Embedding MSCs in Si-HPMC hydrogel decreased MSC-directed host immune response and increased the regenerative potential of macrophages

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.

Oral microbiota and host innate immune response in bisphosphonate-related osteonecrosis of the jaw

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.

Harnessing immunity:Immunomodulatory therapies in COVID-19

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.

From Helicobacter pylori infection to gastric cancer:Current evidence on the immune response

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.

Erratum to “Plant Defense against Necrotrophic Pathogens” [American Journal of Plant Sciences 11(12) (2020) 2122-2138]

The original online version of this article (Ghozlan, M.H., EL-Argawy, E., Tokgöz, S., Lakshman, D.K. and Mitra, A. (2020) Plant Defense against Necrotrophic Pathogens. American Journal of Plant Sciences, 11, 2122-2138. https://doi.org/10.4236/ajps.2020.1112149) was published mistakenly without another co-author, Nikita Gambhir. In this regard, we revise authors and “how to cite” sections by adding her name.

Pathogenesis of the Chikungunya virus and the host immunity response

Along with the running COVID-19 pandemic by the severe acute respiratory syndrome coronavirus 2,the Chikungunya virus is already known as the causative agent of re-emerging Chikungunya fever in many countries after several years of latency;and it’s certainly one of the most important clinical issues possibly due to the lack of appropriate vaccination.Therefore,continuous study and monitoring of this disease outbreak demand attention by the relevant health professionals.Present review has been written in the light of the recently available reports on the Chikungunya virus infection.The genomic structure and its impact on the viral epidemiology,the possible protective immunity,and the infection mitigation strategies have been discussed.It’s already well known that the Chikungunya virus can start infection after getting entrance into the blood circulation through the mosquito bites followed by the dissemination into the major organs like liver,brain,eye,joints and lymph nodes in order to inaugurate the infectivity.Apparently,the occurrence of death is very rare but the extreme fatality and morbidity may occur if the patient has other underlying disease conditions.The molecular aspects of the virus,the site-specific damages caused by the viral infection,and finally,the public awareness of such viral infection as discussed in the current review would help to maintain the public health sustainability especially in the developing countries whereby the knowledge on the required hygiene is poor.

Advances on the Molecular Mechanism of the Interaction between Ralstonia solanacearum and Hosts

Ralstonia solanacearum is an important model phytopathogenic bacterium that causes bacterial wilt disease on many plant species and leads to serious economic losses. The interactions between R. solanacearum and host plants have become a model system for the study of plants and pathogens interactions. This paper reviews the advances on the molecular mechanisms between R. solanacearum and hosts interaction including the formation of plant innate immunity, the suppression of plant innate immunity by this pathogen and the activation of effector-triggered immunity. Furthermore, we made a prospect on how to utilize the interaction mechanism between R. solanacearum and hosts to control the disease.

Effect of Helicobacter pylori cdrA on interleukin-8 secretions and nuclear factor kappa B activation

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.

Pathogenesis and Immunogenicity of an Avian H9N2 Influenza Virus Isolated from Human

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.

Trace metal elements: a bridge between host and intestinal microorganisms

Trace metal elements, such as iron, copper, manganese, and zinc, are essential nutrients for biological processes. Although their intake demand is low, they play a crucial role in cell homeostasis as the cofactors of various enzymes. Symbiotic intestinal microorganisms compete with their host for the use of trace metal elements. Moreover, the metabolic processes of trace metal elements in the host and microorganisms affect the organism's health. Supplementation or the lack of trace metal elements in the host can change the intestinal microbial community structure and function. Functional changes in symbiotic microorganisms can affect the host's metabolism of trace metal elements. In this review, we discuss the absorption and transport processes of trace metal elements in the host and symbiotic microorganisms and the effects of dynamic changes in the levels of trace metal elements on the intestinal microbial community structure. We also highlight the participation of trace metal elements as enzyme cofactors in the host immune process. Our findings indicate that the host uses metal nutrition immunity or metal poisoning to resist pathogens and improve immunity.

Plant Defense against Necrotrophic Pathogens

Necrotrophic pathogenic bacteria, fungi and oomycetes are widely distributed and are responsible for significant crop losses. Host plants deploy different defense mechanisms and appropriate immune responses to defend them against these pathogens. Regardless of the pathogen’s lifestyle, infection activates plant immune responses either through Pathogen/Microbe Associated Molecular Pattern (P/MAMP) or through Effector Triggered Immunity (ETI). However, as R-genes are not usually associated with resistance to necrotrophs, resistance is largely dependent on the balanced interplay between crucial phytohormones in complex signaling pathways involving jasmonic acid (JA), ethylene, salicylic acid (SA) and abscisic acid (ABA). An increase in salicylic acid levels enhances susceptibility to necrotrophic pathogens but promotes resistance to hemibiotrophs, whereas a deficiency in SA or SA signaling has either no significant impact or affects resistance only at the primary infection site. The same fashion is observed for JA signaling system that appears to elicit resistance against diseases caused by necrotrophic pathogens and can trigger systemic immunity conferring resistance against them. On the other hand, ABA can play a positive or negative role in plant defense responses to necrotrophs as ABA-mediated defense responses are dependent on specific plant-pathogen interactions. Understanding plant immune response against necrotrophic pathogens may lead to the development of resistant or tolerant crop cultivars.

Advances in single-cell sequencing technology in microbiome research

With the rapid development of histological techniques and the widespread applica-tion of single-cell sequencing in eukaryotes,researchers desire to explore individual microbial.genotypes and functional expression,which deepens our understanding of microorganisms.In this review,the history of the development of microbial detection technologies was revealed and the difficulties in the application of single-cell sequencing in microorganisms were dissected as well.Moreover,the characteristics of the currently emerging microbial single-cell sequencing(Microbe-seq)technology were summarized,and the prospects of the application of Microbe-seq in microorganisms were distilled based on the current development status.Despite its mature development,the Microbe-seq technology was still in the optimization stage.A retrospective study was conducted,aiming to promote the widespread application of single-cell sequencing in microorganisms and facilitate further improvement in the technol-ogy.

Co-evolved plant and blast fungus ascorbate oxidases orchestrate the redox state of host apoplast to modulate rice immunity

Apoplastic ascorbate oxidases(AOs)play a critical role in reactive oxygen species(RoS)-mediated innate host immunity by regulating the apoplast redox state.To date,little is known about how apoplastic effectors of the riceblast fungus Magnaportheoryzaemodulate the apoplast redox state of rice to subvert plant immunity.In this study,we demonstrated that M.oryzae MoAo1 is an Ao that plays a role in virulence by modulating the apoplast redox status of rice cells.We showed that MoAo1 inhibits the activity of rice OsAO3and OsAO4,which also regulate the apoplast redox status and plant immunity.In addition,we found that MoAo1,OsAO3,andOsAO4 allexhibit polymorphic variations whosevaried interactions orchestrate pathogen virulence and rice immunity.Taken together,our results reveal a critical role for extracellular redox enzymes during rice blast infection and shed light on the importance of the apoplast redox state anditsregulation inplant-pathogeninteractions.

Gene therapy: light is finally in the tunnel

After two decades of ups and downs,gene therapy has recently achieved a milestone in treating patients with Leber’s congenital amaurosis(LCA).LCA is a group of inherited blinding diseases with retinal degeneration and severe vision loss in early infancy.Mutations in several genes,including RPE65,cause the disease.Using adenoassociated virus as a vector,three independent teams of investigators have recently shown that RPE65 can be delivered to retinal pigment epithelial cells of LCA patients by subretinal injections resulting in clinical benefits without side effects.However,considering the whole field of gene therapy,there are still major obstacles to clinical applications for other diseases.These obstacles include innate and immune barriers to vector delivery,toxicity of vectors and the lack of sustained therapeutic gene expression.Therefore,new strategies are needed to overcome these hurdles for achieving safe and effective gene therapy.In this article,we shall review the major advancements over the past two decades and,using lung gene therapy as an example,discuss the current obstacles and possible solutions to provide a roadmap for future gene therapy research.

Recent progress on chikungunya virus research

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.

Systematic Discovery and Pathway Analyses of Metabolic Disturbance in COVID-19

Background:The ongoing global coronavirus disease 2019(COVID-19)pandemic is posing a serious public health threat to nations worldwide.Understanding the pathogenesis of the disease and host immune responses will facilitate the discovery of therapeutic targets and better management of infected patients.Metabolomics technology can provide an unbiased tool to explore metabolic perturbation.Methods:Twenty-six healthy controls and 50 COVID-19 patients with mild,moderate,and severe symptoms in the Fifth Medical Center of PLA General Hospital from January 22 to February 16,2020 were recruited into the study.Fasting blood samples were collected and subject to metabolomics analysis by liquid chromatography–mass spectrometry.Metabolite abundance was measured by peak area and was log-transformed before statistical analysis.The principal component analysis,different expression analysis,and metabolic pathway analysis were performed using R package.Co-regulated metabolites and their associations with clinical indices were identified by the weighted correlation network analysis and Spearman correlation coefficients.The potential metabolite biomarkers were analyzed using a random forest model.Results:We uncovered over 100 metabolites that were associated with COVID-19 disease and many of them correlated with disease severity.Sets of highly correlated metabolites were identified and their correlations with clinical indices were presented.Further analyses linked the differential metabolites with biochemical reactions,metabolic pathways,and biomedical MeSH terms,offering contextual insights into disease pathogenesis and host responses.Finally,a panel of metabolites was discovered to be able to discriminate COVID-19 patients from healthy controls,and also another list for mild against more severe cases.Our findings showed that in COVID-19 patients,citrate cycle,sphingosine 1-phosphate in sphingolipid metabolism,and steroid hormone biosynthesis were downregulated,while purine metabolism and tryptophan metabolism were disturbed.Conclusion:This study discovered key metabolites as well as their related biological and medical concepts pertaining to COVID-19 pathogenesis and host immune response,which will facilitate the selection of potential biomarkers for prognosis and discovery of therapeutic targets.

CLP gene family,a new gene family of Cotesia vestalis bracovirus inhibits melanization of Plutella xylostella hemolymph

Polydnaviruses(PDVs)are obligatory symbionts of parasitoid wasps and play an important role in suppressing host immune defenses.Although PDV genes that inhibit host melanization are known in Microplitis bracovirus,the functional homologs in Cotesia bracoviruses remain unknown.Here,we find that Cotesia vestalis bracovirus(CvBV)can inhibit hemolymph melanization of its host,Plutella xylostella larvae,during the early stages of parasitization,and that overexpression of highly expressed CvBV genes reduced host phenoloxidase activity.Furthermore,CvBV-7-I in particular reduced host phenolox-idase activity within 12 h,and the injection of anti-CvBV-7-1 antibody increased the melanization of parasitized host larvae.Further analyses showed that CvBV-7-1 and three homologs from other Cotesia bracoviruses possessed a C-terminal leucine/isoleucine-rich region and had a similar flinction in inhibiting melanization.Therefore,a new family of bracovirus genes was proposed and named as C-terminal Leucine/isoleucine-rich Protein(CLP).Ectopic expression of CvBV-7-1 in Drosophila hemocytes increased susceptibility to bacterial repression of melanization and reduced the melanotic encapsulation of par-asitized D.melanogaster by the parasitoid Leptopilina boulardi.The formation rate of wasp pupae and the eclosion rate of C.vestalis were affected when the function of CvBV-7-1 was blocked.Our findings suggest that CLP genes from Cotesia bracoviruses encoded proteins that contain a C-terminal leucine/isoleucine-rich region and function as melanization inhibitors during the early stage of parasitization,which is important for successful parasitization.