更多
BACKGROUND Coronavirus disease 2019(COVID-19)is a highly contagious infection caused by the severe acute respiratory syndrome coronavirus 2 virus and has a unique underlying pathogenesis.Hemodialysis(HD)patients exper...BACKGROUND Coronavirus disease 2019(COVID-19)is a highly contagious infection caused by the severe acute respiratory syndrome coronavirus 2 virus and has a unique underlying pathogenesis.Hemodialysis(HD)patients experience high risk of contamination with COVID-19 and are considered to have higher mortality rates than the general population by most but not all clinical series.We aim to highlight the peculiarities in the immune state of HD patients,who seem to have both immune-activation and immune-depression affecting their outcome in COVID-19 infection.CASE SUMMARY We report the opposite clinical outcomes(nearly asymptomatic course vs death)of two diabetic elderly patients infected simultaneously by COVID-19,one being on chronic HD and the other with normal renal function.They were both admitted in our hospital with COVID-19 symptoms and received the same treatment by protocol.The non-HD sibling deteriorated rapidly and was intubated and transferred to the Intensive Care Unit,where he died despite all supportive care.The HD sibling,although considered more“high-risk”for adverse outcome,followed a benign course and left the hospital alive and well.CONCLUSION These cases may shed light on aspects of the immune responses to COVID-19 between HD and non-HD patients and stimulate further research in pathophysiology and treatment of this dreadful disease.展开更多
Chikungunya virus(CHIKV) is an arbovirus transmitted by Aedes mosquitos in tropical and subtropical regions across the world. After decades of sporadic outbreaks, it re-emerged in Africa,Asia, India Ocean and America ...Chikungunya virus(CHIKV) is an arbovirus transmitted by Aedes mosquitos in tropical and subtropical regions across the world. After decades of sporadic outbreaks, it re-emerged in Africa,Asia, India Ocean and America suddenly, causing major regional epidemics recently and becoming a notable global health problem. Infection by CHIKV results in a spectrum of clinical diseases including an acute self-limiting febrile illness in most individuals, a chronic phase of recurrent join pain in a proportion of patients, and long-term arthralgia for months to years for the unfortunate few. No specific anti-viral drugs or licensed vaccines for CHIKV are available so far. A better understanding of virus-host interactions is essential for the development of therapeutics and vaccines. To this end, we reviewed the existing knowledge on CHIKV's epidemiology, clinical presentation, molecular virology, diagnostic approaches, host immune response, vaccine development, and available animal models. Such a comprehensive overview, we believe, will shed lights on the promises and challenges in CHIKV vaccine development.展开更多
AIM： To investigate genetic diversity of Helicobacter pylori （H. pylorl） cell division-related gene A （cdrA） and its effect on the host response.METHODS： Inactivation of H. py/ori cdrA, which is involved in ceil...AIM： To investigate genetic diversity of Helicobacter pylori （H. pylorl） cell division-related gene A （cdrA） and its effect on the host response.METHODS： Inactivation of H. py/ori cdrA, which is involved in ceil division and morphological elonga- tion, has a role in chronic persistent infections. Ge- netic property of H. pylori cdrA was evaluated using polymerase chain reaction and sequencing in 128 （77 American and 51 Japanese） clinical isolates obtained from 48 and 51 patients, respectively. Enzyme-linked immunosorbent assay was performed to measure in- terleukin-8 （IL-8） secretion with gastric biopsy speci- mens obtained from American patients colonized with cdrA-positive or -negative strains and AGS cells co- cultured with wild-type HPK5 （cdrA-positive） or its de- rivative HPKT510 （cdrA-disruptant）. Furthermore, the cytotoxin-associated gene A （cagA） status （transloca- tion and phosphorylation） and kinetics of transcription factors [nuclear factor-kappa B （NF-~：B） and inhibition kappa B] were investigated in AGS cells co-cultured with HPK5, HPKT510 and its derivative HPKSCA （cagA- disruptant） by western blotting analysis with immuno- precipitation. RESULTS： Genetic diversity of the H. pylori cdrA gene demonstrated that the cdrA status segregated into two categories including four allele types, cdrA-positive （al- lele types, I and 11 ） and cdrA-negative （allele types; 111 and IV） categories, respectively. Almost all Japanese isolates were cdrA-positive （ 1 ： 7.8% and 11 ： 90.2%）, whereas 16.9% of American isolates were cdrA-positive （11） and 83.1% were cdrA-negative （nl： 37.7% and IV： 45.5%）, indicating extended diversity of cdrA in individual American isolates. Comparison of each isolate from different regions （antrum and corpus） in the stomach of 29 Americans revealed that cdrA status was identical in both isolates from different regions in 17 cases. However, 12 cases had a different cdrA al- lele and 6 of them exhibited a different cdrA category between two regions in the stomach. Furthermore, in 5 of the 6 cases possessing a different cdrA category, cdrA-negative isolate existed in the corpus, suggesting that cdrA-negative strain is more adaptable to coloni- zation in the corpus. IL-8 secretions from AGS revealed that IL-8 levels induced by a cdrA-disrupted HPKT510 was significantly lower （P 〈 0.01） compared to wild- type HPK5： corresponding to 50%-60% of those of wild-type HPK5. These data coincided with in vivo data that an average value of IL-8 in biopsy specimens from cdrA-positive and cdrA-negative groups was 215.6 and 135.9 pg/mL, respectively. Western blotting analysis documented that HPKT510 had no effect on CagA translocation and phosphorylation, however, nuclear accumulation of NF-κB was lower by HPKT510 com- pared to HPK5. CONCLUSION： Colonization by a cdrA-negative or cdrA-dysfunctional strain resulted in decreased IL-8 production and repression of NF-κB, and hence, atten- uate the host immunity leading to persistent infection.展开更多
Embedding mesenchymal stromal cells(MSCs)in biomaterial is a subject of increasing interest in the field of Regenerative Medicine.Speeding up the clinical use of MSCs is dependent on the use of non-syngeneic models in...Embedding mesenchymal stromal cells(MSCs)in biomaterial is a subject of increasing interest in the field of Regenerative Medicine.Speeding up the clinical use of MSCs is dependent on the use of non-syngeneic models in accordance with Good Manufacturing Practices(GMP)requirements and on costs.To this end,in this study,we analyzed the in vivo host immune response following local injection of silanized hydroxypropyl methylcellulose(Si-HPMC)-embedded human MSCs in a rat model developing colorectal damage induced by ionizing radiation.Plasma and lymphocytes from mesenteric lymph nodes were harvested in addition to colonic tissue.We set up tests,using flow cytometry and a live imaging system,to highlight the response to specific antibodies and measure the cytotoxicity of lymphocytes against injected MSCs.We demonstrated that Si-HPMC protects MSCs from specific antibodies production and from apoptosis by lymphocytes.We also observed that Si-HPMC does not modify innate immune response infiltrate in vivo,and that in vitro co-culture of Si-HPMC-embedded MSCs impacts macrophage inflammatory response depending on the microenvironment but,more importantly,increases the macrophage regenerative response through Wnt-family and VEGF gene expression.This study furthers our understanding of the mechanisms involved,with a view to improving the therapeutic benefits of biomaterial-assisted cell therapy by modulating the host immune response.The decrease in specific immune response against injected MSCs protected by Si-HPMC also opens up new possibilities for allogeneic clinical use.展开更多
Objective To investigate the pathogenesis and immunogenicity of H9N2 influenza virus A/Guangzhou/333/99 （a reassortant of G1 and G9 viruses isolated from a female patient in 1999） in a mouse model of infection.Metho...Objective To investigate the pathogenesis and immunogenicity of H9N2 influenza virus A/Guangzhou/333/99 （a reassortant of G1 and G9 viruses isolated from a female patient in 1999） in a mouse model of infection.Methods Mice were infected with increasing virus titers.Viral load in the lungs and trachea was determined by EID50 assay.Pulmonary histopathology was assessed by hematoxylin‐eosin staining.Anti‐HI antibody titers and T‐cell responses to viral HA were determined by ELISPOT and confirmed by flow cytometry.Results Mice presented a mild syndrome after intranasal infection with A/Guangzhou/333/99 （H9N2） influenza virus.Virus was detected in the trachea and lungs of mice harvested on days 3,6,and 9 post‐infection.A T‐cell response to viral HA was detected on day 6 and H9 HA‐specific CD 4＋ T‐cells predominated.Seroconversion was detected after 14 days and antibody persisted for at least 28 weeks.Conclusion Our results suggest that H9N2 （A/Guangzhou/333/99） can replicate in the murine respiratory tract without prior adaptation,and both humoral and cell‐mediated immunity play an important role in the immune response.展开更多
An overly exuberant immune response,characterized by a cytokine storm and uncontrolled inflammation,has been identified as a significant driver of severe coronavirus disease 2019(COVID-19)cases.Consequently,decipherin...An overly exuberant immune response,characterized by a cytokine storm and uncontrolled inflammation,has been identified as a significant driver of severe coronavirus disease 2019(COVID-19)cases.Consequently,deciphering the intricacies of immune dysregulation in COVID-19 is imperative to identify specific targets for intervention and modulation.With these delicate dynamics in mind,immunomodulatory therapies have emerged as a promising avenue for miti-gating the challenges posed by COVID-19.Precision in manipulating immune pathways presents an opportunity to alter the host response,optimizing antiviral defenses while curbing deleterious inflammation.This review article compre-hensively analyzes immunomodulatory interventions in managing COVID-19.We explore diverse approaches to mitigating the hyperactive immune response and its impact,from corticosteroids and non-steroidal drugs to targeted biologics,including anti-viral drugs,cytokine inhibitors,JAK inhibitors,convalescent plasma,monoclonal antibodies(mAbs)to severe acute respiratory syndrome coronavirus 2,cell-based therapies(i.e.,CAR T,etc.).By summarizing the current evidence,we aim to provide a clear roadmap for clinicians and researchers navigating the complex landscape of immunomodulation in COVID-19 treatment.CS Glucocorticoids are among the most widely prescribed drugs with their immune-suppressive and anti-inflammatory effect[84].The current guidelines for the treatment of COVID-19 recommend against the use of dexamethasone or other systemic CS in non-hospitalized patients in the absence of another indication[70].The RECOVERY trial demonstrates the reduced 28-d mortality among hospitalized patients with COVID-19 using dexamethasone compared to the usual standard of care,along with other investigators,such as Ahmed and Hassan[85].The benefit of dexamethasone was seen only among participants receiving either oxygen alone or invasive mechanical ventilation at randomization but not among those receiving no respiratory support at enrollment[85].In a systematic review and meta-analysis,Albuquerque et al[86]showed that in comparison to tocilizumab,baricitinib,and sarilumab are associated with high probabilities of similar mortality reductions among hospitalized COVID-19 concurrently treated with CS.As a result of the absence of SARS-CoV-2-specific antiviral medications,the effectiveness of COVID-19 treatments is reduced.Several COVID-19 therapies are now under investigation.However,the majority of them lack specificity,efficacy,and safety[87].Immunotherapy is a ground-breaking medical treatment that manipulates the immune system to fight diseases.Translational research is rapidly progressing,recognized as a significant breakthrough in 2013[88].Among the immunotherapeutic options for treating COVID-19 are Immunoglobulin,CP,antibodies,mAbs(mAbs),NK cells,T cells,TLR,cytokine therapies and immune modulators.展开更多
Despite considerable recent progress in defining neutrophil functions and behaviors in tissue repair,much remains to be determined with regards to its overall role in the tissue integration of biomaterials.This articl...Despite considerable recent progress in defining neutrophil functions and behaviors in tissue repair,much remains to be determined with regards to its overall role in the tissue integration of biomaterials.This article provides an overview of the neutrophil’s numerous,important roles in both inflammation and resolution,and subsequently,their role in biomaterial integration.Neutrophils function in three primary capacities:generation of oxidative bursts,release of granules and formation of neutrophil extracellular traps(NETs);these combined functions enable neutrophil involvement in inflammation,macrophage recruitment,M2 macrophage differentiation,resolution of inflammation,angiogenesis,tumor formation and immune system activation.Neutrophils exhibit great flexibility to adjust to the prevalent microenvironmental conditions in the tissue;thus,the biomaterial composition and fabrication will potentially influence neutrophil behavior following confrontation.This review serves to highlight the neutrophil’s plasticity,reiterating that neutrophils are not just simple suicidal killers,but the true maestros of resolution and regeneration.展开更多
The Omicron family of SARS-CoV-2 variants are currently driving the COVID-19 pandemic.Here we analyzed the clinical laboratory test results of 9911 Omicron BA.2.2 sublineages-infected symptomatic patients without earl...The Omicron family of SARS-CoV-2 variants are currently driving the COVID-19 pandemic.Here we analyzed the clinical laboratory test results of 9911 Omicron BA.2.2 sublineages-infected symptomatic patients without earlier infection histories during a SARS-CoV-2 outbreak in Shanghai in spring 2022.Compared to an earlier patient cohort infected by SARS-CoV-2 prototype strains in 2020,BA.2.2 infection led to distinct fluctuations of pathophysiological markers in the peripheral blood.In particular,severe/critical cases of COVID19 post BA.2.2 infection were associated with less pro-inflammatory macrophage activation and stronger interferon alpha response in the bronchoalveolar microenvironment.Importantly,the abnormal biomarkers were significantly subdued in individuals who had been immunized by 2 or 3 doses of SARS-CoV-2 prototypeinactivated vaccines,supporting the estimation of an overall 96.02% of protection rate against severe/critical disease in the 4854 cases in our BA.2.2 patient cohort with traceable vaccination records.Furthermore,even though age was a critical risk factor of the severity of COVID-19 post BA.2.2 infection,vaccination-elicited protection against severe/critical COVID-19 reached 90.15% in patients aged≥60 years old.Together,our study delineates the pathophysiological features of Omicron BA.2.2 sublineages and demonstrates significant protection conferred by prior prototype-based inactivated vaccines.展开更多
During virus infection, viral RNAs and mRNAs function as blueprints for viral protein synthesis and possibly as pathogen-associated molecular patterns （PAMPs） in innate immunity. Here, considering recent research pr...During virus infection, viral RNAs and mRNAs function as blueprints for viral protein synthesis and possibly as pathogen-associated molecular patterns （PAMPs） in innate immunity. Here, considering recent research progress in microRNAs （miRNAs） and competitive endogenous RNAs （ceRNAs）, we speculate that viral RNAs act as sponges and can sequester endogenous miRNAs within infected cells, thus cross-regulating the stability and translational efficiency of host mRNAs with shared miRNA response elements. This cross-talk and these reciprocal interactions between viral RNAs and host mRNAs are termed ＂competitive viral and host RNAs＂ （cvhRNAs）. We further provide recent experimental evidence for the existence of cvhRNAs networks in hepatitis B virus （HBV）, as well as Her- pesvirus saimiri （HVS）, lytic murine cytomegalovirus （MCMV） and human cytomegalovirus （HCMV） infec- tions. In addition, the cvhRNA hypothesis also pre- dicts possible cross-regulation between host and other viruses, such as hepatitis C virus （HCV）, HIV, influenza virus, human papillomaviruses （HPV）. Since the interaction between miRNAs and viral RNAs also inevitably leads to repression of viral RNA function, we speculate that virus may evolve either to employ cvhRNA networks or to avoid miRNA targeting for optimal fitness within the host. CvhRNA networks may therefore play a fundamental role in the regulation of viral replication, infection establishment, and viral pathogenesis.展开更多
Background:Immunosuppression is closely related to the pathogenesis of sepsis,but the underlying mechanisms have not yet been fully elucidated.In this study,we aimed to examine the role of the Sterile Alpha Motif,Src ...Background:Immunosuppression is closely related to the pathogenesis of sepsis,but the underlying mechanisms have not yet been fully elucidated.In this study,we aimed to examine the role of the Sterile Alpha Motif,Src Homology 3 domain and nuclear localization signal 1(SAMSN1)in sepsis and elucidate its potential molecular mechanism in sepsis induced immunosuppression.Methods:RNA sequencing databases were used to validate SAMSN1 expression in sepsis.The impact of SAMSN1 on sepsis was verified using gene knockout mice.Flow cytometry was employed to delineate how SAMSN1 affects immunity in sepsis,focusing on immune cell types and T cell functions.Clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein 9(Cas9)-mediated gene editing in RAW264.7 macrophages enabled interrogation of SAMSN1’s regulatory effects on essential macrophage functions,including cell proliferation and phagocytic capacity.The mechanism of SAMSN1 in the interaction between macrophages and T cells was investigated using the RAW264.7 cell line and primary cell lines.Results:SAMSN1 expression was significantly increased in patients with sepsis and was positively correlated with sepsis mortality.Genetic deletion of Samsn1 in murine sepsis model improved T cell survival,elevated T cell cytolytic activity,and activated T cell signaling transduction.Concurrently,Samsn1 knockout augmented macrophage proliferation capacity and phagocytic efficiency.In macrophage,SAMSN1 binds to Kelch-like epichlorohydrin-associated protein 1(KEAP1),causing nuclear factor erythroid 2-related factor 2(NRF2)to dissociate from the KEAP1–NRF2 complex and translocate into the nucleus.This promotes the transcription of the coinhibitory molecules CD48/CD86/carcinoembryonic antigen related cell adhesion molecule 1(CEACAM1),which bind to their corresponding receptors natural killer cell receptor 2B4/CD152/T cell immunoglobulin and mucin domain-containing protein 3(TIM3)on the surface of T cells,inducing T-cell exhaustion.Conclusions:SAMSN1 deletion augmented adaptive T cell immunity and macrophage phagocytic-proliferative dual function.Furthermore,it mediates the KEAP1–NRF2 axis,which affects the expression of coinhibitory molecules on macrophages,leading to T-cell exhaustion.This novel immunosuppression mechanism potentially provides a candidate molecular target for sepsis immunotherapy.展开更多
基金supported by the National Natural Science Foundation of China(82073529,81903316,81773416,81972492,21904107,81672086)Zhejiang Ten-thousand Talents Program(2019R52039)+3 种基金Zhejiang Provincial Natural Science Foundation for Distinguished Young Scholars(LR19C050001)the 5010 Program for Clinical Researches(2007032)the Sun Yat-sen University,Hangzhou Agriculture and Society Advancement Program(20190101A04)Tencent foundation(2020)。
文摘Gut microbial dysbiosis has been linked to many noncommunicable diseases.However,little is known about specific gut microbiota composition and its correlated metabolites associated with molecular signatures underlying host response to infection.Here,we describe the construction of a proteomic risk score based on 20 blood proteomic biomarkers,which have recently been identified as molecular signatures predicting the progression of the COVID-19.We demonstrate that in our cohort of 990 healthy individuals without infection,this proteomic risk score is positively associated with proinflammatory cytokines mainly among older,but not younger,individuals.We further discover that a core set of gut microbiota can accurately predict the above proteomic biomarkers among 301 individuals using a machine learning model and that these gut microbiota features are highly correlated with proinflammatory cytokines in another independent set of 366 individuals.Fecal metabolomics analysis suggests potential amino acid-related pathways linking gut microbiota to host metabolism and inflammation.Overall,our multi-omics analyses suggest that gut microbiota composition and function are closely related to inflammation and molecular signatures of host response to infection among healthy individuals.These results may provide novel insights into the cross-talk between gut microbiota and host immune system.
基金supported by National Key R&D Program of China(2025YFE0105200)the Innovation Capability Support Program of Shaanxi(program no.2023-CX-TD-56)+2 种基金the National Natural Science Foundation of China(32172381 and 32302326)the Biological Breeding-National Science and Technology Major Project(2023ZD04025)the 111 Project from the Ministry of Education of China(BP0719026).
文摘Crown rot(CR),caused by Fusarium pseudograminearum and related species,is a soil-borne disease threatening global wheat(Triticum aestivum)production,with yield losses exceeding 50%under severe infections.The rapid spread of CR in China,driven by straw retention policies and warming climates,highlights the need for interdisciplinary solutions.This review systematically integrates advances in CR research and addresses pathogen biology,host resistance,and sustainable management.Research on pathogen biology has clarified the distribution of major Fusarium species,the infection process,toxin profiles,mating types,and virulence factors.Host resistance to CR is quantitatively controlled,and through quantitative trait locus(QTL)mapping and omics-based approaches,several genes encoding transcription factors,receptor-like kinases and enzymes,signaling pathways and secondary metabolites involved in resistance have been identified.Advances in control strategies,including chemical and biological methods,as well as the application of nanotechnology,have shown promising results.The review also highlights future research directions,such as investigating the molecular mechanisms of pathogen-host interactions,identifying effectors and susceptibility genes for CR in wheat,and integrating multi-omics studies with high-resolution genetic maps to pinpoint CR resistance genes.These efforts are crucial for improving our understanding of the disease and developing effective management strategies.
基金supported by NIH grants CA172894, CA180277, DE020891New York University Research Funds
文摘Bacterial biofilms have emerged as potential critical triggers in the pathogenesis of bisphosphonate（BP）-related osteonecrosis of the jaw（ONJ） or BRONJ. BRONJ lesions have shown to be heavily colonized by oral bacteria, most of these difficult to cultivate and presents many clinical challenges. The purpose of this study was to characterize the bacterial diversity in BRONJ lesions and to determine host immune response. We examined tissue specimens from three cohorts（n530）; patients with periodontal disease without a history of BP therapy（Control, n510）, patients with periodontal disease having history of BP therapy but without ONJ（BP, n55） and patients with BRONJ（BRONJ, n515）. Denaturing gradient gel electrophoresis of polymerase chain reaction（PCR）-amplified 16 S r RNA gene fragments revealed less bacterial diversity in BRONJ than BP and Control cohorts. Sequence analysis detected six phyla with predominant affiliation to Firmicutes in BRONJ（71.6%）, BP（70.3%） and Control（59.1%）. Significant differences（P,0.05） in genera were observed, between Control/BP, Control/BRONJ and BP/BRONJ cohorts. Enzyme-linked immunosorbent assay（ELISA）results indicated that the levels of myeloperoxidase were significantly lower, whereas interleukin-6 and tumor necrosis factor-alpha levels were moderately elevated in BRONJ patients as compared to Controls. PCR array showed significant changes in BRONJ patients with downregulation of host genes, such as nucleotide-binding oligomerization domain containing protein 2, and cathepsin G, the key modulators for antibacterial response and upregulation of secretory leukocyte protease inhibitor, proteinase 3 and conserved helix–loop–helix ubiquitous kinase. The results suggest that colonization of unique bacterial communities coupled with deficient innate immune response is likely to impact the pathogenesis of ONJ.
基金financed in part by the Coordenac¸ao~de Aperfec¸oamento de Pessoal de N�ıvel Superior(CAPES)—Finance Code 001(scholarship for Dr Ferreira)。
文摘Dental-derived stem cells(DSCs)are attractive cell sources due to their easy access,superior growth capacity and low immunogenicity.They can respond to multiple extracellular matrix signals,which provide biophysical and biochemical cues to regulate the fate of residing cells.However,the direct transplantation of DSCs suffers from poor proliferation and differentiation toward functional cells and low survival rates due to local inflammation.Recently,elegant advances in the design of novel biomaterials have been made to give promise to the use of biomimetic biomaterials to regulate various cell behaviors,including proliferation,differentiation and migration.Biomaterials could be tailored with multiple functionalities,e.g.,stimuli-responsiveness.There is an emerging need to summarize recent advances in engineered biomaterials-mediated delivery and therapy of DSCs and their potential applications.Herein,we outlined the design of biomaterials for supporting DSCs and the host response to the transplantation.
文摘Background： The community-based Ontology of Biological and Clinical Statistics （OBCS） represents and standardizes biological and clinical data and statistical methods. Methods： Both OBCS and the Vaccine Ontology （VO） were used to ontologically model various components and relations in a typical host response to vaccination study. Such a model was then applied to represent and compare three microarray studies of host responses to the yellow fever vaccine YF-17D. A literature meta-analysis was then conducted to survey yellow fever vaccine response papers and summarize statistical methods, using OBCS. Results： A general ontological model was developed to identify major components in a typical host response to vaccination. Our ontology modeling of three similar studies identified common and different components which may contribute to varying conclusions. Although these three studies all used the same vaccine, human blood samples, similar sample collection time post vaccination, and microarray assays, statistically differentially expressed genes and associated gene functions differed, likely due to the differences in specific variables （e.g., microarray type and human variations）. Our manual annotation of 95 papers in human responses to yellow fever vaccines identified 38 data analysis methods. These statistical methods were consistently represented and classified with OBCS. Eight statistical methods not available in existing ontologies were added to OBCS. Conclusions： The study represents the first single use case of applying OBCS ontology to standardize, integrate, and use biomedical data and statistical methods. Our ontology-based meta-analysis showed that different experimental results might be due to different experimental assays and conditions, sample variations, and data analysis methods.
文摘Gastric cancer(GC)is the result of a multifactorial process whose main components are infection by Helicobacter pylori(H.pylori),bacterial virulence factors,host immune response and environmental factors.The development of the neoplastic microenvironment also depends on genetic and epigenetic changes in oncogenes and tumor suppressor genes,which results in deregulation of cell signaling pathways and apoptosis process.This review summarizes the main aspects of the pathogenesis of GC and the immune response involved in chronic inflammation generated by H.pylori.
文摘Sepsis is a life-threatening syndrome caused by a dysregulated host response to infection,resulting in very high mortality.Dysfunction of the tightly regulated immune response occurs when the body exerts an exacerbated hyperinflammatory response that is counteracted by an anti-inflammatory response,which results in immune paralysis if it is sustained for long.Innate lymphoid cells(ILCs)are immune effector cells of lymphoid origin that are devoid of recombination-activating gene-dependent rearranged antigen receptors,as in T and B cells.1 This evolutionary adaptation eliminates the necessity for antigen presentation to activate these cells,and therefore,these cells can rapidly sense and respond to infection and inflammation.ILCs sense tissue injury and pathogen infiltration through numerous cytokine,chemokine,and pattern recognition receptors.ILCs are of lymphoid origin and arise from a common lymphoid progenitor(CLP).
文摘Infection with hepatitis B virus (HBV) leads to a wide spectrum of clinical presentations ranging from an asymptomatic carrier state to self-limited acute or fulminant hepatitis to chronic hepatitis with progression to cirrhosis and hepatocellular carcinoma. Infection with HBV is one of the most common viral diseases affecting man. Both viral factors as well as the host immune response have been implicated in the pathogenesis and clinical outcome of HBV infection. In this review, we will discuss the impact of virus-host interactions for the pathogenesis of HBV infection and liver disease. These interactions include the relevance of naturally occurring viral variants for clinical disease, the role of virus-induced apoptosis for HBV-induced liver cell injury and the impact of antiviral immune responses for outcome of infection.
基金supported by the National Natural Science Foundation of China(81730057 by YMY,81801935 by CR)Sanming Project of Medicine in Shenzhen(SZSM20162011 by YMY and YWF)the Military Medical Innovation Program of Chinese PLA(18CXZ026 by YMY)。
文摘Sepsis is a life-threatening condition that is characterized by multiple organ dysfunction due to abnormal host response to various pathogens,like bacteria,fungi and virus.The differences between viral and bacterial sepsis are indeed of great significance to deepen the understanding of the pathogenesis of sepsis,especially under pandemics of SARS-CoV-2 infection.
文摘Neospora caninum (N. caninum), a cyst-forming protozoan parasite, is a major cause of bovine abortions and neonatal mortality worldwide. N. caninum has a broad intermediate host range, and its sexual cycle occurs exclusively in canids. Another species of Neospora, Neospora hughesi (N. hughesi), has been identified and causes myeloencephalitis in horses. Although molecular epidemiology studies are in their infancy, the 18S ribosomal RNA (rRNA) and ITS1 regions within the small subunit ribosomal RNA (ssuRNA) and an N. caninum species-specific DNA probe (pNc5) have been used extensively to differentiate Neospora from other closely related apicomplexan parasites. While these repetitive regions have higher sensitivity and specificity than housekeeping or antigen genes, they suffer from low discriminatory power and fail to capture intra-species diversity. Similarly, although multiple minisatellite or microsatellite marker studies have shown clear geographic substructures within Neospora, strains are often misclassified due to a convergence in the size of different alleles at microsatellite loci, known as homoplasy. Only one strain, N. caninum Liverpool (Nc-Liv), has been genome sequenced and compared with its closest relative, Toxoplasma gondii (T. gondii). Hence, detailed population genomics studies based on whole-genome sequences from multiple strains worldwide are needed in order to better understand the current population genetic structure of Neospora, and ultimately to determine more effective vaccine candidates against bovine neosporosis. The aim of this review is to outline our current understanding of the molecular epidemiology and genomics of Neospora in juxtaposition with the closely related apicomplexan parasites Hammondia hammondi and T. gondii.
文摘BACKGROUND Coronavirus disease 2019(COVID-19)is a highly contagious infection caused by the severe acute respiratory syndrome coronavirus 2 virus and has a unique underlying pathogenesis.Hemodialysis(HD)patients experience high risk of contamination with COVID-19 and are considered to have higher mortality rates than the general population by most but not all clinical series.We aim to highlight the peculiarities in the immune state of HD patients,who seem to have both immune-activation and immune-depression affecting their outcome in COVID-19 infection.CASE SUMMARY We report the opposite clinical outcomes(nearly asymptomatic course vs death)of two diabetic elderly patients infected simultaneously by COVID-19,one being on chronic HD and the other with normal renal function.They were both admitted in our hospital with COVID-19 symptoms and received the same treatment by protocol.The non-HD sibling deteriorated rapidly and was intubated and transferred to the Intensive Care Unit,where he died despite all supportive care.The HD sibling,although considered more“high-risk”for adverse outcome,followed a benign course and left the hospital alive and well.CONCLUSION These cases may shed light on aspects of the immune responses to COVID-19 between HD and non-HD patients and stimulate further research in pathophysiology and treatment of this dreadful disease.
基金supported in part by the National Key Program Project Grant from MOST #2016YFC1201000
文摘Chikungunya virus(CHIKV) is an arbovirus transmitted by Aedes mosquitos in tropical and subtropical regions across the world. After decades of sporadic outbreaks, it re-emerged in Africa,Asia, India Ocean and America suddenly, causing major regional epidemics recently and becoming a notable global health problem. Infection by CHIKV results in a spectrum of clinical diseases including an acute self-limiting febrile illness in most individuals, a chronic phase of recurrent join pain in a proportion of patients, and long-term arthralgia for months to years for the unfortunate few. No specific anti-viral drugs or licensed vaccines for CHIKV are available so far. A better understanding of virus-host interactions is essential for the development of therapeutics and vaccines. To this end, we reviewed the existing knowledge on CHIKV's epidemiology, clinical presentation, molecular virology, diagnostic approaches, host immune response, vaccine development, and available animal models. Such a comprehensive overview, we believe, will shed lights on the promises and challenges in CHIKV vaccine development.
基金Supported by The Project Research Fund from Kochi University,to Takeuchi Ha Grant-in-Aid for Scientific Research from the Ministry of Education,Science and Culture of Japan,No. 21590631 and 21590629,in part
文摘AIM： To investigate genetic diversity of Helicobacter pylori （H. pylorl） cell division-related gene A （cdrA） and its effect on the host response.METHODS： Inactivation of H. py/ori cdrA, which is involved in ceil division and morphological elonga- tion, has a role in chronic persistent infections. Ge- netic property of H. pylori cdrA was evaluated using polymerase chain reaction and sequencing in 128 （77 American and 51 Japanese） clinical isolates obtained from 48 and 51 patients, respectively. Enzyme-linked immunosorbent assay was performed to measure in- terleukin-8 （IL-8） secretion with gastric biopsy speci- mens obtained from American patients colonized with cdrA-positive or -negative strains and AGS cells co- cultured with wild-type HPK5 （cdrA-positive） or its de- rivative HPKT510 （cdrA-disruptant）. Furthermore, the cytotoxin-associated gene A （cagA） status （transloca- tion and phosphorylation） and kinetics of transcription factors [nuclear factor-kappa B （NF-~：B） and inhibition kappa B] were investigated in AGS cells co-cultured with HPK5, HPKT510 and its derivative HPKSCA （cagA- disruptant） by western blotting analysis with immuno- precipitation. RESULTS： Genetic diversity of the H. pylori cdrA gene demonstrated that the cdrA status segregated into two categories including four allele types, cdrA-positive （al- lele types, I and 11 ） and cdrA-negative （allele types; 111 and IV） categories, respectively. Almost all Japanese isolates were cdrA-positive （ 1 ： 7.8% and 11 ： 90.2%）, whereas 16.9% of American isolates were cdrA-positive （11） and 83.1% were cdrA-negative （nl： 37.7% and IV： 45.5%）, indicating extended diversity of cdrA in individual American isolates. Comparison of each isolate from different regions （antrum and corpus） in the stomach of 29 Americans revealed that cdrA status was identical in both isolates from different regions in 17 cases. However, 12 cases had a different cdrA al- lele and 6 of them exhibited a different cdrA category between two regions in the stomach. Furthermore, in 5 of the 6 cases possessing a different cdrA category, cdrA-negative isolate existed in the corpus, suggesting that cdrA-negative strain is more adaptable to coloni- zation in the corpus. IL-8 secretions from AGS revealed that IL-8 levels induced by a cdrA-disrupted HPKT510 was significantly lower （P 〈 0.01） compared to wild- type HPK5： corresponding to 50%-60% of those of wild-type HPK5. These data coincided with in vivo data that an average value of IL-8 in biopsy specimens from cdrA-positive and cdrA-negative groups was 215.6 and 135.9 pg/mL, respectively. Western blotting analysis documented that HPKT510 had no effect on CagA translocation and phosphorylation, however, nuclear accumulation of NF-κB was lower by HPKT510 com- pared to HPK5. CONCLUSION： Colonization by a cdrA-negative or cdrA-dysfunctional strain resulted in decreased IL-8 production and repression of NF-κB, and hence, atten- uate the host immunity leading to persistent infection.
基金supported by the French‘Agence Nationale pour le Recherche’(Anthos project-ANR13-RPIB-008).
文摘Embedding mesenchymal stromal cells(MSCs)in biomaterial is a subject of increasing interest in the field of Regenerative Medicine.Speeding up the clinical use of MSCs is dependent on the use of non-syngeneic models in accordance with Good Manufacturing Practices(GMP)requirements and on costs.To this end,in this study,we analyzed the in vivo host immune response following local injection of silanized hydroxypropyl methylcellulose(Si-HPMC)-embedded human MSCs in a rat model developing colorectal damage induced by ionizing radiation.Plasma and lymphocytes from mesenteric lymph nodes were harvested in addition to colonic tissue.We set up tests,using flow cytometry and a live imaging system,to highlight the response to specific antibodies and measure the cytotoxicity of lymphocytes against injected MSCs.We demonstrated that Si-HPMC protects MSCs from specific antibodies production and from apoptosis by lymphocytes.We also observed that Si-HPMC does not modify innate immune response infiltrate in vivo,and that in vitro co-culture of Si-HPMC-embedded MSCs impacts macrophage inflammatory response depending on the microenvironment but,more importantly,increases the macrophage regenerative response through Wnt-family and VEGF gene expression.This study furthers our understanding of the mechanisms involved,with a view to improving the therapeutic benefits of biomaterial-assisted cell therapy by modulating the host immune response.The decrease in specific immune response against injected MSCs protected by Si-HPMC also opens up new possibilities for allogeneic clinical use.
基金supported by the National Basic Research Program of China (973 program: 2005CB523006)
文摘Objective To investigate the pathogenesis and immunogenicity of H9N2 influenza virus A/Guangzhou/333/99 （a reassortant of G1 and G9 viruses isolated from a female patient in 1999） in a mouse model of infection.Methods Mice were infected with increasing virus titers.Viral load in the lungs and trachea was determined by EID50 assay.Pulmonary histopathology was assessed by hematoxylin‐eosin staining.Anti‐HI antibody titers and T‐cell responses to viral HA were determined by ELISPOT and confirmed by flow cytometry.Results Mice presented a mild syndrome after intranasal infection with A/Guangzhou/333/99 （H9N2） influenza virus.Virus was detected in the trachea and lungs of mice harvested on days 3,6,and 9 post‐infection.A T‐cell response to viral HA was detected on day 6 and H9 HA‐specific CD 4＋ T‐cells predominated.Seroconversion was detected after 14 days and antibody persisted for at least 28 weeks.Conclusion Our results suggest that H9N2 （A/Guangzhou/333/99） can replicate in the murine respiratory tract without prior adaptation,and both humoral and cell‐mediated immunity play an important role in the immune response.
基金Supported by the European Union-Next Generation EU,through the National Recovery and Resilience Plan of the Republic of Bulgaria,No.BG-RRP-2.004-0008.
文摘An overly exuberant immune response,characterized by a cytokine storm and uncontrolled inflammation,has been identified as a significant driver of severe coronavirus disease 2019(COVID-19)cases.Consequently,deciphering the intricacies of immune dysregulation in COVID-19 is imperative to identify specific targets for intervention and modulation.With these delicate dynamics in mind,immunomodulatory therapies have emerged as a promising avenue for miti-gating the challenges posed by COVID-19.Precision in manipulating immune pathways presents an opportunity to alter the host response,optimizing antiviral defenses while curbing deleterious inflammation.This review article compre-hensively analyzes immunomodulatory interventions in managing COVID-19.We explore diverse approaches to mitigating the hyperactive immune response and its impact,from corticosteroids and non-steroidal drugs to targeted biologics,including anti-viral drugs,cytokine inhibitors,JAK inhibitors,convalescent plasma,monoclonal antibodies(mAbs)to severe acute respiratory syndrome coronavirus 2,cell-based therapies(i.e.,CAR T,etc.).By summarizing the current evidence,we aim to provide a clear roadmap for clinicians and researchers navigating the complex landscape of immunomodulation in COVID-19 treatment.CS Glucocorticoids are among the most widely prescribed drugs with their immune-suppressive and anti-inflammatory effect[84].The current guidelines for the treatment of COVID-19 recommend against the use of dexamethasone or other systemic CS in non-hospitalized patients in the absence of another indication[70].The RECOVERY trial demonstrates the reduced 28-d mortality among hospitalized patients with COVID-19 using dexamethasone compared to the usual standard of care,along with other investigators,such as Ahmed and Hassan[85].The benefit of dexamethasone was seen only among participants receiving either oxygen alone or invasive mechanical ventilation at randomization but not among those receiving no respiratory support at enrollment[85].In a systematic review and meta-analysis,Albuquerque et al[86]showed that in comparison to tocilizumab,baricitinib,and sarilumab are associated with high probabilities of similar mortality reductions among hospitalized COVID-19 concurrently treated with CS.As a result of the absence of SARS-CoV-2-specific antiviral medications,the effectiveness of COVID-19 treatments is reduced.Several COVID-19 therapies are now under investigation.However,the majority of them lack specificity,efficacy,and safety[87].Immunotherapy is a ground-breaking medical treatment that manipulates the immune system to fight diseases.Translational research is rapidly progressing,recognized as a significant breakthrough in 2013[88].Among the immunotherapeutic options for treating COVID-19 are Immunoglobulin,CP,antibodies,mAbs(mAbs),NK cells,T cells,TLR,cytokine therapies and immune modulators.
基金This work was supported by the Memphis Research Consortium.
文摘Despite considerable recent progress in defining neutrophil functions and behaviors in tissue repair,much remains to be determined with regards to its overall role in the tissue integration of biomaterials.This article provides an overview of the neutrophil’s numerous,important roles in both inflammation and resolution,and subsequently,their role in biomaterial integration.Neutrophils function in three primary capacities:generation of oxidative bursts,release of granules and formation of neutrophil extracellular traps(NETs);these combined functions enable neutrophil involvement in inflammation,macrophage recruitment,M2 macrophage differentiation,resolution of inflammation,angiogenesis,tumor formation and immune system activation.Neutrophils exhibit great flexibility to adjust to the prevalent microenvironmental conditions in the tissue;thus,the biomaterial composition and fabrication will potentially influence neutrophil behavior following confrontation.This review serves to highlight the neutrophil’s plasticity,reiterating that neutrophils are not just simple suicidal killers,but the true maestros of resolution and regeneration.
基金support from the National Natural Science Foundation of China(Nos.82100158 and 81861148030)the Natural Science Foundation of Shanghai(Nos.21ZR1480900 and 21YF1427900)+4 种基金Shanghai Clinical Research Center for Hematologic Disease(No.119MC1910700)ShanghaiMajor Project for Clinical Medicine(No.2017ZZ01002)Shanghai Shenkang Hospital Development Center(No.SHDC2020CR5002)Innovative Research Team of High-level Local Universities in Shanghai,and Shanghai Collaborative Innovation Program on Regenerative Medicineand StemCell Research(No.2019CXJQ01)support from the ASTRA computing platform in the National Research Center for Translational Medicine(Shanghai)and the Pi computing platform in the Center for High-Performance Computing at Shanghai Jiao Tong University.
文摘The Omicron family of SARS-CoV-2 variants are currently driving the COVID-19 pandemic.Here we analyzed the clinical laboratory test results of 9911 Omicron BA.2.2 sublineages-infected symptomatic patients without earlier infection histories during a SARS-CoV-2 outbreak in Shanghai in spring 2022.Compared to an earlier patient cohort infected by SARS-CoV-2 prototype strains in 2020,BA.2.2 infection led to distinct fluctuations of pathophysiological markers in the peripheral blood.In particular,severe/critical cases of COVID19 post BA.2.2 infection were associated with less pro-inflammatory macrophage activation and stronger interferon alpha response in the bronchoalveolar microenvironment.Importantly,the abnormal biomarkers were significantly subdued in individuals who had been immunized by 2 or 3 doses of SARS-CoV-2 prototypeinactivated vaccines,supporting the estimation of an overall 96.02% of protection rate against severe/critical disease in the 4854 cases in our BA.2.2 patient cohort with traceable vaccination records.Furthermore,even though age was a critical risk factor of the severity of COVID-19 post BA.2.2 infection,vaccination-elicited protection against severe/critical COVID-19 reached 90.15% in patients aged≥60 years old.Together,our study delineates the pathophysiological features of Omicron BA.2.2 sublineages and demonstrates significant protection conferred by prior prototype-based inactivated vaccines.
文摘During virus infection, viral RNAs and mRNAs function as blueprints for viral protein synthesis and possibly as pathogen-associated molecular patterns （PAMPs） in innate immunity. Here, considering recent research progress in microRNAs （miRNAs） and competitive endogenous RNAs （ceRNAs）, we speculate that viral RNAs act as sponges and can sequester endogenous miRNAs within infected cells, thus cross-regulating the stability and translational efficiency of host mRNAs with shared miRNA response elements. This cross-talk and these reciprocal interactions between viral RNAs and host mRNAs are termed ＂competitive viral and host RNAs＂ （cvhRNAs）. We further provide recent experimental evidence for the existence of cvhRNAs networks in hepatitis B virus （HBV）, as well as Her- pesvirus saimiri （HVS）, lytic murine cytomegalovirus （MCMV） and human cytomegalovirus （HCMV） infec- tions. In addition, the cvhRNA hypothesis also pre- dicts possible cross-regulation between host and other viruses, such as hepatitis C virus （HCV）, HIV, influenza virus, human papillomaviruses （HPV）. Since the interaction between miRNAs and viral RNAs also inevitably leads to repression of viral RNA function, we speculate that virus may evolve either to employ cvhRNA networks or to avoid miRNA targeting for optimal fitness within the host. CvhRNA networks may therefore play a fundamental role in the regulation of viral replication, infection establishment, and viral pathogenesis.
基金This work was supported by grants from the National Key Research&Development Program of China(No.2022YFC2504500)the 1.3.5 project for disciplines of excellence,West China Hospital,Sichuan University(No.ZYGD23012)the National Natural Science Foundation of China(Nos.82172142 and 82272199).
文摘Background:Immunosuppression is closely related to the pathogenesis of sepsis,but the underlying mechanisms have not yet been fully elucidated.In this study,we aimed to examine the role of the Sterile Alpha Motif,Src Homology 3 domain and nuclear localization signal 1(SAMSN1)in sepsis and elucidate its potential molecular mechanism in sepsis induced immunosuppression.Methods:RNA sequencing databases were used to validate SAMSN1 expression in sepsis.The impact of SAMSN1 on sepsis was verified using gene knockout mice.Flow cytometry was employed to delineate how SAMSN1 affects immunity in sepsis,focusing on immune cell types and T cell functions.Clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR-associated protein 9(Cas9)-mediated gene editing in RAW264.7 macrophages enabled interrogation of SAMSN1’s regulatory effects on essential macrophage functions,including cell proliferation and phagocytic capacity.The mechanism of SAMSN1 in the interaction between macrophages and T cells was investigated using the RAW264.7 cell line and primary cell lines.Results:SAMSN1 expression was significantly increased in patients with sepsis and was positively correlated with sepsis mortality.Genetic deletion of Samsn1 in murine sepsis model improved T cell survival,elevated T cell cytolytic activity,and activated T cell signaling transduction.Concurrently,Samsn1 knockout augmented macrophage proliferation capacity and phagocytic efficiency.In macrophage,SAMSN1 binds to Kelch-like epichlorohydrin-associated protein 1(KEAP1),causing nuclear factor erythroid 2-related factor 2(NRF2)to dissociate from the KEAP1–NRF2 complex and translocate into the nucleus.This promotes the transcription of the coinhibitory molecules CD48/CD86/carcinoembryonic antigen related cell adhesion molecule 1(CEACAM1),which bind to their corresponding receptors natural killer cell receptor 2B4/CD152/T cell immunoglobulin and mucin domain-containing protein 3(TIM3)on the surface of T cells,inducing T-cell exhaustion.Conclusions:SAMSN1 deletion augmented adaptive T cell immunity and macrophage phagocytic-proliferative dual function.Furthermore,it mediates the KEAP1–NRF2 axis,which affects the expression of coinhibitory molecules on macrophages,leading to T-cell exhaustion.This novel immunosuppression mechanism potentially provides a candidate molecular target for sepsis immunotherapy.
