A Viral Immunoevasin Controls Innate Immunity by Targeting the Prototypical Natural Killer Cell Receptor Family.

Natural killer (NK) cells play a key role in innate immunity by detecting alterations in self and non-self ligands via paired NK cell receptors (NKRs). Despite identification of numerous NKR-ligand interactions, physiological ligands for the prototypical NK1.1 orphan receptor remain elusive. Here, we identify a viral ligand for the inhibitory and activating NKR-P1 (NK1.1) receptors. This murine cytomegalovirus (MCMV)-encoded protein, m12, restrains NK cell effector function by directly engaging the inhibitory NKR-P1B receptor. However, m12 also interacts with the activating NKR-P1A/C receptors to counterbalance m12 decoy function. Structural analyses reveal that m12 sequesters a large NKR-P1 surface area via a "polar claw" mechanism. Polymorphisms in, and ablation of, the viral m12 protein and host NKR-P1B/C alleles impact NK cell responses in vivo. Thus, we identify the long-sought foreign ligand for this key immunoregulatory NKR family and reveal how it controls the evolutionary balance of immune recognition during host-pathogen interplay.

Central tolerance shapes the neutralizing B cell repertoire against a persisting virus in its natural host.

Viral mimicry of host cell structures has been postulated to curtail the B cell receptor (BCR) repertoire against persisting viruses through tolerance mechanisms. This concept awaits, however, experimental testing in a setting of natural virus-host relationship. We engineered mouse models expressing a monoclonal BCR specific for the envelope glycoprotein of lymphocytic choriomeningitis virus (LCMV), a naturally persisting mouse pathogen. When the heavy chain of the LCMV-neutralizing antibody KL25 was paired with its unmutated ancestor light chain, most B cells underwent receptor editing, a behavior reminiscent of autoreactive clones. In contrast, monoclonal B cells expressing the same heavy chain in conjunction with the hypermutated KL25 light chain did not undergo receptor editing but exhibited low levels of surface IgM, suggesting that light chain hypermutation had lessened KL25 autoreactivity. Upon viral challenge, these IgMlow cells were not anergic but up-regulated IgM, participated in germinal center reactions, produced antiviral antibodies, and underwent immunoglobulin class switch as well as further affinity maturation. These studies on a persisting virus in its natural host species suggest that central tolerance mechanisms prune the protective antiviral B cell repertoire.

The US3 Kinase of Herpes Simplex Virus Phosphorylates the RNA Sensor RIG-I To Suppress Innate Immunity.

Recent studies have demonstrated that the signaling activity of the cytosolic pathogen sensor retinoic acid-inducible gene-I (RIG-I) is modulated by a variety of posttranslational modifications (PTMs) to fine-tune the antiviral type I interferon (IFN) response. Whereas K63-linked ubiquitination of the RIG-I caspase activation and recruitment domains (CARDs) catalyzed by TRIM25 or other E3 ligases activates RIG-I, phosphorylation of RIG-I at S8 and T170 represses RIG-I signal transduction by preventing the TRIM25-RIG-I interaction and subsequent RIG-I ubiquitination. While strategies to suppress RIG-I signaling by interfering with its K63-polyubiquitin-dependent activation have been identified for several viruses, evasion mechanisms that directly promote RIG-I phosphorylation to escape antiviral immunity are unknown. Here, we show that the serine/threonine (Ser/Thr) kinase US3 of herpes simplex virus 1 (HSV-1) binds to RIG-I and phosphorylates RIG-I specifically at S8. US3-mediated phosphorylation suppressed TRIM25-mediated RIG-I ubiquitination, RIG-I-MAVS binding, and type I IFN induction. We constructed a mutant HSV-1 encoding a catalytically-inactive US3 protein (K220A) and found that, in contrast to the parental virus, the US3 mutant HSV-1 was unable to phosphorylate RIG-I at S8 and elicited higher levels of type I IFNs, IFN-stimulated genes (ISGs), and proinflammatory cytokines in a RIG-I-dependent manner. Finally, we show that this RIG-I evasion mechanism is conserved among the alphaherpesvirus US3 kinase family. Collectively, our study reveals a novel immune evasion mechanism of herpesviruses in which their US3 kinases phosphorylate the sensor RIG-I to keep it in the signaling-repressed state. IMPORTANCE Herpes simplex virus 1 (HSV-1) establishes lifelong latency in the majority of the human population worldwide. HSV-1 occasionally reactivates to produce infectious virus and to facilitate dissemination. While often remaining subclinical, both primary infection and reactivation occasionally cause debilitating eye diseases, which can lead to blindness, as well as life-threatening encephalitis and newborn infections. To identify new therapeutic targets for HSV-1-induced diseases, it is important to understand the HSV-1-host interactions that may influence infection outcome and disease. Our work uncovered direct phosphorylation of the pathogen sensor RIG-I by alphaherpesvirus-encoded kinases as a novel viral immune escape strategy and also underscores the importance of RNA sensors in surveilling DNA virus infection.

Crosstalk between nucleocytoplasmic trafficking and the innate immune response to viral infection.

The nuclear pore complex is the sole gateway connecting the nucleoplasm and cytoplasm. In humans, the nuclear pore complex is one of the largest multiprotein assemblies in the cell, with a molecular mass of ∼110 MDa and consisting of 8 to 64 copies of about 34 different nuclear pore proteins, termed nucleoporins, for a total of 1000 subunits per pore. Trafficking events across the nuclear pore are mediated by nuclear transport receptors and are highly regulated. The nuclear pore complex is also used by several RNA viruses and almost all DNA viruses to access the host cell nucleoplasm for replication. Viruses hijack the nuclear pore complex, and nuclear transport receptors, to access the nucleoplasm where they replicate. In addition, the nuclear pore complex is used by the cell innate immune system, a network of signal transduction pathways that coordinates the first response to foreign invaders, including viruses and other pathogens. Several branches of this response depend on dynamic signaling events that involve the nuclear translocation of downstream signal transducers. Mounting evidence has shown that these signaling cascades, especially those steps that involve nucleocytoplasmic trafficking events, are targeted by viruses so that they can evade the innate immune system. This review summarizes how nuclear pore proteins and nuclear transport receptors contribute to the innate immune response and highlights how viruses manipulate this cellular machinery to favor infection. A comprehensive understanding of nuclear pore proteins in antiviral innate immunity will likely contribute to the development of new antiviral therapeutic strategies.

When RING finger family proteins meet SARS-CoV-2.

The pandemic coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently the most formidable challenge to humankind. Understanding the complicated virus-host interplay is crucial for fighting against viral infection. A growing number of studies point to the critical roles of RING (really interesting new gene) finger (RNF) proteins during SARS-CoV-2 infection. RNF proteins exert direct antiviral activity by targeting genome and envelope glycoproteins of SARS-CoV-2. Additionally, some RNF members serve as potent regulators for antiviral innate immunity and antibody-dependent neutralization of SARS-CoV-2. Notably, SARS-CoV-2 also hijacks the RNF proteins-mediated ubiquitination process to evade host antiviral innate immunity and enhance viral replication. In this mini-review, we discuss the diverse antiviral mechanisms of RNF proteins and viral immune evasion in an RNF proteins-dependent manner. Understanding the crosstalk between RNF proteins and SARS-CoV-2 infection would help design potential novel targets for COVID-19 treatment.

COVID-19: Unanswered questions on immune response and pathogenesis.

The novel coronavirus disease 2019 has rapidly increased in pandemic scale since it first appeared in Wuhan, China, in December 2019. In these troubled days the scientific community is asking for rapid replies to prevent and combat the emergency. It is generally accepted that only achieving a better understanding of the interactions between the virus and the host immune response and of the pathogenesis of infection is crucial to identify valid therapeutic tools to control virus entry, replication, and spread as well as to impair its lethal effects. On the basis of recent research progress of severe acute respiratory syndrome coronavirus 2 and the results on previous coronaviruses, in this contribution we underscore some of the main unsolved problems, mostly focusing on pathogenetic aspects and host immunity to the virus. On this basis, we also touch important aspects regarding the immune response in asymptomatic subjects, the immune evasion of severe acute respiratory syndrome coronavirus 2 in severe patients, and differences in disease severity by age and sex.

Mouse Cytomegalovirus m153 Protein Stabilizes Expression of the Inhibitory NKR-P1B Ligand Clr-b.

Natural killer (NK) cells are a subset of innate lymphoid cells (ILC) capable of recognizing stressed and infected cells through multiple germ line-encoded receptor-ligand interactions. Missing-self recognition involves NK cell sensing of the loss of host-encoded inhibitory ligands on target cells, including MHC class I (MHC-I) molecules and other MHC-I-independent ligands. Mouse cytomegalovirus (MCMV) infection promotes a rapid host-mediated loss of the inhibitory NKR-P1B ligand Clr-b (encoded by Clec2d) on infected cells. Here we provide evidence that an MCMV m145 family member, m153, functions to stabilize cell surface Clr-b during MCMV infection. Ectopic expression of m153 in fibroblasts augments Clr-b cell surface levels. Moreover, infections using m153-deficient MCMV mutants (Δm144-m158 and Δm153) show an accelerated and exacerbated Clr-b downregulation. Importantly, enhanced loss of Clr-b during Δm153 mutant infection reverts to wild-type levels upon exogenous m153 complementation in fibroblasts. While the effects of m153 on Clr-b levels are independent of Clec2d transcription, imaging experiments revealed that the m153 and Clr-b proteins only minimally colocalize within the same subcellular compartments, and tagged versions of the proteins were refractory to coimmunoprecipitation under mild-detergent conditions. Surprisingly, the Δm153 mutant possesses enhanced virulence in vivo, independent of both Clr-b and NKR-P1B, suggesting that m153 potentially targets additional host factors. Nevertheless, the present data highlight a unique mechanism by which MCMV modulates NK ligand expression.IMPORTANCE Cytomegaloviruses are betaherpesviruses that in immunocompromised individuals can lead to severe pathologies. These viruses encode various gene products that serve to evade innate immune recognition. NK cells are among the first immune cells that respond to CMV infection and use germ line-encoded NK cell receptors (NKR) to distinguish healthy from virus-infected cells. One such axis that plays a critical role in NK recognition involves the inhibitory NKR-P1B receptor, which engages the host ligand Clr-b, a molecule commonly lost on stressed cells ("missing-self"). In this study, we discovered that mouse CMV utilizes the m153 glycoprotein to circumvent host-mediated Clr-b downregulation, in order to evade NK recognition. These results highlight a novel MCMV-mediated immune evasion strategy.

The hepatitis C virus (HCV) protein, p7, suppresses inflammatory responses to tumor necrosis factor (TNF)-α via signal transducer and activator of transcription (STAT)3 and extracellular signal-regulated kinase (ERK)-mediated induction of suppressor of cytokine signaling (SOCS)3.

Viruses use a spectrum of immune evasion strategies that enable infection and replication. The acute phase of hepatitis C virus (HCV) infection is characterized by nonspecific and often mild clinical symptoms, suggesting an immunosuppressive mechanism that, unless symptomatic liver disease presents, allows the virus to remain largely undetected. We previously reported that HCV induced the regulatory protein suppressor of cytokine signaling (SOCS)3, which inhibited TNF-α-mediated inflammatory responses. However, the mechanism by which HCV up-regulates SOCS3 remains unknown. Here we show that the HCV protein, p7, enhances both SOCS3 mRNA and protein expression. A p7 inhibitor reduced SOCS3 induction, indicating that p7's ion channel activity was required for optimal up-regulation of SOCS3. Short hairpin RNA and chemical inhibition revealed that both the Janus kinase-signal transducer and activator of transcription (JAK-STAT) and MAPK pathways were required for p7-mediated induction of SOCS3. HCV-p7 expression suppressed TNF-α-mediated IκB-α degradation and subsequent NF-κB promoter activity, revealing a new and functional, anti-inflammatory effect of p7. Together, these findings identify a molecular mechanism by which HCV-p7 induces SOCS3 through STAT3 and ERK activation and demonstrate that p7 suppresses proinflammatory responses to TNF-α, possibly explaining the lack of inflammatory symptoms observed during early HCV infection.-Convery, O., Gargan, S., Kickham, M., Schroder, M., O'Farrelly, C., Stevenson, N. J. The hepatitis C virus (HCV) protein, p7, suppresses inflammatory responses to tumor necrosis factor (TNF)-α via signal transducer and activator of transcription (STAT)3 and extracellular signal-regulated kinase (ERK)-mediated induction of suppressor of cytokine signaling (SOCS)3.

Cytosolic DNA-sensing immune response and viral infection.

How host cells recognize many kinds of RNA and DNA viruses and initiate innate antiviral responses against them has not yet been fully elucidated. Over the past decade, investigations into the mechanisms underlying these antiviral responses have focused extensively on immune surveillance sensors that recognize virus-derived components (such as lipids, sugars and nucleic acids). The findings of these studies have suggested that antiviral responses are mediated by cytosolic or intracellular compartment sensors and their adaptor molecules (e.g., TLR, myeloid differentiation primary response 88, retinoic acid inducible gene-I, IFN-ß promoter stimulator-1, cyclic GMP-AMP synthase and stimulator of IFN genes axis) for the primary sensing of virus-derived nucleic acids, leading to production of type I IFNs, pro-inflammatory cytokines and chemokines by the host cells. Thus, host cells have evolved an elaborate host defense machinery to recognize and eliminate virus infections. In turn, to achieve sustained viral infection and induce pathogenesis, viruses have also evolved several counteracting strategies for achieving immune escape by targeting immune sensors, adaptor molecules, intracellular kinases and transcription factors. In this review, we discuss recent discoveries concerning the role of the cytosolic nucleic acid-sensing immune response in viral recognition and control of viral infection. In addition, we consider the regulatory machinery of the cytosolic nucleic acid-sensing immune response because these immune surveillance systems must be tightly regulated to prevent aberrant immune responses to self and non-self-nucleic acids.

Diverse mechanisms evolved by DNA viruses to inhibit early host defenses.

In mammalian cells, early defenses against infection by pathogens are mounted through a complex network of signaling pathways shepherded by immune-modulatory pattern-recognition receptors. As obligate parasites, the survival of viruses is dependent on the evolutionary acquisition of mechanisms that tactfully dismantle and subvert the cellular intrinsic and innate immune responses. Here, we review the diverse mechanisms by which viruses that accommodate DNA genomes are able to circumvent activation of cellular immunity. We start by discussing viral manipulation of host defense protein levels by either transcriptional regulation or protein degradation. We next review viral strategies used to repurpose or inhibit these cellular immune factors by molecular hijacking or by regulating their post-translational modification status. Additionally, we explore the infection-induced temporal modulation of apoptosis to facilitate viral replication and spread. Lastly, the co-evolution of viruses with their hosts is highlighted by the acquisition of elegant mechanisms for suppressing host defenses via viral mimicry of host factors. In closing, we present a perspective on how characterizing these viral evasion tactics both broadens the understanding of virus-host interactions and reveals essential functions of the immune system at the molecular level. This knowledge is critical in understanding the sources of viral pathogenesis, as well as for the design of antiviral therapeutics and autoimmunity treatments.

Ebola virus secreted glycoprotein decreases the anti-viral immunity of macrophages in early inflammatory responses.

During Ebola virus (EBOV) infection, secreted glycoprotein (sGP) is found in large quantities in the serum of both patients and infected animal models. It is thought to serve as a decoy for anti-EBOV antibodies. Using an in vitro model incorporating treatment of non-infected human THP-1 macrophages with recombinant EBOV sGP, this study sought to examine the impact of sGP upon key macrophage functions. Macrophage polarization and phagocytic capacity of activated macrophages were found to be unaltered by sGP treatment. However, treatment with sGP inhibited macrophage production of the pro-inflammatory cytokines TNFα and IL-6 while the yield of anti-inflammatory cytokine, IL-10, remained intact. Interestingly, the migratory ability of macrophages was also diminished by sGP, potentially due to a decrease in expression of CD11b, a vital macrophage integrin. Thus, EBOV sGP may operate to diminish functional contributions of non-infected macrophages to increase the potential viral dissemination.

Cellular distribution of CD200 receptor in rats and its interaction with cytomegalovirus e127 protein.

CD200 is a membrane protein that interacts with CD200R on the surface of immune cells and delivers an inhibitory signal. In this study, we characterized the distribution of inhibitory CD200R in rats. In addition, we investigated if e127, a homologue of rat CD200 expressed by rat cytomegalovirus (RCMV), can suppress immune functions in vitro. RT-PCR analysis was carried out to test the expression of CD200R in different rat tissues and flow cytometry was performed to characterize CD200R at the cellular level. To test the inhibitory functions of e127, a co-culture system was utilized in which immune cells were incubated with e127-expressing cells. The strongest CD200R expression was detected in lymphoid organs such as bone marrow and spleen. Flow cytometry analyses showed that CD200R+ cells were mainly CD4- dendritic cells (DC) and CD4+ T cells in the spleen. In blood, nearly all monocytes and granulocytes expressed CD200R and in bone marrow the NKRP1low subset of natural killer cells highly expressed CD200R. In addition, both peritoneal macrophages and the NR8383 macrophage cell line carried CD200R. At the functional level, viral e127 conferred an inhibitory signal on TNFα and IL6 cytokine release from IFNγ-stimulated macrophages. However, e127 did not affect the cytotoxic activity of DC. CD200R in the rat is mainly expressed on myeloid cells but also on non-myeloid cell subsets, and RCMV e127 can deliver inhibitory signals to immune cells by engaging CD200R. The RCMV model provides a useful tool to study potential immune evasion mechanisms of the herpesviridae and opens new avenues for understanding and controlling herpesvirus infections.

Herpesviral capture of immunomodulatory host genes.

Herpesviruses have acquired numerous genes from their hosts. Although these homologs are not essential for viral replication, they often have important immunomodulatory functions that ensure viral persistence in the host. Some of these viral molecules are called virokines as they mimic cellular cytokines of their host such as interleukin-10 (cIL-10). In recent years, many viral homologs of IL-10 (vIL-10s) have been discovered in the genome of members of the order Herpesvirales. For some, gene and protein structure as well as biological activity and potential use in the clinical context have been explored. Besides virokines, herpesviruses have also captured genes encoding membrane-bound host immunomodulatory proteins such as major histocompatibility complex (MHC) molecules. These viral MHC mimics also retain many of the functions of the cellular genes, in particular directly or indirectly modulating the activity of natural killer cells. The mechanisms underlying capture of cellular genes by large DNA viruses are still enigmatic. In this review, we provide an update of the advances in the field of herpesviral gene piracy and discuss possible scenarios that could explain how the gene transfer from host to viral genome was achieved.

Immunological evasion of immediate-early varicella zoster virus proteins.

The varicella zoster virus (VZV) causes the childhood disease commonly known as chickenpox and can later in life reactivate as herpes zoster. The adaptive immune system is known to play an important role in suppressing VZV reactivation. A central aspect of this system is the presentation of VZV-derived peptides by the major histocompatibility complex (MHC) proteins. Here, we investigate if key VZV proteins have evolved their amino acid sequence to avoid presentation by MHC based on predictive models of MHC-peptide affinity. This study shows that the immediate-early proteins of all characterized VZV strains are profoundly depleted for high-affinity MHC-I-restricted epitopes. The same depletion can be found in its closest animal analog, the simian varicella virus. Further orthology analysis towards other herpes viruses suggests that the protein amino acid frequency is one of the primary drivers of targeted epitope depletion.

Respiratory syncytial virus NS1 inhibits anti-viral Interferon-α-induced JAK/STAT signaling, by limiting the nuclear translocation of STAT1.

Human respiratory viruses are the most prevalent cause of disease in humans, with the highly infectious RSV being the leading cause of infant bronchiolitis and viral pneumonia. Responses to type I IFNs are the primary defense against viral infection. However, RSV proteins have been shown to antagonize type I IFN-mediated antiviral innate immunity, specifically dampening intracellular IFN signaling. Respiratory epithelial cells are the main target for RSV infection. In this study, we found RSV-NS1 interfered with the IFN-α JAK/STAT signaling pathway of epithelial cells. RSV-NS1 expression significantly enhanced IFN-α-mediated phosphorylation of STAT1, but not pSTAT2; and neither STAT1 nor STAT2 total protein levels were affected by RSV-NS1. However, expression of RSV-NS1 significantly reduced ISRE and GAS promoter activity and anti-viral IRG expression. Further mechanistic studies demonstrated RSV-NS1 bound STAT1, with protein modeling indicating a possible interaction site between STAT1 and RSV-NS1. Nuclear translocation of STAT1 was reduced in the presence of RSV-NS1. Additionally, STAT1's interaction with the nuclear transport adapter protein, KPNA1, was also reduced, suggesting a mechanism by which RSV blocks STAT1 nuclear translocation. Indeed, reducing STAT1's access to the nucleus may explain RSV's suppression of IFN JAK/STAT promoter activation and antiviral gene induction. Taken together these results describe a novel mechanism by which RSV controls antiviral IFN-α JAK/STAT responses, which enhances our understanding of RSV's respiratory disease progression.

Exploring type I interferon pathway: virulent vs. attenuated strain of African swine fever virus revealing a novel function carried by MGF505-4R.

African swine fever virus represents a significant reemerging threat to livestock populations, as its incidence and geographic distribution have surged over the past decade in Europe, Asia, and Caribbean, resulting in substantial socio-economic burdens and adverse effects on animal health and welfare. In a previous report, we described the protective properties of our newly thermo-attenuated strain (ASFV-989) in pigs against an experimental infection of its parental Georgia 2007/1 virulent strain. In this new study, our objective was to characterize the molecular mechanisms underlying the attenuation of ASFV-989. We first compared the activation of type I interferon pathway in response to ASFV-989 and Georgia 2007/1 infections, employing both in vivo and in vitro models. Expression of IFN-α was significantly increased in porcine alveolar macrophages infected with ASFV-989 while pigs infected with Georgia 2007/1 showed higher IFN-α than those infected by ASFV-989. We also used a medium-throughput transcriptomic approach to study the expression of viral genes by both strains, and identified several patterns of gene expression. Subsequently, we investigated whether proteins encoded by the eight genes deleted in ASFV-989 contribute to the modulation of the type I interferon signaling pathway. Using different strategies, we showed that MGF505-4R interfered with the induction of IFN-α/ß pathway, likely through interaction with TRAF3. Altogether, our data reveal key differences between ASFV-989 and Georgia 2007/1 in their ability to control IFN-α/ß signaling and provide molecular mechanisms underlying the role of MGF505-4R as a virulence factor.

A large-scale type I CBASS antiphage screen identifies the phage prohead protease as a key determinant of immune activation and evasion.

Cyclic oligonucleotide-based signaling system (CBASS) is an antiviral system that protects bacteria from phage infection and is evolutionarily related to human cGAS-STING immunity. cGAS-STING signaling is initiated by the recognition of viral DNA, but the molecular cues activating CBASS are incompletely understood. Using a screen of 975 type I CBASS operon-phage challenges, we show that operons with distinct cGAS/DncV-like nucleotidyltransferases (CD-NTases) and CD-NTase-associated protein (Cap) effectors exhibit marked patterns of phage restriction. We find that some type I CD-NTase enzymes require a C-terminal AGS-C immunoglobulin (Ig)-like fold domain for defense against select phages. Escaper phages evade CBASS via protein-coding mutations in virion assembly proteins, and acquired resistance is largely operon specific. We demonstrate that the phage Bas13 prohead protease interacts with the CD-NTase EcCdnD12 and can induce CBASS-dependent growth arrest in cells. Our results define phage virion assembly as a determinant of type I CBASS immune evasion and support viral protein recognition as a putative mechanism of cGAS-like enzyme activation.

SARS-CoV-2 and the host-immune response.

The SARS-CoV-2 pandemic and the COVID-19 disease have affected everyone globally, leading to one of recorded history's most significant research surges. As our knowledge evolves, our approaches to the virus and treatments must also evolve. The evaluation of future research approaches to SARS-CoV-2 will necessitate reviewing the host immune response and viral antagonism of that response. This review provides an overview of the current knowledge on SARS-CoV-2 by summarizing the virus and human response. The focuses are on the viral genome, replication cycle, host immune activation, response, signaling, and antagonism. To effectively fight the pandemic, efforts must focus on the current state of research to help develop treatments and prepare for future outbreaks.

Innate and adaptive immunity to SARS-CoV-2 and predisposing factors.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2), has affected all countries worldwide. Although some symptoms are relatively mild, others are still associated with severe and even fatal clinical outcomes. Innate and adaptive immunity are important for the control of SARS-CoV-2 infections, whereas a comprehensive characterization of the innate and adaptive immune response to COVID-19 is still lacking and the mechanisms underlying immune pathogenesis and host predisposing factors are still a matter of scientific debate. Here, the specific functions and kinetics of innate and adaptive immunity involved in SARS-CoV-2 recognition and resultant pathogenesis are discussed, as well as their immune memory for vaccinations, viral-mediated immune evasion, and the current and future immunotherapeutic agents. We also highlight host factors that contribute to infection, which may deepen the understanding of viral pathogenesis and help identify targeted therapies that attenuate severe disease and infection.

Reprogramming viral immune evasion for a rational design of next-generation vaccines for RNA viruses.

Type I interferons (IFNs-α/ß) are antiviral cytokines that constitute the innate immunity of hosts to fight against viral infections. Recent studies, however, have revealed the pleiotropic functions of IFNs, in addition to their antiviral activities, for the priming of activation and maturation of adaptive immunity. In turn, many viruses have developed various strategies to counteract the IFN response and to evade the host immune system for their benefits. The inefficient innate immunity and delayed adaptive response fail to clear of invading viruses and negatively affect the efficacy of vaccines. A better understanding of evasion strategies will provide opportunities to revert the viral IFN antagonism. Furthermore, IFN antagonism-deficient viruses can be generated by reverse genetics technology. Such viruses can potentially serve as next-generation vaccines that can induce effective and broad-spectrum responses for both innate and adaptive immunities for various pathogens. This review describes the recent advances in developing IFN antagonism-deficient viruses, their immune evasion and attenuated phenotypes in natural host animal species, and future potential as veterinary vaccines.