Acute Infection of Viral Pathogens and Their Innate Immune Escape

Viral infections can cause rampant disease in human beings, ranging from mild to acute, that can often be fatal unless resolved. An acute viral infection is characterized by sudden or rapid onset of disease, which can be resolved quickly by robust innate immune responses exerted by the host or, instead, may kill the host. Immediately after viral infection, elements of innate immunity, such as physical barriers, various phagocytic cells, group of cytokines, interferons (IFNs), and IFN-stimulated genes, provide the first line of defense for viral clearance. Innate immunity not only plays a critical role in rapid viral clearance but can also lead to disease progression through immune-mediated host tissue injury. Although elements of antiviral innate immunity are armed to counter the viral invasion, viruses have evolved various strategies to escape host immune surveillance to establish successful infections. Understanding complex mechanisms underlying the interaction between viruses and host’s innate immune system would help develop rational treatment strategies for acute viral infectious diseases. In this review, we discuss the pathogenesis of acute infections caused by viral pathogens and highlight broad immune escape strategies exhibited by viruses.


INTRODUCTION
Viral pathogens are infectious particles containing either DNA or RNA as their genome. A large number of viruses belonging to various families cause rampant disease in human beings, ranging from mild and self-limiting to acute fatal diseases (Herrington et al., 2015;Keighley et al., 2015;Jacob et al., 2020). Various viral families, such as Filoviridae, Arenaviridae, Bunyaviridae, Paramyxoviridae, Coronaviridae, Orthomyxoviridae, Flaviviridae, Togaviridae, Hepeviridae, and so forth, infect humans and/or animals. Unfortunately, emerging and re-emerging viral pathogens often cause catastrophic pandemics that may take millions of human lives. For example, the most devastating "Spanish flu" pandemic in 1918 took over 50 million lives. The subsequent emergence of flu pandemics, such as "Asian flu" and "Hong Kong flu" in 1957 and1968, respectively, killed about three million people (Salomon and Webster, 2009). During 2002 and 2003, a novel severe acute respiratory syndrome coronavirus (SARS-CoV) infected over 8,000 people, causing 774 deaths in 27 countries (World Health Organization, 2018). A new virulent Influenza A Virus (IAV) H1N1 strain (H1N1pdm09) emerged in 2009 that killed ∼151,700-575,400 people worldwide (Centre for Disease Control and Prevention (CDC), 2012). A new avian IAV strain (H7N9), "Bird flu, " and the Middle East respiratory syndrome (MERS)-CoV in 2013 also emerged . Some viruses re-emerged after a number of years, such as the reemergence of the Ebola virus (EBOV) in 2014 (Shen et al., 2015), resurgences of the Zika virus (ZIKV) in 2015 and 2016 (Shuaib et al., 2016), and so forth (Chauhan et al., 2020;Guo, 2020). The ongoing pandemic caused by SARS-CoV-2 has already ravaged humanity and is still on the rise across the globe. Health challenges and economic consequences caused by the ongoing Covid-19 pandemic are potentially devastating and may remain an enduring puzzle. Therefore, a better understanding of the complex underlying mechanisms of viral pathogenesis caused by acute infections is truly important to the human community.
Innate immunity is a critical first line of defense against viral invasion. A well-specialized immune system consisting of distinct physical and chemical barriers, such as mucosal surfaces, skin, and their secretions, counter against viral invasion during viral entry into the host. Viruses are further sensed by various pattern recognition receptors (PRRs) after their entry, which leads to the activation of innate immune signaling pathways that control the production of interferons (IFNs), pro-inflammatory cytokines, and chemokines. Type I and III IFNs produced by various types of cells stimulate the expression of hundreds of genes, collectively known as IFN-stimulated genes (ISGs), which prime cells into an antiviral state (Iwasaki and Pillai, 2014;Chen et al., 2018). Secreted pro-inflammatory cytokines cause local and systemic inflammation. Chemokines produced at the site of infection may recruit additional immune cells, including neutrophils, monocytes, and natural killer cells (Christensen and Thomsen, 2009;Chen et al., 2018). Then, virus-infected cells could be targeted by immune cells, which mediates viral clearance (Iwasaki and Pillai, 2014). An acute viral infection is characterized by sudden or rapid onset of disease that may be fatal. Viral clearance during acute infection correlates with rapid induction of innate immunity, especially induction of ISGs, and subsequent induction of adaptive immune responses (Heim and Thimme, 2014). On the other hand, viruses are ever-evolving and can emerge and re-emerge into newer/novel virulent strains. The emergence of viral variants with increased adaptability and/or virulence indicates that viruses are acquiring new strainspecific mechanisms of immune escape. Viruses can develop multiple tactics to subvert innate immune surveillance and escape detection by innate immune sensors, leading to suppression of PRRs and their downstream signaling cascades to establish a successful infection. For instance, non-structural proteins of influenza and members of Flaviviridae viruses deploy numerous tactics to potently inhibit type I IFN signaling (Marc, 2014;Li et al., 2015;Chen et al., 2017). SARS-CoV-2 deregulates type I IFN responses through multiple mechanisms (Acharya et al., 2020). ZIKV circumvents host innate immunity by targeting the adaptor proteins MAVS and MITA . Enteroviruses brilliantly exploit their viral proteinase (3C pro and 2A pro ) to cleave PRRs (RIG-I, MDA5) and immune adaptor molecules (MAVS and TRIF), and thereby dampen the production of type I and III IFNs (Mukherjee et al., 2011;Feng et al., 2014;Lind et al., 2016). Cooperation among non-structural proteins (NS1, NS4B, and NS2B3) of ZIKV appeared to attenuate antiviral immunity . In this review, we describe the pathogenesis of acute viral infections in relation to host innate immunity and discuss how viruses escape innate immune surveillance.

PATHOGENESIS OF ACUTE VIRAL INFECTIONS
Being obligated intracellular parasitic infectious particles, viruses replicate only inside their specific host cell or tissue. For viruses to cause diseases, they must first infect their specific host, replicate efficiently within the host, and damage targeted tissues. Viral pathogenesis is complex and disease outcomes are determined by multiple factors (MacLachlan and Dubovi, 2017). Viruses rely on numerous host factors (determinants) to replicate efficiently in the host to cause disease (MacLachlan and Dubovi, 2017;Long et al., 2019;Gerold et al., 2020). Some hosts are highly susceptible to viral infection, while some are resistant. Differential host susceptibility to viral infection and disease progression depends on both viral infectivity (virulence) and host responses (Long et al., 2019;Gerold et al., 2020). Of those host responses, innate immunity plays a critical role in viral clearance and disease progression. During viral infection, various factors including delicate and dynamic equilibrium between pro-inflammatory and anti-inflammatory responses, immune cell activation and deactivation, and IFNs upregulation and IFN-reversion to the baseline, play important roles in viral pathogenesis and progression of disease (Virgin et al., 2009;Osburn et al., 2013;Maarouf et al., 2018;Blanco-Melo et al., 2020). For example, an imbalanced response that is characterized by low levels of type I and III IFNs juxtaposed to elevated chemokines and high expression of IL-6 to SARS-CoV-2 drives the development of COVID-19 (Blanco-Melo et al., 2020).
An acute viral infection can be resolved quickly by immune responses exerted by the host. For example, acute Hepatitis B Virus (HBV) infection can be spontaneously resolved in more than 90% of infected adults, although HBV can sometimes result in chronic persistent infection (Shin et al., 2016). The inflammatory response must be well-regulated in the course of viral clearance. However, excessive inflammatory responses can be lethal. Elevated levels of a broad array of pro-inflammatory cytokines and chemokines have been observed in diseases caused by various acute viral infections, such as EBOV disease, severe lung injury by infection of IAV, respiratory syncytial virus (RSV), and SARS-CoV-2 (Virgin et al., 2009;Shin et al., 2016;Troy and Bosco, 2016;Maarouf et al., 2018;Blanco-Melo et al., 2020). Acute respiratory infections are the leading cause of global disease (Troy and Bosco, 2016). Immune responses and disease outcomes in acute HAV (Hepatitis A Virus), HBV, and HCV infections have been previously described (Shin et al., 2016). Clinical manifestations, etiology, and outcome of various viral diseases caused by a large group of numerous viral infections have been described/reviewed elsewhere (Whitton et al., 2005;Ascenzi et al., 2008;Gould and Solomon, 2008;Ramos-Casals et al., 2008;Rojek and Kunz, 2008;Newton et al., 2016;Troy and Bosco, 2016;Zuberbier et al., 2018).

Roles of Interferons in Antiviral Responses
Interferons (IFNs), a family of cytokines, are critical elements of innate immunity responsible for rapid and efficient viral clearance (Fensterl and Sen, 2009). Virtually all nucleated cells could express IFNs during viral infection and IFN production is the key antiviral process of innate immunity during viral infection. Type I (IFN-α/β) and Type III IFNs are principal IFNs produced during viral infection as a key part of the innate immune response. The typical feature of IFNs is to induce upregulation of a wide array of intracellular antiviral FIGURE 1 | General overview of intracellular innate immune signaling and some representative viral immune escape mechanisms. Sensing virus by PRRs initiates innate immune signaling through the hierarchical activation of PRRs family-specific adaptor proteins (TRIF, MAVS, STING, MYD88, and so forth) to activate transcriptional factors, such as IRF3/5/7, NF-kB, and others. Activated transcriptional factors translocate into nucleus and induce robust expression of IFNs. Secreted IFNs bind to their respective receptors and activate JAK-STAT signaling and form a transcriptional factor called ISGF3. ISGF3, then, translocates into nucleus to induce expression of numerous antiviral effectors (ISGs) to impede viral infection. Although antiviral innate immunity consists of well-equipped arsenals to impede viral infection and invasion, viruses circumvent or escape from these antiviral arsenals to establish successful infection through several mechanisms. Of these escape mechanisms, viral components inhibit innate immune signaling by diversified tactics, such as interacting directly or indirectly with crucial innate elements, targeting and cleaving adaptor proteins involved in innate immune signaling or interference of IFN signaling, degradation of JAK/STAT components, and so forth. Some representative viral immune escape tactics are shown in the Figure 1. effectors called ISGs through JAK-STAT signal pathway (Fensterl and Sen, 2009;Schoggins, 2014;Majoros et al., 2017;Paul et al., 2018). Type I and type III IFNs bind to their respective receptors on the infected cell and neighboring cells, which leads to activation of JAK-STAT pathway and nuclear translocation of STAT1/STAT2/IRF9 (ISGF3) (Reviewed in Fensterl and Sen, 2009;Schoggins, 2014;Paul et al., 2018) and results in induction of numerous ISGs, such as Mx proteins, ISG15, protein kinase PKR, 2'-5'-oligoadenylate synthetases (OAS), ribonuclease L (RNaseL), IFN-inducible dsRNA-dependent protein kinase (PKR), adenosine deaminase RNA-specific and apolipoprotein B mRNA-editing enzyme, catalytic polypeptide 3, and others to establish an antiviral state (Iwasaki and Pillai, 2014;Chen et al., 2018). Of note, some ISGs, such as OAS and PKR, are further activated by dsRNA, which, in turn, inhibit viral replication by various mechanisms (Ishikawa et al., 2009;Iwasaki and Pillai, 2014;Chen et al., 2018). Additionally, IFNs may also exert immunomodulatory functions that affect cell migration, crosspresentation, CD4 + T cell stimulation or CD8 + T cell clonal expansion, and B cell activation, and enhance antiviral humoral responses (Iwasaki and Pillai, 2014). Thus, before the effective adaptive immunity is initiated, IFN-mediated innate immune response plays critical roles in eliminating virus invasion (Iwasaki and Pillai, 2014). Although viral infection induces the rapid expression of IFNs and antiviral effectors, at the same time, viral components can suppress IFNs signaling. Theoretically, virusinduced robust IFNs production, IFN-reversion to baseline by viral antagonisms, and optimal ISGs expression could establish a steady, delicate, and dynamic equilibrium. However, destruction of such a steady state, particularly in acute viral infection, by hyper-production of IFNs and hyper-effective immune evasion is the primary cause of viral pathogenesis Blanco-Melo et al., 2020). Both hyper-production of IFNs and hyper-effective immune evasion are disadvantageous to the host. Imbalanced levels of IFNs expression and differential ISGs production differ across type of viruses, which also determines the viral pathogenesis. For instance, among three Hepatitis (A, B, and C) viruses, HCV infection induces the robust expression of a large number of ISGs, whereas HAV infection minimally induces ISG expression and HBV infection might not induce ISG expression (Shin et al., 2016). Moreover, viruses are ever-evolving to escape away from innate immunity, particularly at acute infection. For example, IFITM is a critical antiviral ISG against several viruses including Human Immunodeficiency Virus (HIV-1), however, transmitted founder HIV-1viruses are uniquely IFITM resistant, a property that is lost during chronic infection. This is in part due to escape mutations acquired in response to autologous neutralizing responses (Foster et al., 2016).

VIRAL INNATE IMMUNE ESCAPE STRATEGIES
Nonetheless, the host is well-equipped with innate antiviral arsenals to eliminate invading viral pathogens; viruses evolved strategies to escape innate immune surveillance. At the early stage of viral entry into the host, viruses breach hosts' physical barriers by various ways. Upon breaching physical barriers, viruses exploit diverse mechanisms to inhibit the activation of PRRs and their downstream signaling cascades, such as concealing their PAMPs, interacting directly or indirectly with crucial innate elements, such as PRRs, transcriptional factors, targeting and cleaving adaptor proteins involved in innate immune signaling or interference of IFN signaling, degradation of JAK/STAT components, and so forth ( Table 1). A broad mechanism of viral innate immune escape tactics is discussed below.

Penetrating Physical Barriers
Physical barriers, such as skin or the surface of the respiratory, genital, or gastrointestinal tracts, including fluid repleted with antimicrobials, neutralizing immunoglobulins, mucus, and the epithelial cell layers, guard viral invaders. Viruses breach such barriers in a multitude of ways. For instance, specific viral proteins interact with cell receptor proteins present in the apical junctional complex to modify the barrier properties of the epithelium (Gonzalez-Mariscal et al., 2009). Interestingly, lower pathogenic avian influenza viruses generally do not cause severe pneumonia because mucus restrains and removes these viruses before approaching lower respiratory tracts, however, highly pathogenic IAV can breach such mucosal barriers (Van Riel et al., 2010). Although the skin is the most important physical barrier, it contains numerous permissive cells for flavivirus infection, such as ZIKV, DENV, and WNV, therefore, these viruses exploit permissive cells at the first site of infection (Garcia et al., 2017). HIV and SIV appear to be capable of flexibly exploiting multiple mechanisms to transit different epithelial barriers and gain access to susceptible target cells to establish a systemic infection (Keele and Estes, 2011).

Escaping From the Recognition From PRRs
Knowing that viruses are sensed by PRRs, viruses circumvent/minimize PRRs' sensing through numerous viral tactics, such as by sequestering/hiding viral genome, interacting with PRRs, targeting/cleaving adapter proteins, and so on. An in vitro study determined the effect of HCV proteins (NS3, NS3/4A, NS4B, or NS5A) on the TLR signaling pathways, where cells expressing these proteins were found to inhibit the activation of the TLR2, TLR4, TLR7, and TLR9 signaling pathways (Abe et al., 2007). Several viral proteins can specifically interact with PRRs. For an example, p7 of HCV associates with DNA sensor IFI6-16 (Qi et al., 2017). HBV conceals its genome into the viral capsid to escape away from cGAS sensing (Verrier et al., 2018). The human papillomavirus (HPV) E6 oncoprotein targets USP15 and TRIM25 to suppress RIG-I-mediated innate immune signaling (Chiang et al., 2018). Some viruses have evolved with strategies to modify viral RNAs and viral RNA-binding proteins to escape away from sensing by RIG-I, MDA5 (Bowie and Unterholzner, 2008). Viral dsRNA genome is highly susceptible to recognition by MDA5; both positive-sense RNA viruses and some DNA viruses produce dsRNA intermediate during their replication cycle, while some viruses conceal their dsRNA by encoding dsRNA binding proteins or even sequester viral RNA (Table 1). More interestingly, unlike positive-strand RNA and DNA viruses, negative-sense RNA viruses uniquely do not produce dsRNA intermediates; this unique property minimizes detection by PRRs (Weber et al., 2006). Moreover, a recent report showed that SARS-CoV-2 RNAs are capped at the 5' end and escape recognition from PRRs (Encinar and Menendez, 2020). Viral mechanisms of escaping from PRRs' recognition have been reviewed elsewhere (Weber et al., 2006;Abe et al., 2007;Bowie and Unterholzner, 2008;Chan and Gack, 2016;Qi et al., 2017;Chiang et al., 2018;Verrier et al., 2018;Encinar and Menendez, 2020;Kikkert, 2020;Lhomme et al., 2020;Liu et al., 2020;Zhu and Zheng, 2020).

Inactivation of Transcriptional Factors
At the basal level, transcriptional factors are inactive. After viral infection, transcriptional factors, such as IRF3/5/7, NF-κB, AP1, and others translocate into the nucleus and then induce the robust expression of IFNs (Christensen and Thomsen, 2009;Iwasaki and Pillai, 2014;Chen et al., 2018). Several conserved viral proteins, predominantly non-structural (NS) proteins, are extensively reported to exert potent antagonistic effects of IFN responses by several mechanisms. Viruses are reported to inhibit IFN induction by inducing degradation transcription factors, inhibiting their activation by blocking downstream signaling of PRRs, sequestering them, impeding their nuclear translocation, or inhibiting their binding to promoters of downstream antiviral genes, and so forth ( Table 1). For example, IAV NS1 protein, extensively characterized as a potent antagonist of IFN-signaling, inhibits activation and nuclear translocation of IRF3 and NF-κB (Wang et al., 2000). Human cytomegalovirus (HCMV) is wellknown for establishing long-term latent infections. The innate immune escape strategy of HCMV is appeared to be pivotal for establishing such infections. UL44 protein of HCMV decelerates antiviral responses by inhibiting the binding of IRF3 and NF-κB to the promoters of downstream antiviral genes (Fu et al., 2019).

Regulating the Transcriptional and Translation of Key Elements of Innate Immunity
Transcription and translation of key elements of antiviral innate immunity, such as PRRs, IRFs, IFNs, STATs, ISGs, and others are very important for eliciting an antiviral response. Cumulative reports suggest that viruses can deregulate the transcription and translation of such elements. Caliciviridae, Coronaviridae, Picornaviridae, Orthomyxoviridae, Reoviridae, and many others exploit multiple tactics to induce host translational shut-off and thus prevent the infected cells from synthesizing new peptides and proteins, including those IFN-stimulated IRFs and STATs (reviewed in Chiang and Liu, 2019). HIV-1 Vpu protein potently suppresses NF-κB-elicited antiviral immune responses at the transcriptional level (Langer et al., 2019). Epstein-Barr virus BRLF1 inhibits the transcription of IRF3 and IRF7 (Bentz et al., 2010). IAV induces rapid degradation of eukaryotic translation initiation factor 4B (an integral component of the translation initiation apparatus) and contributes to viral replication at least by suppressing IFITM3 protein expression (Wang et al., 2014).

Viral Invasion of ISGs
Global ISG response plays a very important role in viral clearance. Delayed ISG production is advantageous for viral replication and spread into host tissues. Viruses also exploit several distinct approaches to antagonize the global ISG response (Short, 2009). Highly pathogenic influenza viruses and coronaviruses induce repressive histone modifications, which downregulates the global expression of ISG subsets (Menachery et al., 2014). Although interferon-induced transmembrane proteins (IFITMs) play an antiviral role against a large group of viruses, particularly during viral invasion to the host at entry stage, human cytomegalovirus can exploit IFITM proteins to facilitate morphogenesis of the virion assembly compartment (Xie et al., 2015). Viral invasion of ISGs has been extensively reviewed elsewhere ( Table 1; Kanodia et al., 2007;Short, 2009;Su et al., 2016).

Other Mechanisms
In addition to the aforementioned viral immune escape mechanisms, a large group of viruses often encode proteins to inactivate released cytokines or chemokines by binding, solubilizing, and altering the cellular responsiveness (Lucas et al., 2001). Numerous viruses including HIV-1, HCV, HBV, HSV-1, RSV, EBOV, IAV, and others induce robust expression of suppressors of cytokine signaling (SOCS) proteins (Akhtar and Benveniste, 2011). SOCS proteins induced by cytokine signaling during viral infection function as negative feedback regulators to reduce inflammation and promote viral replication (Akhtar and Benveniste, 2011). More interestingly, some viruses can directly induce SOCS proteins independently of cytokine signaling. For example, the influenza virus induces the expression of SOCS3 in a cytokine-independent manner to circumvent IL-6/STAT3-mediated immune response . Virusinduced stress granules, the cytoplasmic dense aggregates of proteins and RNAs produced when cells are in stress, can also play an important role in innate immunity by recruiting viral sensors, such as RIG-I, MDA5, PKR, and so forth to initiate downstream antiviral innate immune signaling (McCormick and Khaperskyy, 2017). Several viruses brilliantly inhibit such stress granule formation by diverse mechanisms (Wu et al., 2014;McCormick and Khaperskyy, 2017). Moreover, viruses can also circumvent antiviral immunity through sequestering critical elements of innate immunity, such as TBK1, IKKε, and IRF3 into viral inclusion bodies (Wu et al., 2014). Other famous escape mechanisms include hijacking transcriptional and translational machineries for their survival, which can also mediate the circumvention of innate immune response in multiple ways. For example, the Nsp1 protein of SARS-CoV-2 mediates host translation shutdown and evades innate immunity (Thoms et al., 2020).

PERSPECTIVES AND CONCLUSION
Obstructing viral immune invasion could potentially provide an alternative approach for the prevention and treatment of disease caused by an acute infection of viral pathogens. Increasing data regarding viral innate immune escape mechanisms have been reported. However, most of these data are limited to in vitro (cell culture system) and in vivo animal models. The relevance of viral escape mechanisms identified by these models may not apply the same in human. Therefore, this issue remains to be addressed by extensive ex vivo experiments in the human model. The molecular basis of antiviral innate immune signaling is complex, multi-waved, inter-connected, and may not always be antiviral. For instance, it is well-known that TLR signals induce robust expression of antiviral innate immunity for viral clearance. However, in certain circumstances, the activation of particular TLR responses by pathogens might serve as an escape mechanism from the host defense (Netea et al., 2004). Furthermore, studies for the in-depth understanding of virushost interaction are very important because the molecular basis of viral escape mechanisms and crosstalk among immune signaling for the progression of disease are still largely unexplored.
Of several conserved viral proteins, predominantly NS proteins appear to be major antagonists of the elements of innate immunity. Since viral NS proteins play a vital role in innate immune escape mechanisms, there is a pressing need for scientists to uncover host factors countering those viral NS proteins. Supportively, recent reports have arguably characterized host factors countering such viral proteins. For instances, virus-induced TRIM22, viperin, and p27Kip1 mediate rapid degradation of HCV NS5A, ZIKA NS, and IAV NS1 proteins, respectively Panayiotou et al., 2018;Rai et al., 2020). Identification and characterization of such types of host factors countering these viral proteins in the future are truly indispensable in elaborating antiviral innate immunity.
A virus may exploit numerous and multiple immune escape tactics collectively and cooperatively for effective immune evasion. However, most of the previously published experimental data are mostly limited to viral escape tactics specifically at the individual level. Comprehensive studies on how viruses exploit their overall immune escape tactics together for disease progression or host killing in acute viral infection or in establishing successful infection should have been experimentally substantiated. Moreover, the consequences of cytokine storms in acute viral infection have been widely studied but the mechanistic basis of differential cytokine storm production and why the magnitude of cytokine storm production differs from one individual to another are largely unknown.
In conclusion, an acute viral infection can cause sudden or rapid onset of disease that may be resolved quickly or may be fatal. Innate immunity provides the first line of defense for viral clearance. However, viruses have evolved strategies to escape the host's antiviral innate immune surveillance that may kill the host or establish persistent infections. There are still many unanswered questions regarding the impact of viral escape strategies on host killing and viral persistence. Comprehensive understanding of the underlying complex molecular basis of viral escapology would help provide landmark achievements in our ongoing battle against viral infections.