Evasion of influenza A viruses from innate and adaptive immune responses

Abstract

The influenza A virus is one of the leading causes of respiratory tract infections in humans. Upon infection with an influenza A virus, both innate and adaptive immune responses are induced. Here we discuss various strategies used by influenza A viruses to evade innate immune responses and recognition by components of the humoral and cellular immune response, which consequently may result in reduced clearing of the virus and virus-infected cells. Finally, we discuss how the current knowledge about immune evasion can be used to improve influenza A vaccination strategies.

Keywords: adaptive immunity; evasion; influenza; innate immunity.

Figure 1

Antigenic drift and shift to escape immunity. The gradual accumulation of mutations, mainly in the highly variable globular head region of HA, causes the influenza virus to escape recognition by virus neutralizing antibodies and allows it to cause seasonal epidemic outbreaks. This phenomenon is called antigenic drift. The introduction of a novel subtype into the human population is called antigenic shift and may cause a pandemic outbreak in the naïve human population when the virus is efficiently transmitted from human to human, since antibodies directed against the novel subtype are absent. Past pandemic outbreaks were caused by exchange (re-assortment) of gene segments between two or more influenza strains, e.g., avian and human. However, recent studies in ferrets suggest that avian influenza viruses, like H5N1, could be directly transmitted from animal reservoirs into the human population, requiring only a small number of adaptive mutations [9] as indicated by the dotted line in this figure.

Figure 2

The RIG-I signaling pathway and inhibition by influenza A viruses (Figure adapted from [48]). By-products of viral replication are 5'-triphosphates ssRNA and dsRNA which can bind to the RIG-1 receptor, leading to conformational changes, causing exposure of the CARDS which are ubiqutinated by TRIM25. Subsequently, RIG-1 associates with MAVS and thereby starts a signaling cascade leading to activation of transcription factors IRF3, NF-κB and ATF-2/JunC, resulting in the transcription of IFN-β mRNA. Indicated in red are sites at which the influenza A virus interferes with this pathway, as explained in the text.

Figure 3

The type I IFN signaling pathway and inhibition by influenza A viruses (Figure adapted from [48]). IFN-β produced by influenza virus-infected cells binds IFN receptors causing the phosphorylation of Tyk2 and Jak1. This is followed by binding and phosphorylation of STAT1 and STAT2 which subsequently form a complex with IRF9. This ISGF-3 complex acts as a transcription factor for >300 genes, several of which display an antiviral effect (see text). The expressed protein PKR is activated upon recognition of viral dsRNA, leading to inhibition of protein synthesis, including viral proteins. PKR is inhibited by the cellular protein P58^IPK, however P58^IPK activity is downregulated by binding cellular hsp40. The IRF7 protein is phosphorylated in the presence of influenza A virus, leading to activation of a positive feedback loop, causing the transcription of IFN-α and IFN-β. Indicated in red are mechanisms of the influenza A virus to interfere with this pathway, these interfering mechanisms are explained more extensively in the text.

Figure 4

Induction of humoral and cellular immunity. Induction of immune responses after a primary influenza A virus infection is indicated by solid arrows. The more rapid activation of virus-specific memory cell populations upon secondary encounter with an influenza A virus are indicated by dotted arrows.

Figure 5

MHC class I presentation of influenza A virus epitopes and viral escape. This figure represents a virus-infected cell and the presentation of viral epitopes by MHC class I molecules. The virus can escape recognition by virus specific CTLs by: (1) Mutations in TCR contact residues of CTL epitopes in order to prevent recognition of the epitope MHC class I complex by specific CTLs, or (2) mutating the anchor residues of the CTL epitope which prevents binding of the epitope to MHC class I molecules. Furthermore, mutations outside the CTL epitope may affect antigen processing by the proteasome or transport via the TAP respectively (3 and 4).