Virus versus host: influenza A virus circumvents the immune responses

Abstract

Influenza A virus (IAV) is a highly contagious pathogen causing dreadful losses to humans and animals around the globe. As is known, immune escape is a strategy that benefits the proliferation of IAVs by antagonizing, blocking, and suppressing immune surveillance. The HA protein binds to the sialic acid (SA) receptor to enter the cytoplasm and initiate viral infection. The conserved components of the viral genome produced during replication, known as the pathogen-associated molecular patterns (PAMPs), are thought to be critical factors for the activation of effective innate immunity by triggering dependent signaling pathways after recognition by pattern recognition receptors (PRRs), followed by a cascade of adaptive immunity. Viral infection-induced immune responses establish an antiviral state in the host to effectively inhibit virus replication and enhance viral clearance. However, IAV has evolved multiple mechanisms that allow it to synthesize and transport viral components by "playing games" with the host. At its heart, this review will describe how host and viral factors interact to facilitate the viral evasion of host immune responses.

Keywords: adaptive immunity; host-virus interaction; immune escape; influenza A virus; innate immunity.

Figure 1

Structure of IAV. The image was created with Adobe Illustrator.

Figure 2

Schematic diagram of the mechanism of NS1-mediated immune escape in IAV. NS1 mediates the innate immune escape of viruses in five main ways. (A–D) could reduce IFN-β synthesis by inhibiting IFN signaling pathways, thereby circumventing the antiviral effect of host immunity, while E contributes to the immune escape of IAV by inhibiting the inflammatory response pathway. (A1,A2) mainly play the virus against the host by blocking the RIG-I signaling pathway. (B) NS1 mainly acts through host factors (SPL and SSU72) to subvert the antiviral response. (C) The NS1 protein can escape host innate immunity through amino acid substitutions such as single mutation F9Y, double mutation (R108K/G189D), and conserved FTEE motif (aa150-153). (D) NS1 truncation leads to the blocking of TLR production and weakens the antiviral effect. (E) NS1 can also interact with TRIM25 through the NLRP3-mediated inflammasome activation pathway to reduce IL-1β signaling, which may have additional antagonistic effects on host pro-inflammatory responses and create a favorable environment for viral replication. The image was created with BioRender.com.

Figure 3

Working model of polymerase acidic proteins-mediated regulation of innate immune escape signal transduction. (A) PB1 delivers MAVS to autophagosomes for degradation through the PB1-RNF5-MAVS-NBR1 axis, blocking RIG-I-MAVS-mediated degradation, ultimately leading to IFN decline and promotion of H7N9 infection. (B) The N-terminal functional domain of PA blocks IRF3 phosphorylation, which is responsible for IFN-β suppression. (C) The ESIE motif can sufficiently antagonize the induction of IFN, which may be associated with the pandemic risk of IAV. The image was created with BioRender.com.

Figure 4

The progression of PA-X and HA-mediated immune escape of IAV. (A) PA-X protein assisted H9N2 subtype AIVs in escaping immune response of mucosal DCs. The binding of PA-X to CCL20 blocks the recruitment of CD11b⁺ CDs and CD103⁺ CDs to the nasal mucosa. It downregulates the expression of CCR7 to reduce the expression of CD4⁺ T cells, which mediates the adaptive immune escape of the virus. (B) PA-X reduces the expression of interferon by inhibiting RIG-I and NF-κB pathways and increases the replication advantage of the virus. (C) The interaction between HA and PARP1 decomposes IFNAR1, inhibits the phosphorylation of STAT1, and then reduces IFN-β, which finally mediates the innate immune escape of the virus. The image was created with BioRender.com.