Nucleotide oligomerization domain 2 contributes to the innate immune response in THCE cells stimulated by Aspergillus fumigatus conidia

AIM: To investigate the expression of nucleotide oligomerization domain 2 (NOD2) in the immortalized human corneal epithelial cell line (THCE), and its role in the innate immune response triggered by inactive Aspergillus fumigatus (Af) conidia. METHODS: The normal THCE cells were investigated as controls. After incubation with inactive Af conidia for 0.5, 2, 4, 6, and 8 hours, THCE cells were harvested, mRNA expression of NOD2 and receptor interacting protein 2 (RIP2) was detected by RT-PCR. Intracellular proteins including NOD2, NF-kappa B and proinflammatory cytokines such as TNF-alpha, IL-8, IL-6 in the cell supernatant were analyzed by ELISA. RESULTS: Our data indicate that NOD2 expressed in the normal THCE cells. After triggered by the inactive Af conidia, the expression of NOD2, RIP2 mRNA and the secretion of NOD2, NF-kappa B, TNF-alpha, IL-8, IL-6 both increased in a time-depended manner, and reached the peak point at 4, 6, 6, 4, 6, 6, 4 hours, respectively. And after pretreated with NOD2 neutralizing antibody, the expression of RIP2, NF-kappa B, TNF-alpha, IL-8 both decreased dramatically at the peak point, while the secretion of IL-6 changed little. CONCLUSION: The results of this study suggest that NOD2 exists and expresses in the THCE cells, and contributes to the innate immune responses triggered by inactive Afconidia by induction of proinflammatory cytokines such as TNF-alpha and IL-8 through the NF-kappa B pathway.

Expression patterns and action analysis of genes associated with physiological responses during rat liver regeneration:Innate immune response

AIM： To study the relationship between innate immune response and liver regeneration （LR） at transcriptional level.METHODS： Genes associated with innate immunity response were obtained by collecting the data from databases and retrieving articles, Gene expression changes in rat regenerating liver were detected by rat genome 230 2.0 array.RESULTS： A total of 85 genes were found to be associated with LR. The initially and totally expressed number of genes at the phases of initiation [0.5-4 h after partial hepatectomy （PH）], transition from GO to G1 （4-6 h after PH）, cell proliferation （6-66 h after PH）, cell differentiation and structure-function reconstruction （66-168 h after PH） was 36, 9, 47, 4 and 36, 26, 78, 50, respectively, illustrating that the associated genes were mainly triggered at the initial phase of LR and worked at different phases. According to their expression similarity, these genes were classified into 5 types： 41 up-regulated, 4 predominantly up-regulated, 26 downregulated, 6 predominantly down-regulated, and 8 approximately up/down-regulated genes, respectively. The expression of these genes was up-regulated 350 times and down-regulated 129 times respectively, demonstrating that the expression of most genes was enhanced while the expression of a small number of genes was decreased during LR. Their time relevance was classified into 14 groups, showing that the cellular physiological and biochemical activities dudng LR were staggered. According to the gene expression patterns,they were classified into 28 types, indicating that the cellular physiological and biochemical activities were diverse and complicated during LR. CONCLUSION： Congenital cellular immunity is enhanced mainly in the forepart, prophase and anaphase of LR while congenital molecular immunity is increased dominantly in the forepart and anaphase of LR. A total of 85 genes associated with LR play an important role in innate immunity.

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.

Calmodulin-like 5 promotes PEDV replication by regulating late-endosome synthesis and innate immune response

The infection caused by porcine epidemic diarrhea virus(PEDV)is associated with high mortality in piglets worldwide.Host factors involved in the efficient replication of PEDV,however,remain largely unknown.Our recent proteomic study in the virus-host interaction network revealed a significant increase in the accumulation of CALML5(EF-hand protein calmodulin-like 5)following PEDV infection.A further study unveiled a biphasic increase of CALML5 in 2 and 12 h after viral infection.Similar trends were observed in the intestines of piglets in the early and late stages of the PEDV challenge.Moreover,CALML5 depletion reduced PEDV mRNA and protein levels,leading to a one-order-of-magnitude decrease in virus titer.At the early stage of PEDV infection,CALML5 affected the endosomal trafficking pathway by regulating the expression of endosomal sorting complex related cellular proteins.CALML5 depletion also suppressed IFN-βand IL-6 production in the PEDV-infected cells,thereby indicating its involvement in negatively regulating the innate immune response.Our study reveals the biological function of CALML5 in the virology field and offers new insights into the PEDV-host cell interaction.

Mycobacterium tuberculosis Mce2E suppresses the macrophage innate immune response and promotes epithelial cell proliferation

The intracellular pathogen Mycobacterium tuberculosis(Mtb)can survive in the host and cause disease by interfering with a variety of cellular functions.The mammalian cell entry 2(mce2)operon of Mtb has been shown to contribute to tuberculosis pathogenicity.However,little is known about the regulatory roles of Mtb Mce2 family proteins towards host cellular functions.Here we show that the Mce2 family protein Mce2E suppressed the macrophage innate immune response and promoted epithelial cell proliferation.Mce2E inhibited activation of the extracellular signal-regulated kinase(ERK)and Jun N-terminal kinase(JNK)mitogen-activated protein kinase(MAPK)signaling pathways in a non-canonical D motif(a MAPK-docking motif)-dependent manner,leading to reduced expression of TNF and IL-6 in macrophages.Furthermore,Mce2E promoted proliferation of human lung epithelium-derived lung adenoma A549 cells by inhibiting K48-linked polyubiquitination of eEF1A1 in aβstrand region-dependent manner.In summary,Mce2E is a novel multifunctional Mtb virulence factor that regulates host cellular functions in a niche-dependent manner.Our data suggest a potential novel target for TB therapy.

ZDHHC11 modulates innate immune response to DNA virus by mediating MITA–IRF3 association

MITA is a central adaptor in innate immune responses to DNA viruses.The mechanisms responsible for recruitment of downstream kinase TBK1 and the transcription factor IRF3 to MITA remains enigmatic.Here we identified ZDHHC11,a member of DHHC palmitoyl transferase family,as a positive regulator of DNA virus-triggered signaling.Overexpression of ZDHHC11 activated the IFN-βpromoter,while ZDHHC11-deficiency specifically impaired DNA virus HSV-1-induced transcription of downstream antiviral genes.Zdhhc11^(−/−)mice exhibited lower serum cytokine levels and higher lethality after HSV-1 infection.Mechanistically,ZDHHC11 facilitated the optimal recruitment of IRF3 to MITA.Our findings support an important role for ZDHHC11 in mediating MITA-dependent innate immune responses against DNA viruses.

The roles of interferon-inducible p200 family members IFI16 and p204 in innate immune responses,cell differentiation and proliferation

p204 is a member of the interferon-inducible p200 family proteins in mice.The p200 family has been reported to be multifunctional regulators of cell proliferation,differentiation,apoptosis and senescence.Interferon-inducible protein 16(IFI16)is regarded as the human ortholog of p204 in several studies.This is possibly due to the similarity of their structures.However the consistency of their functions is still elusive.Currently,an emerging focus has been placed upon the role of the p200 proteins as sensors for microbial DNA in innate immune responses and provides new insights into infections as well as autoimmune diseases.This review specially focuses on IFI16 and p204,the member of p200 family in human and murine respectively,and their pathophysiological roles in innate immune responses,cell differentiation and proliferation.

PLA_(2) mediates the innate immune response in Asian corn borer, Ostrinia furnacalis

The eicosanoid signaling pathway mediates insect immune reactions to a wide range of stimuli. This pathway begins with the biosynthesis of arachidonic acid (AA) from the hydrolysis of phospholipids catalyzed by phospholipase A_(2) (PLA_(2)). We report here that the PLA_(2) inhibitor, dexamethasone (DEX), impaired the innate immune response including nodulation, encapsulation, and melanization in Ostrinia furnacalis larvae, while AA partially reversed these effects of DEX. We cloned a full-length complementary DNA encoding a PLA_(2), designated as OfsPLA_(2), from O. furnacalis. The open reading frame of OfsPLA_(2) encodes a 195-amino acid residue protein with a 22-residue signal peptide. Sequence alignment analyses indicated that O. furnacalis PLA_(2) might be a Group III secretory PLA_(2). The highest transcript levels of OfsPLA_(2) were detected in the fat body, and its transcript levels increased dramatically after infection with Escherichia coli, Micrococcus luteus, or Beauveria bassiana. Recombinant OfsPLA_(2) significantly induced prophenoloxidase (PPO) activation in larval hemolymph in the presence of Ca^(2+) and encapsulation of agarose beads. Injection of recombinant OfsPLA_(2) into larvae resulted in increased transcript levels of attacin, defencin, and moricin-3 genes. Our results demonstrate the involvement of the eicosanoid signaling pathway in the innate immune response of O. furnacalis larvae and provide new information about the roles of O. furnacalis secretory PLA_(2) in activating PPO and antimicrobial peptide production.

The SUMOylation of TAB2 mediated by TRIM60 inhibits MAPK/NF-κB activation and the innate immune response

Activation of the TAK1 signalosome is crucial for mediating the innate immune response to pathogen invasion and is regulated by multiple layers of posttranslational modifications,including ubiquitination,SUMOylation,and phosphorylation;however,the underlying molecular mechanism is not fully understood.In this study,TRIM60 negatively regulated the formation and activation of the TAK1 signalosome.Deficiency of TRIM60 in macrophages led to enhanced MAPK and NF-κB activation,accompanied by elevated levels of proinflammatory cytokines but not IFN-I.Immunoprecipitation-mass spectrometry assays identified TAB2 as the target of TRIM60 for SUMOylation rather than ubiquitination,resulting in impaired formation of the TRAF6/TAB2/TAK1 complex and downstream MAPK and NF-κB pathways.The SUMOylation sites of TAB2 mediated by TRIM60 were identified as K329 and K562;substitution of these lysines with arginines abolished the SUMOylation of TAB2.In vivo experiments showed that TRIM60-deficient mice showed an elevated immune response to LPS-induced septic shock and L.monocytogenes infection.Our data reveal that SUMOylation of TAB2 mediated by TRIM60 is a novel mechanism for regulating the innate immune response,potentially paving the way for a new strategy to control antibacterial immune responses.

p62/SQSTM1 Participates in the Innate Immune Response of Macrophages Against Candida albicans Infection

Objective: This study was designed to evaluate whether p62/SQSTM1 (hereafter referred to as p62) is involved in the immune response of macrophages against challenge byCandida albicans (C. albicans).Methods: We cultured bone marrow-derived macrophages (BMDMs) to investigate the immune response to challenge byC. albicans. The p62 gene was knocked down by transfection with p62 small interfering RNA (siRNA) in the p62 siRNA group. BMDMs transfected with nonsense siRNA served as the negative control (NC) group. These two groups of BMDMs were challenged withC. albicans in vitro. We detected p62 expression through quantitative reverse transcription PCR and western blotting. The phagocytosis ability of BMDMs was evaluated by flow cytometry and microscopic examination using an Olympus FV1000 laser scanning confocal microscope. Moreover, we determined the level of reactive oxygen species (ROS) in BMDMs. The mRNA levels of proinflammatory cytokines were determined by quantitative reverse transcription PCR.Results: After stimulation byC. albicans, the relative expression of p62 mRNA was increased in a dose-dependent manner, the relative expression of p62 and the ratio of BMDMs toC. albicans is 1.893 ± 0.2156 (1:1,P < 0.05), 2.873 ± 0.4787 (1:3,P < 0.05) and 3.556 ± 0.2892 (1:5,P < 0.01). The p62 protein level was also increased. After transfection with p62 siRNA, the mRNA and protein levels of p62 were significantly decreased in BMDMs (P < 0.05). After 0.5, 1 and 2 hours of co-culture of BMDMs withC. albicans, flow cytometry showed that the phagocytosis rates ofC. albicans by BMDMs were significantly lower in the p62 siRNA group than in the NC group (39.70 ± 1.69%vs. 55.23 ± 0.72%, 46.70 ± 0.89%vs. 60.80 ± 1.78%, 51.90 ± 0.98%vs. 64.43 ± 2.0%, respectively, allP < 0.05). Consistent results were seen in the production of ROS (4269 ± 392.6vs. 13426 ± 1859.7, 4967 ± 721.2vs. 13687 ± 2611.2, 7647 ± 1950.0vs. 17719 ± 1814.2, respectively, allP < 0.05). The ROS levels were higher in BMDMs of the NC group than in BMDMs transfected with p62 siRNA at 0.5, 1, and 2 hours after treatment withC. albicans. BMDMs was co-cultured withC. albicans for 4 and 12 hours, the mRNA levels of interleukin-1β and interleukin-18 in NCs were also higher than p62 siRNA group, interleukin-1β: (6.14 ± 1.63vs. 12.12 ± 0.54, 8.81 ± 0.86vs. 26.2 ± 4.67, respectively, allP < 0.05), IL-18: (0.38 ± 0.02vs. 0.97 ± 0.06, 0.44 ± 0.02vs. 2.23 ± 0.46, respectively, allP < 0.05).Conclusion: p62 plays an important role in the process of phagocytosis in BMDMs challenged byC. albicans through ROS production and expression of proinflammatory cytokines.

The antimicrobial peptide Brevinin-2ISb enhances the innate immune response against methicillinresistant Staphylococcus aureus by activating DAF-2/DAF-16 signaling in Caenorhabditis elegans,as determined by in vivo imaging

Objective::In order to study the important role and molecular mechanism of Brevinin-2 family antimicrobial peptide Brevinin-2ISb in methicillin-resistant Staphylococcus aureus(MRSA)infection of Caenorhabditis(C.)elegans,and to find the optimal therapeutic concentration of Brevinin-2ISb.Methods::By using a C.elegans model and MRSA infection modelto study the therapeutic effect of different concentrations of Brevinin-2ISb on C.elegans.Real-time PCR was used for investigating the effect of Brevinin-2ISb on the downstream gene expression of DAF-2/DAF-16 innate immune pathway and the major virulence factor gene expression of MRSA.With protein activity tests to study the inhibitory effect of Brevinin-2ISb on MRSA virulence factor protein activity.Finally,laser confocal imaging was carried out to observe real-time expression and distribution of downstream antimicrobial proteins to further prove the effect of Brevinin-2ISb on the activation of DAF-2/DAF-16 pathway by in vivo imaging.All animal study procedures were approved by the Academic Committee at Xidian University and Xi’an Jiaotong University Animal Care and Use Committee,China(approval No.JGC201207)on July 15,2017.Results::Host immunity was largely enhanced by Brevinin-2ISb,and the expression of staphylococcal enterotoxin genes,as well as virulence factors,was suppressed by Brevinin-2ISb.Indeed,the expression of many C.elegans innate immune genes,including lys-7,spp-1,K05D8.5 and C29F3.7,was induced by Brevinin-2ISb.In particular,robust,sustained expression of the antibacterial gene lys-7 was observed after Brevinin-2ISb treatment,resulting in increased protein levels.These effects correlated with a reduction in the MRSA-mediated death of the C.elegans host.Low concentrations of Brevinin-2ISb exhibited very low hemolytic activity,and may play a positive role in host innate immunity.Specifically,activation of the DAF-2/DAF-16 pathway appears to be essential for immune activation in C.elegans treated with Brevinin-2ISb.Based on the evolutionary conservation of innate immune pathways,our results suggest that Brevinin-2ISb not only has strong antibacterial activity,but may also enhance the innate immune response in humans.This study demonstrates that Brevinin-2ISb-related peptides are potential candidates for the development of novel anti-inflammatory or anti-microbial drugs.Conclusion::Antimicrobial peptide Brevinin-2ISb effectively inhibits MRSA at low concentration.This antimicrobial peptide can prolong the life of MRSA-infected C.elegans,has very low hemolytic activity and inhibits the activity and expression of various MRSA virulence factors.More importantly,Brevinin-2ISb activated the expression of antimicrobial genes downstream of DAF-2/DAF-16,which enhanced the MRSA resistance of C.elegans.This peptide could be used as the basis for developing new drugs to replace antibiotics.

Cytokines as critical co-stimulatory molecules in modulating the immune response of natural killer cells

Cytokines are involved in directing the activation of natural killer （NK） cells. NK cells are involved in the recognition of cells that have been altered; thus they do not recognize specific insults to the host, but when activated, are capable of destroying infected cells directly, as well as promoting the recruitment and response of the other components of the immune system by the release of cytokines and chemokines. It is these properties that have made NK cells a critical part of innate immunity and adaptive immunity, and they play a principal role linking innate and adaptive immunity by the recruitment of an adaptive immune response to an innate immune reaction.

Current research progress on the viral immune evasion mechanisms of African swine fever virus

African swine fever(ASF),caused by the ASF virus(ASFV),is an acute,severe,and highly contagious infectious disease in domestic pigs and wild boars.Domestic pigs infected with a virulent ASFV strain can have morbidity and mortality rates of up to 100%.The epidemic of ASF has caused serious economic losses to the global pig industry.Currently,there is no safe and efective vaccine or specifc drug for treating ASF.Therefore,ASFV still poses a great threat to pig factories.ASFV is a double-stranded DNA virus with a complex icosahedral multilayer structure.The ASFV genome contains 150-170 open reading frames(ORFs)that encode 150-200 proteins.Some ASFV-encoded proteins are involved in virus invasion,genome replication,DNA repair,and virion formation.Some ASFV proteins execute immunomodulatory functions by regulating the host antiviral innate immune response.Accumulating studies have shown that the immunomodulatory functions of ASFV genes are closely related to the virulence and pathogenicity of ASFV isolates.This review summarizes the research advances on ASFV immune evasion mechanisms in African swine fever patients and provides new insights for developing attenuated live vaccine candidates to prevent and control ASF.

Contribution of Toll-like receptors to the control of hepatitis B virus infection by initiating antiviral innate responses and promoting specific adaptive immune responses

It is well accepted that adaptive immunity plays a key role in the control of hepatitis B virus （HBV） infection. In contrast, the contribution of innate immunity has only received attention in recent years. Toll-like receptors （TLRs） sense pathogen-associated molecule patterns and activate antiviral mechanisms, including intracellular antiviral pathways and the production of antiviral effector interferons （IFNs） and pro-inflammatory cytokines. Experimental results from in vitroand in vivo models have demonstrated that TLRs mediate the activation of cellular signaling pathways and the production of antiviral cytokines, resulting in a suppression of HBV replication. However, HBV infection is associated with downregulation of TLR expression on host cells and blockade of the activation of downstream signaling pathways. In primary HBV infection, TLRs may slow down HBV infection, but contribute only indirectly to viral clearance. Importantly, TLRs may modulate HBV-specific T- and B-cell responses in vivo, which are essential for the termination of HBV infection. Thus, TLR agonists are promising candidates to act as immunomodulators for the treatment of chronic HBV infection. Antiviral treatment may recover TLR expression and function in chronic HBV infection and may increase the efficacy of therapeutic approaches based on TLR activation. A combined therapeutic strategy with antiviral treatment and TLR activation could facilitate the restoration of HBV-specific immune responses and thereby, achieve viral clearance in chronically infected HBV patients.

Decitabine induces IRF7-mediated immune responses in p53-mutated triple-negative breast cancer:a clinical and translational study

p53 is mutated in half of cancer cases.However,no p53-targeting drugs have been approved.Here,we reposition decitabine for triple-negative breast cancer(TNBC),a subtype with frequent p53 mutations and extremely poor prognosis.In a retrospective study on tissue microarrays with 132 TNBC cases,DNMT1 overexpression was associated with p53 mutations(P=0.037)and poor overall survival(OS)(P=0.010).In a prospective DEciTabinE and Carboplatin in TNBC(DETECT)trial(NCT03295552),decitabine with carboplatin produced an objective response rate(ORR)of 42%in 12 patients with stage IV TNBC.Among the 9 trialed patients with available TP53 sequencing results,the 6 patients with p53 mutations had higher ORR(3/6 vs.0/3)and better OS(16.0 vs.4.0 months)than the patients with wild-type p53.In a mechanistic study,isogenic TNBC cell lines harboring DETECT-derived p53 mutations exhibited higher DNMT1 expression and decitabine sensitivity than the cell line with wild-type p53.In the DETECT trial,decitabine induced strong immune responses featuring the striking upregulation of the innate immune player IRF7 in the p53-mutated TNBC cell line(upregulation by 16-fold)and the most responsive patient with TNBC.Our integrative studies reveal the potential of repurposing decitabine for the treatment of p53-mutated TNBC and suggest IRF7 as a potential biomarker for decitabine-based treatments.

Control of hepatitis B virus replication by interferons and Toll-like receptor signaling pathways

Hepatitis B virus (HBV) infection is one of the major causes of liver diseases, affecting more than 350 million people worldwide. The interferon (IFN)-mediated innate immune responses could restrict HBV replication at the different steps of viral life cycle. Indeed, IFN-&#x003b1; has been successfully used for treatment of patients with chronic hepatitis B. However, the role of the innate immune response in HBV replication and the mechanism of the anti-HBV effect of IFN-&#x003b1; are not completely explored. In this review, we summarized the currently available knowledge about the IFN-mediated anti-HBV effect in the HBV life cycle and the possible effectors downstream the IFN signaling pathway. The antiviral effect of Toll-like receptors (TLRs) in HBV replication is briefly discussed. The strategies exploited by HBV to evade the IFN- and TLR-mediated antiviral actions are summarized.

MAP Kinases in Immune Responses

MAP kinases are evolutionarily conserved signaling regulators from budding yeast to mammals and play essential roles in both innate and adaptive immune responses.There are three main families of MAPKs in mammals.Each of them has its own activators,inactivators,substrates and scaffolds,which altogether form a fine signaling network in response to different extracellular or intracellular stimulation.In this review,we summarize recent advances in understanding of the regulation of MAP kinases and the roles of MAP kinases in innate and adaptive immune responses.Cellular & Molecular Immunology.2005;2(1):20-27.

Dephosphorylation of cGAS by PPP6C impairs its substrate binding activity and innate antiviral response

The cyclic GMP-AMP (cGAMP) synthase (cGAS) plays a critical role in host defense by sensing cytosollc DNA derived from microbial pathogens or mls-located cellular DNA.Upon DNA binding,cGAS utilizes GTP and ATP as substrates to synthesize cGAMP,leading to MITA-mediated innate immune response.In this study,we identified the phosphatase PPP6C as a negative regulator of cGASmediated innate immune response.PPP6C is constitutively associated with cGAS in un-stimulated cells.DNA virus infection causes rapid disassociation of PPP6C from cGAS,resulting in phosphorylation of human cGAS S435 or mouse cGAS S420 in its catalytic pocket.Mutation of this eerine residue of cGAS impairs its ability to synthesize cGAMP upon DNA virus infection.In vitro experiments indicate that S420-phosphorylated mcGAS has higher affinity to GTP and enzymatic activity.PPP6Cdeficiency promotes innate immune response to DNA virus in various cells.Our findings suggest that PPP6Cmediated dephosphorylation of a catalytic pocket serine residue of cGAS impairs its substrate binding activity and innate immune response,which provides a mechanism for keeping the DNA sensor cGAS inactive in the absence of infection to avoid autoimmune response.

Role of the gut microbiota in inflammatory bowel disease pathogenesis: What have we learnt in the past 10 years?

Our understanding of the microbial involvement in inflammatory bowel disease (IBD) pathogenesis has increased exponentially over the past decade. The development of newer molecular tools for the global assessment of the gut microbiome and the identification of nucleotide-binding oligomerization domain-containing protein 2 in 2001 and other susceptibility genes for Crohn&#x02019;s disease in particular has led to better understanding of the aetiopathogenesis of IBD. The microbial studies have elaborated the normal composition of the gut microbiome and its perturbations in the setting of IBD. This altered microbiome or &#x0201c;dysbiosis&#x0201d; is a key player in the protracted course of inflammation in IBD. Numerous genome-wide association studies have identified further genes involved in gastrointestinal innate immunity (including polymorphisms in genes involved in autophagy: ATG16L1 and IGRM), which have helped elucidate the relationship of the local innate immunity with the adjacent luminal bacteria. These developments have also spurred the search for specific pathogens which may have a role in the metamorphosis of the gut microbiome from a symbiotic entity to a putative pathogenic one. Here we review advances in our understanding of microbial involvement in IBD pathogenesis over the past 10 years and offer insight into how this will shape our therapeutic management of the disease in the coming years.

VRK2 is involved in the innate antiviral response by promoting mitostress-induced mtDNA release

Mitochondrial stress (mitostress) triggered by viral infection or mitochondrial dysfunction causes the release of mitochondrial DNA (mtDNA) into the cytosol and activates the cGAS-mediated innate immune response. The regulation of mtDNA release upon mitostress remains uncharacterized. Here, we identified mitochondria-associated vaccinia virus-related kinase 2 (VRK2) as a key regulator of this process. VRK2 deficiency inhibited the induction of antiviral genes and caused earlier and higher mortality in mice after viral infection. Upon viral infection, VRK2 associated with voltage-dependent anion channel 1 (VDAC1) and promoted VDAC1 oligomerization and mtDNA release, leading to the cGAS-mediated innate immune response. VRK2 was also required for mtDNA release and cGAS-mediated innate immunity triggered by nonviral factors that cause Ca^(2+) overload but was not required for the cytosolic nucleic acid-triggered innate immune response. Thus, VRK2 plays a crucial role in the mtDNA-triggered innate immune response and may be a potential therapeutic target for infectious and autoimmune diseases associated with mtDNA release.