Influenza A viruses (IAVs) are contagious pathogens responsible for severe respiratory infection in humans and animals worldwide. Upon detection of IAV infection, host immune system aims to defend against and clear the viral infection. Innate immune system is comprised of physical barriers (mucus and collectins), various phagocytic cells, group of cytokines, interferons (IFNs), and IFN-stimulated genes, which provide first line of defense against IAV infection. The adaptive immunity is mediated by B cells and T cells, characterized with antigen-specific memory cells, capturing and neutralizing the pathogen. The humoral immune response functions through hemagglutinin-specific circulating antibodies to neutralize IAV. In addition, antibodies can bind to the surface of infected cells and induce antibody-dependent cell-mediated cytotoxicity or complement activation. Although there are neutralizing antibodies against the virus, cellular immunity also plays a crucial role in the fight against IAVs. On the other hand, IAVs have developed multiple strategies to escape from host immune surveillance for successful replication. In this review, we discuss how immune system, especially innate immune system and critical molecules are involved in the antiviral defense against IAVs. In addition, we highlight how IAVs antagonize different immune responses to achieve a successful infection.

/pdf/host-immune-response-to-influenza-a-virus-infection-32cticzhxg.pdf

Host Immune Response to Influenza A Virus Infection.

Respiratory viruses cause infections of the upper or lower respiratory tract and they are responsible for the common cold—the most prevalent disease in the world. In many cases the common cold results in severe illness due to complications, such as fever or pneumonia. Children, old people, and immunosuppressed patients are at the highest risk and require fast diagnosis and therapeutic intervention. However, the availability and efficiencies of existing therapeutic approaches vary depending on the virus. Investigation of the pathologies that are associated with infection by respiratory viruses will be paramount for diagnosis, treatment modalities, and the development of new therapies. Changes in redox homeostasis in infected cells are one of the key events that is linked to infection with respiratory viruses and linked to inflammation and subsequent tissue damage. Our review summarizes current knowledge on changes to redox homeostasis, as induced by the different respiratory viruses.

https://www.mdpi.com/1999-4915/10/8/392/pdf

Redox Biology of Respiratory Viral Infections.

Influenza viruses are major human pathogens responsible for respiratory diseases affecting millions of people worldwide and characterized by high morbidity and significant mortality. Influenza infections can be controlled by vaccination and antiviral drugs. However, vaccines need annual updating and give limited protection. Only two classes of drugs are currently approved for the treatment of influenza: M2 ion channel blockers and neuraminidase inhibitors. However, they are often associated with limited efficacy and adverse side effects. In addition, the currently available drugs suffer from rapid and extensive emergence of drug resistance. All this highlights the urgent need for developing new antiviral strategies with novel mechanisms of action and with reduced drug resistance potential. Several new classes of antiviral agents targeting viral replication mechanisms or cellular proteins/processes are under development. This review gives an overview of novel strategies targeting the virus and/or the host cell for counteracting influenza virus infection.

/pdf/antiviral-strategies-against-influenza-virus-towards-new-3qr0m4hvz4.pdf

Antiviral strategies against influenza virus: towards new therapeutic approaches.

NF-κB plays central roles in regulation of diverse biological processes, including innate and adaptive immunity and inflammation. HSV-1 is the archetypal member of the alphaherpesviruses, with a large genome encoding over 80 viral proteins, many of which are involved in virus-host interactions and show immune modulatory capabilities. In this study, we demonstrated that the HSV-1 ICP0 protein, a viral E3 ubiquitin ligase, was shown to significantly suppress tumor necrosis factor alpha (TNF-α)-mediated NF-κB activation. ICP0 was demonstrated to bind to the NF-κB subunits p65 and p50 by coimmunoprecipitation analysis. ICP0 bound to the Rel homology domain (RHD) of p65. Fluorescence microscopy demonstrated that ICP0 abolished nuclear translocation of p65 upon TNF-α stimulation. Also, ICP0 degraded p50 via its E3 ubiquitin ligase activity. The RING finger (RF) domain mutant ICP0 (ICP0-RF) lost its ability to inhibit TNF-α-mediated NF-κB activation and p65 nuclear translocation and degrade p50. Notably, the RF domain of ICP0 was sufficient to interact with p50 and abolish NF-κB reporter gene activity. Here, it is for the first time shown that HSV-1 ICP0 interacts with p65 and p50, degrades p50 through the ubiquitin-proteasome pathway, and prevents NF-κB-dependent gene expression, which may contribute to immune evasion and pathogenesis of HSV-1.

https://jvi.asm.org/content/jvi/87/23/12935.full.pdf

Herpes Simplex Virus 1 E3 Ubiquitin Ligase ICP0 Protein Inhibits Tumor Necrosis Factor Alpha-Induced NF-κB Activation by Interacting with p65/RelA and p50/NF-κB1

Nuclear factor κB (NF-κB) plays important roles in innate immune responses by regulating the expression of a large number of target genes involved in the immune and inflammatory response, apoptosis, cell proliferation, differentiation, and survival. To survive in the host cells, viruses have evolved multiple strategies to evade and subvert the host immune response. Herpes simplex virus 1 (HSV-1) bears a large DNA genome, with the capacity to encode many different viral proteins to counteract the host immune responses. In the present study, we demonstrated that HSV-1 protein kinase US3 significantly inhibited NF-κB activation and decreased the expression of inflammatory chemokine interleukin-8 (IL-8). US3 was also shown to hyperphosphorylate p65 at serine 75 and block its nuclear translocation. Two US3 mutants, K220M and D305A, still interacted with p65; however, they could not hyperphosphorylate p65, indicating that the kinase activity of US3 was indispensable for the function. The attenuation of NF-κB activation by HSV-1 US3 protein kinase may represent a critical adaptation to enable virus persistence within the host. Importance: This study demonstrated that HSV-1 protein kinase US3 significantly inhibited NF-κB activation and decreased the expression of inflammatory chemokine interleukin-8 (IL-8). US3 hyperphosphorylated p65 at serine 75 to inhibit NF-κB activation. The kinase activity of US3 was indispensable for its hyperphosphorylation of p65 and abrogation of the nuclear translocation of p65. The present study elaborated a novel mechanism of HSV-1 US3 to evade the host innate immunity.

Herpes simplex virus 1 protein kinase US3 hyperphosphorylates p65/RelA and dampens NF-κB activation.

Summary


The IKK/NF-κB pathway is an essential signalling process initiated by the cell as a defence against viral infection like influenza virus. This pathway is therefore a prime target for viruses attempting to counteract the host response to infection. Here, we report that the influenza A virus NS1 protein specifically inhibits IKK-mediated NF-κB activation and production of the NF-κB induced antiviral genes by physically interacting with IKK through the C-terminal effector domain. The interaction between NS1 and IKKα/IKKβ affects their phosphorylation function in both the cytoplasm and nucleus. In the cytoplasm, NS1 not only blocks IKKβ-mediated phosphorylation and degradation of IκBα in the classical pathway but also suppresses IKKα-mediated processing of p100 to p52 in the alternative pathway, which leads to the inhibition of nuclear translocation of NF-κB and the subsequent expression of downstream NF-κB target genes. In the nucleus, NS1 impairs IKK-mediated phosphorylation of histone H3 Ser 10 that is critical to induce rapid expression of NF-κB target genes. These results reveal a new mechanism by which influenza A virus NS1 protein counteracts host NF-κB-mediated antiviral response through the disruption of IKK function. In this way, NS1 diminishes antiviral responses to infection and, in turn, enhances viral pathogenesis.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/cmi.12005

Influenza A virus-encoded NS1 virulence factor protein inhibits innate immune response by targeting IKK.

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Influenza A virus-encoded NS1 virulence factor protein inhibits innate immune response by targeting IKK.