Abstract
A large number of human genes associated with viral infections contain single nucleotide polymorphisms (SNPs), which represent a genetic variation caused by the change of a single nucleotide in the DNA sequence. SNPs are located in coding or non-coding genomic regions and can affect gene expression or protein function by different mechanisms. Furthermore, they have been linked to multiple human diseases, highlighting their medical relevance. Therefore, the identification and analysis of this kind of polymorphisms in the human genome has gained high importance in the research community, and an increasing number of studies have been published during the last years. As a consequence of this exhaustive exploration, an association between the presence of some specific SNPs and the susceptibility or severity of many infectious diseases in some risk population groups has been found. In this review, we discuss the relevance of SNPs that are important to understand the pathology derived from influenza A virus (IAV) infections in humans and the susceptibility of some individuals to suffer more severe symptoms. We also discuss the importance of SNPs for IAV vaccine effectiveness.
Highlights
Each viral ribonucleoprotein complexes (vRNPs) acts as an independent transcription-replication unit using an uncommon mechanism among negative-sense RNA viruses, given that viral RNA synthesis occurs in the infected-cells nucleus. vRNAs are used as templates by the viral polymerase to synthesize two positive-sense RNA molecules, the complementary RNAs, from which the same viral polymerase synthesizes more copies of genomic vRNA, and the mRNAs for viral protein synthesis [1,2,3,4,5,6]
The rare allele A of two IFN regulatory factors (IRF)-7 SNPs, rs12272434 and rs12290989, both located at exon/intron boundaries, were significantly associated with impaired levels of IFNα production by human plasmacytoid dendritic cells in response to human immunodeficiency virus 1 (HIV-1) infection [114]
Rs12252 in the IFITM3 gene, in which the majority T allele is replaced for a minority C allele [118]. This leads to an alteration of the first splice acceptor site, originating an IFITM3 protein lacking the first 21 amino acids (N∆21) due to the protein starting from an alternative start codon. According to these results suggesting that this SNP could affect influenza disease, the minority (CC) variant rendered homozygous cells more susceptible to influenza A virus (IAV) infection, and this susceptibility correlated with decreased levels of IFITM3 protein expression in comparison to the majority (TT) variant cells [118]
Summary
Influenza A viruses (IAV) belong to the Orthomyxoviridae family, and they contain a single-stranded (ss) negative-sense viral (v)RNA genome formed by eight segments that are encapsidated into particles with an envelope (Figure 1A). IAV take advantage of multiple strategies, such as alternative splicing, frameshift mechanisms, and Synergistically with NS1, PA-X is able to block the cellular antiviral responses by inhibiting host overlapping open reading frames (ORFs) [7,8,9]. Gene or segment 8 of IAV encodes an mRNA transcript that is alternatively spliced to express two viral proteins, the nonstructural protein 1 (NS1), produced from a continuous primary transcript, and the nuclear export protein (NEP), which is produced by an alternatively processed transcript, using a weak 50 splice site. NS1 has been shown to inhibit the production of interferon (IFN), the activity and expression of multiple interferon-induced genes (ISG) and the processing and nuclear transport of host mRNAs causing cellular shut-off [25,26]. The PA-X protein has been shown to modulate host inflammation, immune responses, apoptosis, and virus pathogenesis [25,26,27,28,29,30]
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