Host Single Nucleotide Polymorphisms Modulating Influenza A Virus Disease in Humans

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. multiple mechanisms, although there are some differences between strains. For that genome plasticity, IAV take advantage of multiple strategies, such as alternative splicing, frameshift mechanisms, and overlapping open reading frames (ORFs) [7][8][9]. In addition, the coding capability of the viral genome is extended by encoding multifunctional proteins that act at different steps during virus infection. of synthetized vRNP, ensuring that the vRNPs are available for packaging [24]. Moreover, NEP has also other functions during IAV infection, contributing to viral budding and to regulate viral RNA synthesis. NS1 is a multifunctional protein and a key viral factor that counteracts the host antiviral responses. 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]. Segment 3 of IAV also encodes two proteins, the polymerase component PA and PA-X. PA is translated directly from the PA mRNA, whereas PA-X is translated using a +1 frameshift mechanism from the same open reading frame (ORF) [9]. Synergistically with NS1, PA-X is also able to block the cellular antiviral responses by inhibiting host protein expression. Moreover, the PA-X protein has been shown to modulate host inflammation, immune responses, apoptosis, and virus pathogenesis [25][26][27][28][29][30].

Genetic influences on viral-induced cytokine responses in the lung

“…In IAV infections, the most severe responses are associated with 'cytokine storms' or hypercytokinemia. As previously reviewed, 117 SNPs in TNF, CCR5, IL1A and IL1B are associated with susceptibility and severity of influenza infections, although the mechanism by which these SNPs may increase disease susceptibility remains to be fully elucidated. In accordance with possible anti-inflammatory functions of TNF-α, the TNF −238 A allele, which has been demonstrated to correlate with lower TNF transcripts, was overrepresented in IAV pH1N1/09 infected patients in comparison to healthy controls in a Caucasian population.…”

Pregnancy, Viral Infection, and COVID-19

“…Other factors may also influence the susceptibility for COVID-19 infected persons, and some gene polymorphisms, well-documented for other viral infections (113).…”

Clinical and molecular characterization of COVID-19 hospitalized patients

“…As demonstrated for other viral diseases, the basis of these different outcomes there are host predisposing genetic factors leading to different immunogenicity/cytokine responses as well as specific receptor permissiveness to virus and antiviral defence [4][5][6]. Similarly, during the study of host genetics in influenza disease, a pattern of genetic markers has been identified which underlies increased susceptibility to a more severe clinical outcome (as reviewed in [7]). This hypothesis is also supported by a recent work reporting 50% heritability of COVID-19 symptoms [8].…”