Innate Antiviral Response Research Articles

The PB1 protein of H9N2 influenza A virus inhibits antiviral innate immunity by targeting MAVS for TRIM25-mediated autophagic degradation

The proteins encoded by Influenza A virus (IAV) evade the innate immune system through diverse strategies to facilitate their replication. However, the regulatory mechanisms remain not fully understood. In this study, we identified that the H9N2 PB1 protein suppressed the activities of the IFN-β, ISRE, and NF-κB promoters. Furthermore, H9N2 PB1 inhibited the phosphorylation of IRF3, IκBα, and TBK1 and the secretion of IFN-β. The results demonstrated H9N2 PB1 as a negative regulator of the RIG-I signaling pathway. Subsequent investigations revealed a specific interaction between H9N2 PB1 and MAVS, which disturbed the stability of MAVS. Notably, we discovered that H9N2 PB1 exploited the function of TRIM25, leading to the autophagic degradation of MAVS through K48-linked polyubiquitination. In conclusion, we uncovered a negative regulatory axis consisting of H9N2 PB1-TRIM25-MAVS-IFN-I. These findings provide valuable insights into the molecular interactions involved in the regulation of the host's innate immune antiviral response by IAV.

Development and characterization of high-efficiency cell-adapted live attenuated vaccine candidate against African swine fever

African swine fever (ASF), a contagious and lethal haemorrhagic disease of domestic pigs and wild boars, poses a significant threat to the global pig industry. Although experimental vaccine candidates derived from naturally attenuated, genetically engineered, or cell culture-adapted ASF virus have been tested, no commercial vaccine is accepted globally. We developed a safe and effective cell-adapted live attenuated vaccine candidate (ASFV-MEC-01) by serial passage of a field isolate in CA-CAS-01-A cells. ASFV-MEC-01, isolated via repeated plaque purification using next-generation sequencing analysis, was obtained at passage 18 and showed significant attenuation in 4- and 6-week-old pigs. ASFV-MEC-01 conferred 100% protection against challenge with lethal parental ASFV, which correlated with high ASFV-specific humoral and cellular immune responses. Additionally, ASFV-MEC-01 was not detected in blood until 28 days post-inoculation. Global transcriptome analysis showed that ASFV-MEC-01 lacking 12 genes triggered stronger innate antiviral responses than the parental virus, as exemplified by high levels of mRNA encoding interferon regulatory and inflammatory genes in PAM cells. Ectopic expression of most deleted genes increased replication of DNA viruses by suppressing production of interferons and pro-inflammatory cytokines. Among the genes deleted from ASFV-MEC-01, MGF100-1R interacted specifically with the scaffold dimerization domain of TBK1, thereby preventing TBK1 dimerization and impairing TBK1-mediated type I IFN and NF-κB signaling. These results suggest that attenuation of ASFV-MEC-01 may be mediated by induction of stronger type I IFN and NF-κB signaling within the host innate immune system. Thus, ASFV-MEC-01 could be a safe and effective live attenuated ASFV vaccine candidate with commercial potential.

CNSC-59. EPIGENETIC POTENTIATION OF ANTI-TUMOR IMMUNE RESPONSES USING VIRAL MIMICRY IN GLIOMAS

Abstract Clinical trials using immune checkpoint inhibition(ICI) have traditionally failed in glioblastoma (GBM). Viral mimicry, which augments anti-tumor immune responses and sensitizes response to immunotherapy in other cancers, involves the epigenetic activation of endogenous retroelements (REs). REs are silenced via the HUSH complex and H3K9me3. This process is mediated by ZNF638. We aimed to elucidate the role of viral mimicry in enhancing ICI through epigenetic reprogramming of the HUSH complex. We demonstrated that RE expression among 48 superfamilies inversely correlated with ZNF638 expression in gliomas, based on data from 71 newly-diagnosed GBMs. Using transcriptional deconvolution, we showed ZNF638 negatively correlates with innate antiviral immune response signatures(TLR3)(RTLR3=-0.300,pTLR3=0.00006). We validated these in-silico results in pure glioma cell lines, patient-derived GBM neurospheres, and syngeneic murine models. ZNF638 knockdown induced intracellular RE-mediated dsRNA signaling cascades via RIG-I and TLR3. This knockdown significantly increased PD-L1 expression(p<0.001), reduced H3K9 trimethylation, and enhanced cytoplasmic dsRNA accumulation in glioma cell lines. In patient-derived GBM neurospheres, ZNF638 knockdown upregulated immune and antiviral programs. Additionally, knockdown resulted in upregulation of several endogenous repeat elements (Alu, LTR). Single-cell RNA sequencing showed ZNF638 clustering in neural progenitor-like and oligodendrocyte-like cells, with increased retroelement expression in low ZNF638 cells. Tumors with lower ZNF638 expression showed increased CD8+ populations. Bulk RNA sequencing deconvolution revealed that ZNF638 is linked to reduced CD8 and DC infiltration in gliomas (RCD8=-0.202,RDC=-0.198;pCD8=8.79E-06,pDC=1.34E-05). In immunocompetent mice, ZNF638 KO and PD-L1 inhibition significantly improved survival (mOS >50 days, p<0.0001) and reduced tumor volume (p<0.001). Analysis of cohorts from multiple cancer types treated with anti-PD1 therapy demonstrated that ZNF638 expression predicts therapeutic response and overall survival. Our findings suggest that epigenetic reprogramming through HUSH inhibition may potentiate immunotherapy for GBM.

Mass Spectrometry-Based Metabolomics Reveals a Salivary Signature for Low-Severity COVID-19.

Omics approaches were extensively applied during the coronavirus disease 2019 (COVID-19) pandemic to understand the disease, identify biomarkers with diagnostic and prognostic value, and discover new molecular targets for medications. COVID-19 continues to challenge the healthcare system as the virus mutates, becoming more transmissible or adept at evading the immune system, causing resurgent epidemic waves over the last few years. In this study, we used saliva from volunteers who were negative and positive for COVID-19 when Omicron and its variants became dominant. We applied a direct solid-phase extraction approach followed by non-target metabolomics analysis to identify potential salivary signatures of hospital-recruited volunteers to establish a model for COVID-19 screening. Our model, which aimed to differentiate COVID-19-positive individuals from controls in a hospital setting, was based on 39 compounds and achieved high sensitivity (85%/100%), specificity (82%/84%), and accuracy (84%/92%) in training and validation sets, respectively. The salivary diagnostic signatures were mainly composed of amino acids and lipids and were related to a heightened innate immune antiviral response and an attenuated inflammatory profile. The higher abundance of thyrotropin-releasing hormone in the COVID-19 positive group highlighted the endocrine imbalance in low-severity disease, as first reported here, underscoring the need for further studies in this area.

Helicase protein DDX11 as a novel antiviral factor promoting RIG-I-MAVS-mediated signaling pathway.

Innate immunity is the first and most rapid host defense against virus infection. Recognition of viral RNA by the retinoic acid-inducible gene 1 (RIG-I)-like receptors (RLRs) initiates innate antiviral immune responses. How the binding of viral RNA to and activation of the RLRs are regulated remains enigmatic. In this study, we identified DEAD/H-box helicase 11 (DDX11) as a positive regulator of the RIG-I-mitochondrial antiviral signaling protein (MAVS)-mediated signaling pathways. Mechanistically, we demonstrated that DDX11 bound to viral RNA, interacted with RIG-I, and promoted their binding to viral RNA. DDX11 also promoted the interaction between RIG-I and MAVS and activation of RIG-I-MAVS signaling. Overall, our results elucidate the role of DDX11 in RIG-I-MAVS-dependent signaling pathways and may shed light on innate immune gene regulation.

Pseudorabies virus infection triggers mitophagy to dampen the interferon response and promote viral replication.

Pseudorabies virus (PRV) utilizes multiple strategies to inhibit type I interferon (IFN-I) production and signaling to achieve innate immune evasion. Among several other functions, mitochondria serve as a crucial immune hub in the initiation of innate antiviral responses. It is currently unknown whether PRV inhibits innate immune responses by manipulating mitochondria. In this study, we found that PRV infection damages mitochondrial structure and function, as shown by mitochondrial membrane potential depolarization, reduction in mitochondrial numbers, and an imbalance in mitochondrial dynamics. In addition, PRV infection triggered PINK1-Parkin-mediated mitophagy to eliminate the impaired mitochondria, which resulted in a suppression of IFN-I production, thereby promoting viral replication. Furthermore, we found that mitophagy resulted in the degradation of the mitochondrial antiviral signaling protein, which is located on the mitochondrial outer membrane. In conclusion, the data of the current study indicate that PRV-induced mitophagy represents a previously uncharacterized PRV evasion mechanism of the IFN-I response, thereby promoting virus replication.IMPORTANCEPseudorabies virus (PRV), a pathogen that induces different disease symptoms and is often fatal in domestic animals and wildlife, has caused great economic losses to the swine industry. Since 2011, different PRV variant strains have emerged in Asia, against which current commercial vaccines may not always provide optimal protection in pigs. In addition, there are indications that some of these PRV variant strains may sporadically infect people. In the current study, we found that PRV infection causes mitochondria injury. This is associated with the induction of mitophagy to eliminate the damaged mitochondria, which results in suppressed antiviral interferon production and signaling. Hence, our study reveals a novel mechanism that is used by PRV to antagonize the antiviral host immune response, providing a theoretical basis that may contribute to the research toward and development of new vaccines and antiviral drugs.

Immunological sub-phenotypes and response to convalescent plasma in COVID-19 induced ARDS: a secondary analysis of the CONFIDENT trial

BackgroundConvalescent plasma (CP) reduced the mortality in COVID-19 induced ARDS (C-ARDS) patients treated in the CONFIDENT trial. As patients are immunologically heterogeneous, we hypothesized that clusters may differ in their treatment responses to CP.MethodsWe measured 20 cytokines, chemokines and cell adhesion markers using a multiplex technique at the time of inclusion in the CONFIDENT trial in patients of centers having accepted to participate in this secondary study. We performed descriptive statistics, unsupervised hierarchical cluster analysis, and examined the association between the clusters and CP effect on day-28 mortality.ResultsOf the 475 patients included in CONFIDENT, 391 (82%) were sampled, and 196/391 (50.1%) had been assigned to CP. We identified four sub-phenotypes representing 89 (22.8%), 178 (45.5%), 38 (9.7%), and 86 (22.0%) patients. The most contributing biomarkers in the principal component analysis were IL-1β, IL-12p70, IL-6, IFN-α, IL-17A, IFN-γ, IL-13, TFN-α, total IgG, and CXCL10. Sub-phenotype-1 displayed a lower immune response, sub-phenotype-2 a higher adaptive response, sub-phenotype-3 the highest innate antiviral, pro and anti-inflammatory response, and adhesion molecule activation, and sub-phenotype-4 a higher pro and anti-inflammatory response, migration protein and adhesion molecule activation. Sub-phenotype-2 and sub-phenotype-4 had higher severity at the time of inclusion. The effect of CP treatment on mortality appeared higher than standard care in each sub-phenotype, without heterogeneity between sub-phenotypes (p = 0.97).ConclusionIn patients with C-ARDS, we identified 4 sub-phenotypes based on their immune response. These sub-phenotypes were associated with different clinical profiles. The response to CP was similar across the 4 sub-phenotypes.Trial registration: Ethics Committee of the University Hospital of Liège CE 2020/239. Clinicaltrials.gov NCT04558476. Registered 2020-09-11, https://www.clinicaltrials.gov/study/NCT04558476.

Targeting ZNF638 activates antiviral immune responses and potentiates immune checkpoint inhibition in glioblastoma.

Viral mimicry refers to the activation of innate anti-viral immune responses due to the induction of endogenous retroelement (RE) expression. Viral mimicry has been previously described to augment anti-tumor immune responses and sensitize solid tumors to immunotherapy including colorectal cancer, melanoma, and clear renal cell carcinoma. Here, we found that targeting a novel, master epigenetic regulator, Zinc Finger Protein 638 (ZNF638), induces viral mimicry in glioblastoma (GBM) preclinical models and potentiates immune checkpoint inhibition (ICI). ZNF638 recruits the HUSH complex, which precipitates repressive H3K9me3 marks on endogenous REs. In GBM, ZNF638 is associated with marked locoregional immunosuppressive transcriptional signatures, reduced endogenous RE expression and poor immune cell infiltration (CD8 + T-cells, dendritic cells). ZNF638 knockdown decreased H3K9-trimethylation, increased cytosolic dsRNA and activated intracellular dsRNA-signaling cascades (RIG-I, MDA5 and IRF3). Furthermore, ZNF638 knockdown upregulated antiviral immune programs and significantly increased PD-L1 immune checkpoint expression in patient-derived GBM neurospheres and diverse murine models. Importantly, targeting ZNF638 sensitized mice to ICI in syngeneic murine orthotopic models through innate interferon signaling. This response was recapitulated in recurrent GBM (rGBM) samples with radiographic responses to checkpoint inhibition with widely increased expression of dsRNA, PD-L1 and perivascular CD8 cell infiltration, suggesting dsRNA-signaling may mediate response to immunotherapy. Finally, we showed that low ZNF638 expression was a biomarker of clinical response to ICI and improved survival in rGBM patients and melanoma patients. Our findings suggest that ZNF638 could serve as a target to potentiate immunotherapy in gliomas.

Global remodeling of ADP-ribosylation by PARP1 suppresses influenza A virus infection.

ADP-ribosylation is a highly dynamic and fully reversible post-translational modification performed by poly(ADP-ribose) polymerases (PARPs) that modulates protein function, abundance, localization and turnover. Here we show that influenza A virus infection causes a rapid and dramatic upregulation of global ADP-ribosylation that inhibits viral replication. Mass spectrometry defined for the first time the global ADP-ribosylome during infection, creating an infection-specific profile with almost 4,300 modification sites on ~1,080 host proteins, as well as over 100 modification sites on viral proteins. Our data indicate that the global increase likely reflects a change in the form of ADP-ribosylation rather than modification of new targets. Functional assays demonstrated that modification of the viral replication machinery antagonizes its activity and further revealed that the anti-viral activity of PARPs and ADP-ribosylation is counteracted by the influenza A virus protein NS1, assigning a new activity to the primary viral antagonist of innate immunity. We identified PARP1 as the enzyme producing the majority of poly(ADP-ribose) present during infection. Influenza A virus replicated faster in cells lacking PARP1, linking PARP1 and ADP-ribosylation to the anti-viral phenotype. Together, these data establish ADP-ribosylation as an anti-viral innate immune-like response to viral infection antagonized by a previously unknown activity of NS1.

RNF144B negatively regulates antiviral immunity by targeting MDA5 for autophagic degradation

As a RIG-I-like receptor, MDA5 plays a critical role in antiviral innate immunity by acting as a cytoplasmic double-stranded RNA sensor capable of initiating type I interferon pathways. Here, we show that RNF144B specifically interacts with MDA5 and promotes K27/K33-linked polyubiquitination of MDA5 at lysine 23 and lysine 43, which promotes autophagic degradation of MDA5 by p62. Rnf144b deficiency greatly promotes IFN production and inhibits EMCV replication in vivo. Importantly, Rnf144b−/− mice has a significantly higher overall survival rate than wild-type mice upon EMCV infection. Collectively, our results identify RNF144B as a negative regulator of innate antiviral response by targeting CARDs of MDA5 and mediating autophagic degradation of MDA5.

Up-regulated Lnc BTU promotes the production of duck plague virus DNA polymerase and inhibits the activation of JAK-STAT pathway to facilitate duck plague virus replication

Duck plague virus (DPV) is the only herpes virus known to be transmissible among aquatic animals, leading to immunosuppression in ducks, geese and swans. Long noncoding RNAs (LncRNA) are known to participate in viral infections, acting as either immune defenders or viral targets to evade the host response, but their precise roles in waterfowl virus infections are yet to be fully understood. This study aimed to investigate the role of LncRNA in DPV-induced innate immune responses. Results showed that DPV infection greatly upregulated Lnc BTU expression in duck embryo fibroblasts (DEF) and Lnc BTU promoted DPV replication. Mechanically, 4 DPV proteins, namely UL46, UL42, VP22 and US10, interacted with Lnc BTU, leading to its upregulation. Specifically, Lnc BTU facilitated the production of DNA polymerase by enhancing UL42 expression, thereby promoting DPV replication. Additionally, Lnc BTU suppressed STAT1 expression by targeting the DNA binding domain (DBD) and promoting STAT1 degradation through the proteasome pathway. Furthermore, Lnc BTU inhibited the production of key antiviral factors such as IFN-α, IFN-β, MX and OASL during DPV infection. Treatment with 2 JAK-STAT pathway activators in DEFs resulted in the inhibition of Lnc BTU expression and DPV replication. Interestingly, DPV infection led to a decrease in STAT1 levels, which was reversed by Si-Lnc BTU. These findings suggest that DPV relies on Lnc BTU to inhibit the activation of the JAK-STAT pathway and limit the production of type 1 interferons (IFN) to complete immune evasion. Our study highlights the novel role of DPV proteins UL46, UL42, VP22, US10 as RNA-binding proteins in modulating the innate antiviral immune response, and discover the role of a new host factor, Lnc BTU, in DPV immune evasion, Lnc BTU and STAT1 can be used as a potential therapeutic target for DPV infection and immune evasion.

A screening study identified decitabine as an inhibitor of Varicellovirus equidalpha4 enhancing the innate antiviral response

A screening study identified decitabine as an inhibitor of <i>Varicellovirus equidalpha4</i> enhancing the innate antiviral response

STRAP upregulates antiviral innate immunity against PRV by targeting TBK1

Serine/threonine kinase receptor-associated protein (STRAP) serves as a scaffold protein and is engaged in a variety of cellular activities, although its importance in antiviral innate immunity is unknown. We discovered that STRAP works as an interferon (IFN)-inducible positive regulator, facilitating type I IFN signaling during pseudorabies virus infection. Mechanistically, STRAP interacts with TBK1 to activate type I IFN signaling. Both the CT and WD40 7 − 6 domains contribute to the function of STRAP. Furthermore, TBK1 competes with PRV-UL50 for binding to STRAP, and STRAP impedes the degradation of TBK1 mediated by PRV-UL50, thereby increasing the interaction between STRAP and TBK1. Overall, these findings reveal a previously unrecognized role for STRAP in innate antiviral immune responses during PRV infection. STRAP could be a potential therapeutic target for viral infectious diseases.

Centrifugal Microfluidic Cell Culture Platform for Physiologically Relevant Virus Infection Studies: A Case Study with HSV-1 Infection of Periodontal Cells.

Static well plates remain the gold standard to study viral infections in vitro, but they cannot accurately mimic dynamic viral infections as they occur in the human body. Therefore, we established a dynamic cell culture platform, based on centrifugal microfluidics, to study viral infections in perfusion. To do so, we used human primary periodontal dental ligament (PDL) cells and herpes simplex virus-1 (HSV-1) as a case study. By microscopy, we confirmed that the PDL cells efficiently attached and grew in the chip. Successful dynamic viral infection of perfused PDL cells was monitored using fluorescent imaging and RT-qPCR-based experiments. Remarkably, viral infection in flow resulted in a gradient of HSV-1-infected cells gradually decreasing from the cell culture chamber entrance towards its end. The perfusion of acyclovir in the chip prevented HSV-1 spreading, demonstrating the usefulness of such a platform for monitoring the effects of antiviral drugs. In addition, the innate antiviral response of PDL cells, measured by interferon gene expression, increased significantly over time in conventional static conditions compared to the perfusion model. These results provide evidence suggesting that dynamic viral infections differ from conventional static infections, which highlights the need for more physiologically relevant in vitro models to study viral infections.

Multiple myeloma exosomal miRNAs suppress cGAS-STING antiviral immunity

DNA virus infection is a significant cause of morbidity and mortality in patients with multiple myeloma (MM). Monocyte dysfunction in MM patients plays a central role in infectious complications, but the precise molecular mechanism underlying the reduced resistance of monocytes to viruses in MM patients remains to be elucidated. Here, we found that MM cells were able to transfer microRNAs (miRNAs) to host monocytes/macrophages via MM cell-derived exosomes, resulting in the inhibition of innate antiviral immune responses. The screening of miRNAs enriched in exosomes derived from the bone marrow (BM) of MM patients revealed five miRNAs that negatively regulate the cGAS-STING antiviral immune response. Notably, silencing these miRNAs with antagomiRs in MM-bearing C57BL/KaLwRijHsd mice markedly reduced viral replication. These findings identify a novel mechanism whereby MM cells possess the capacity to inhibit the innate immune response of the host, thereby rendering patients susceptible to viral infection. Consequently, targeting the aberrant expression patterns of characteristic miRNAs in MM patients is a promising avenue for therapeutic intervention. Considering the miRNA score and relevant clinical factors, we formulated a practical and efficient model for the optimal assessment of susceptibility to DNA viral infection in patients with MM.

IRF3 inhibits inflammatory signaling pathways in macrophages to prevent viral pathogenesis.

Viral inflammation contributes to pathogenesis and mortality during respiratory virus infections. IRF3, a critical component of innate antiviral immune responses, interacts with pro-inflammatory transcription factor NF-κB, and inhibits its activity. This mechanism helps suppress inflammatory gene expression in virus-infected cells and mice. We evaluated the cells responsible for IRF3-mediated suppression of viral inflammation using newly engineered conditional Irf3Δ/Δ mice. Irf3Δ/Δ mice, upon respiratory virus infection, showed increased susceptibility and mortality. Irf3 deficiency caused enhanced inflammatory gene expression, lung inflammation, immunopathology, and damage, accompanied by increased infiltration of pro-inflammatory macrophages. Deletion of Irf3 in macrophages (Irf3MKO) displayed, similar to Irf3Δ/Δ mice, increased inflammatory responses, macrophage infiltration, lung damage, and lethality, indicating that IRF3 in these cells suppressed lung inflammation. RNA-seq analyses revealed enhanced NF-κB-dependent gene expression along with activation of inflammatory signaling pathways in infected Irf3MKO lungs. Targeted analyses revealed activated MAPK signaling in Irf3MKO lungs. Therefore, IRF3 inhibited inflammatory signaling pathways in macrophages to prevent viral inflammation and pathogenesis.

Knockdown of DJ-1 Resulted in a Coordinated Activation of the Innate Immune Antiviral Response in HEK293 Cell Line.

PARK7, also known as DJ-1, plays a critical role in protecting cells by functioning as a sensitive oxidation sensor and modulator of antioxidants. DJ-1 acts to maintain mitochondrial function and regulate transcription in response to different stressors. In this study, we showed that cell lines vary based on their antioxidation potential under basal conditions. The transcriptome of HEK293 cells was tested following knockdown (KD) of DJ-1 using siRNAs, which reduced the DJ-1 transcripts to only 12% of the original level. We compared the expression levels of 14k protein-coding transcripts and 4.2k non-coding RNAs relative to cells treated with non-specific siRNAs. Among the coding genes, approximately 200 upregulated differentially expressed genes (DEGs) signified a coordinated antiviral innate immune response. Most genes were associated with the regulation of type 1 interferons (IFN) and the induction of inflammatory cytokines. About a quarter of these genes were also induced in cells treated with non-specific siRNAs that were used as a negative control. Beyond the antiviral-like response, 114 genes were specific to the KD of DJ-1 with enrichment in RNA metabolism and mitochondrial functions. A smaller set of downregulated genes (58 genes) was associated with dysregulation in membrane structure, cell viability, and mitophagy. We propose that the KD DJ-1 perturbation diminishes the protective potency against oxidative stress. Thus, it renders the cells labile and responsive to the dsRNA signal by activating a large number of genes, many of which drive apoptosis, cell death, and inflammatory signatures. The KD of DJ-1 highlights its potency in regulating genes associated with antiviral responses, RNA metabolism, and mitochondrial functions, apparently through alteration in STAT activity and downstream signaling. Given that DJ-1 also acts as an oncogene in metastatic cancers, targeting DJ-1 could be a promising therapeutic strategy where manipulation of the DJ-1 level may reduce cancer cell viability and enhance the efficacy of cancer treatments.

Host Innate Antiviral Response to Influenza A Virus Infection: From Viral Sensing to Antagonism and Escape.

Influenza virus possesses an RNA genome of single-stranded, negative-sensed, and segmented configuration. Influenza virus causes an acute respiratory disease, commonly known as the "flu" in humans. In some individuals, flu can lead to pneumonia and acute respiratory distress syndrome. Influenza A virus (IAV) is the most significant because it causes recurring seasonal epidemics, occasional pandemics, and zoonotic outbreaks in human populations, globally. The host innate immune response to IAV infection plays a critical role in sensing, preventing, and clearing the infection as well as in flu disease pathology. Host cells sense IAV infection through multiple receptors and mechanisms, which culminate in the induction of a concerted innate antiviral response and the creation of an antiviral state, which inhibits and clears the infection from host cells. However, IAV antagonizes and escapes many steps of the innate antiviral response by different mechanisms. Herein, we review those host and viral mechanisms. This review covers most aspects of the host innate immune response, i.e., (1) the sensing of incoming virus particles, (2) the activation of downstream innate antiviral signaling pathways, (3) the expression of interferon-stimulated genes, (4) and viral antagonism and escape.

Non-infectious immune complexes downregulate the production of interferons and tumor necrosis factor-α in primary porcine alveolar macrophages in vitro.

Porcine reproductive and respiratory syndrome (PRRS) caused by the PRRS virus (PRRSV) has been harming the pig industry worldwide for nearly 40 years. Although scientific researchers have made substantial efforts to explore PRRSV pathogenesis, the immune factors influencing PRRSV infection still need to be better understood. Infectious virus-antibody immune complexes (ICs) formed by PRRSV and sub-or non-neutralizing antibodies specific for PRRSV may significantly promote the development of PRRS by enhancing PRRSV replication through antibody-dependent enhancement. However, nothing is known about whether PRRSV infection is affected by non-infectious ICs (NICs) formed by non-pathogenic/infectious antigens and corresponding specific antibodies. Here, we found that PRRSV significantly induced the transcripts and proteins of interferon-α (IFN-α), IFN-β, IFN-γ, IFN-λ1, and tumor necrosis factor-α (TNF-α) in vitro primary porcine alveolar macrophages (PAMs) in the early stage of infection. Our results showed that NICs formed by rabbit-negative IgG (RNI) and pig anti-RNI specific IgG significantly reduced the transcripts and proteins of IFN-α, IFN-β, IFN-γ, IFN-λ1, and TNF-α in vitro PAMs and significantly elevated the transcripts and proteins of interleukine-10 (IL-10) and transforming growth factor-β1 (TGF-β1) in vitro PAMs. NICs-mediated PRRSV infection showed that NICs not only significantly decreased the induction of IFN-α, IFN-β, IFN-γ, IFN-λ1, and TNF-α by PRRSV but also significantly increased the induction of IL-10 and TGF-β1 by PRRSV and considerably enhanced PRRSV replication in vitro PAMs. Our data suggested that NICs could downregulate the production of antiviral cytokines (IFN-α/β/γ/λ1 and TNF-α) during PRRSV infection in vitro and facilitated PRRSV proliferation in its host cells by inhibiting innate antiviral immune response. This study elucidated one novel immune response to PRRSV infection, which would enhance our understanding of the pathogenesis of PRRSV.

Innate Antiviral Response through Mitochondrial Antiviral Signaling Protein (MAVS) in Fish - A Review

Innate Antiviral Response through Mitochondrial Antiviral Signaling Protein (MAVS) in Fish - A Review