Abstract
Despite effective vaccines, influenza remains a major global health threat due to the morbidity and mortality caused by seasonal epidemics, as well as the 2009 pandemic. Also of profound concern are the rare but potentially catastrophic transmissions of avian influenza to humans, highlighted by a recent H7N9 influenza outbreak. Murine and human studies reveal that the clinical course of influenza is the result of a combination of both host and viral genetic determinants. While viral pathogenicity has long been the subject of intensive efforts, research to elucidate host genetic determinants, particularly human, is now in the ascendant, and the goal of this review is to highlight these recent insights.
Influenza virus is a member of the Orthomyxoviridae family, and possesses a negative-sense RNA genome consisting of eight distinct segments encoding for 11 proteins [1]. Among the three types of influenza viruses (A, B, and C), the influenza A and B viruses produce seasonal epidemics in humans, with influenza A virus (IAV) being the major etiological agent. In addition to humans, IAV can infect swine and avian populations, which contributes to the emergence of pandemics as a result of cross species transmission.
Based on the antigenicity of their surface hemagglutinin (HA) and neuraminidase (NA) glycoproteins, IAV is currently categorized into seventeen HA (H1-H17) and ten NA (N1-N10) subtypes [2], with the majority of these subtypes isolated from wild aquatic birds. Of these subtypes, H1-H3 and N1-N2 have caused widespread human infections, with the most common illness produced by H1N1 and H3N2. Although avian influenza viruses rarely infect humans, sporadic cases of infection by H5, H7, and H9 have occurred [3–6]. While cases of human-to-human transmission of these avian viruses are limited, they are still of considerable concern because human populations are immunologically naïve to these virulent HA subtypes, raising the risk of a catastrophic pandemic.
The clinical course of influenza is dictated by the struggle between viral virulence factors and the host's protective strategies. For example, in many instances the host's neutralizing antibodies can bind to invading viruses and prevent cell entry, in turn viruses have evolved hypervariability within their surface antigens [7]. IAV virulence factors such as the NS1 protein that antagonize the host interferon (IFN) responses have been discussed previously [8]. In this review, we will touch briefly on the murine literature then primarily focus on human genetic determinants implicated in modulating IAV pathogenicity.
Murine genetic determinants that modulate IAV infection
Murine models are the mainstay for studying IAV infections in vivo. However, mice are not infected by IAV or IBV in the wild and so may not fully recapitulate the interactions occurring between these viruses and their natural hosts. Furthermore, mice are not susceptible to infection by human-derived IAV because they express avian-like sialic acid linkages (SAα-2, 3-Gal) on their cell surface proteins as opposed to those encountered by the virus on human cells (SAα-2, 6-Gal) [9–10]. Indeed, SA linkage affinity remains a key component of host susceptibility to IAV infection. [11–15]. However, repeated passaging of human-derived IAV in mice can select for HA variants with affinity for SAα-2, 3-Gal receptor thereby permitting the use of mice to characterize immune responses and pathogenicity during IAV infection [16–17].
In addition to surface receptors that determine host susceptibility to virus infection, restriction factors contribute to the host's ability to control viral replication. The Mx1 gene (orthomyxovirus resistance gene 1) was discovered as a restriction factor that inhibits IAV infection in mice [18–20]. The murine Mx1 gene is encoded on chromosome 16 and is one of several IFN stimulated genes (ISGs) that block IAV infection, in this instance via the inhibition of viral RNA transcription [21–24]. Mouse Mx1 protein localizes to both the nucleus and cytoplasm after IFN-induction, whereas Mx1 proteins from other vertebrates are expressed predominantly in the cytosol. Most laboratory mouse strains carry inactive Mx1 alleles and are therefore susceptible to mouseadapted IAV infection [25–26]. In kind, hypomorphic polymorphisms of Mx1 genes in pigs and birds are reported to be associated with enhanced host susceptibility to IAV infection [27–29].
Many studies have been conducted using mouse models to study the relationship between host genetics and IAV pathogenicity (reviewed in [30–31]). However, the conclusions drawn from these efforts must be interpreted in light of the identical genetic backgrounds of inbred mouse populations. To address potential caveats arising from genetic homogeneity, Ferris et. al. recently used the highly genetically diverse incipient lines of the Collaborative Cross (CC) octo-parental recombinant inbred mouse panel (pre-CC population) to study the relationship between host genetic variation and IAV infection [32]. The pre-CC population contains up to eight functionally variant alleles at any given locus with about forty million single nucleotide polymorphisms (SNPs) evenly distributed across the genome [33–36]. The authors conducted quantitative trait loci (QTL) mapping [33], and identified four QTL regions that associate with IAV infection outcomes. Among the four QTL regions, HrI (Host Response to Influenza)-1 was mapped to a 0.71 Mb region on chromosome 16 where the Mx1 gene is encoded and is the key host responsive QTL to IAV infection. Sequencing of the respective Mx1 coding regions of the eight CC founder mouse strains revealed a novel Mx1 allele that is attenuated in inhibiting IAV replication. After careful investigation, Hrl2Hrl3, and Hrl4 were mapped to chromosomes 7, 1, and 15 respectively. Several candidate genes were noted to reside within these QTL regions; the Nox4 gene lies within Hrl2 and plays a role in the innate immune system's Toll like receptor 4 (TLR4) pathway [37], and Grap2 resides within Hrl4 and is involved with leukocyte specific signaling [38].
Human genetic determinants that modulate IAV infection
An epidemiological study using genealogic databases of families in the state of Utah spanning 100 years was conducted to investigate heritable susceptibility to severe IAV infection [39]. The authors compared the influenza-associated mortality rate for consanguineal relatives of persons who died of influenza, with the mortality rates of spouses for such individuals. The results showed that consanguineal relatives of persons who died of influenza had a significantly higher risk of dying from IAV infection than matched spouses, suggesting that genetic similarities may underlie this susceptibility.
Although the vast majority of cases of avian influenza arising in humans involve bird-to-human transmission [3–6], clusters of such infections occur within families, suggesting that human-to-human transmission occurs [40–44] and that host genetic determinants may therefore play a contributory role. Alternatively, such familial clustering of infection may simply occur because of increased exposure in the absence of genetic susceptibility [45]. Of course these two possibilities are not mutually exclusive. However, the allele(s) underlying any possible human susceptibility to avian influenza infection remain(s) unknown (reviewed in [30–31, 46]). One possibility is the MxA protein, which is the human homolog of mouse Mx1 and is encoded on chromosome 21 [47]. Although the MxA protein has been shown to be an antiviral factor [24, 48], the mechanism underlying allelic phenotypic variation within the MxA gene and a connection to human susceptibility to IAV infection and pathogenicity remains an evolving area of investigation. Recently, the MxA protein has been shown to restrict IAV infection in a viral strain-specific manner, with avian influenza viruses exhibiting enhanced susceptibility to MxA-mediated restriction because of molecular determinants residing within their nucleoprotein genes (NP) [49] [50], [51]. Therefore, in addition to SA linkages contributing to avian influenza transmission, allelic variation within the MxA locus may also play a role in avian influenza infections occurring in humans.
A case-control association study was conducted to genotype 91 patients with confirmed severe pneumonia from H1N1 infection, leading to the identification of four single nucleotide polymorphisms (SNPs) that were associated with severe pneumonia [52]. Two of the SNPs were located within genes on chromosome 17, RPAIN – gene of RPA interacting protein, and C1QBP – gene of complement component 1q binding protein. The remaining two SNPs were found within FCGR2A – an Fc receptor gene on chromosome 1, and within a potentially intergenic region of chromosome 3. Two of these SNPs are associated with genes whose products take part in either the clearing of immune complexes (FCGR2A) or complement activation (C1QBP), suggesting that the severe disease outcome of H1N1 infection may result from variations in the host's immune response. However, it was noted that the four SNPs possessed false discovery rates of 22–56% which was attributed to the small sample size of the study [31].
The above noted genetic determinants implicated in influenza pathogenicity, as well as several additional human genes reported to affect host susceptibility to IAV infection and virus pathogenicity, are presented in Table 1. A missense mutation (F303S) of the toll-like receptor 3 (TLR3) gene has been associated with influenza-associated encephalopathy (IAE), a neurological sequelae of severe viral infection [53]. TLR3 recognizes double-stranded RNA (dsRNA), one of the intermediate products of IAV replication, and in turn triggers IFN production leading to an anti-IAV response. In vitro assays showed that a TLR3 receptor containing the F303S mutation was less effective in activating the transcription factor, NF-κB, as well as triggering downstream signaling via the IFNβ receptor, suggesting that this variant may allow enhanced IAV replication [53]. An additional TLR3 SNP (rs5743313, genotype C/T) was identified in a study of 51 children with confirmed H1N1 infection [54]; this TLR3 SNP was found in all of the children with IAV-associated pneumonia (18 cases), but in significantly less children with milder disease (p < 0.0001), further demonstrating the association between TLR3 and IAV pathogenicity.
Table 1.
Host genetic determinants of influenza pathogenicity
Gene | Functions | Authors | Major findings |
---|---|---|---|
TLR3 | Toll-like receptor 3; recognizes dsRNA and triggers IFN production | Hidaka F, et. al. (2006) [53] | The F303S mutation of TLR-3 was found to be associated with IAE, and caused decreased NF-κB and IFNβ receptor functions in vitro. |
Esposito S, et. al. (2012) [54]. | SNP (rs5743313, genotype C/T) was found in all patients with pneumonia (18 cases) but in a significantly lower number of those with milder H1N1-induced disease (p< 0.0001). | ||
RPAIN | Replication Protein A (RPA) interacting protein; supplements RPA for DNA metabolism | Zuniga J, et. al. (2012) [52] | Four disease outcome-associated SNPs were identified on chromosome 17 (RPAIN and C1QBP), chromosome 1 (FCGR2A), and chromosome 3 (unknown gene). C1QBP and GCGR2A play roles in the formation of immune complexes and complement activation, suggesting that the severe disease outcome of H1N1 infection may result from an enhanced host immune response. |
C1QBP | Complement component 1, q subcomponent binding protein; inhibits complement activation | ||
FCGR2A | Fc fragment of IgG, low affinity IIa, receptor (CD32); plays a role in phagocytosis and clearance of immune complexes | ||
CPT2 | Carnitine palmitoyl-transferase II; oxidizes long chain fatty acids in mitochondria | Yao D, et. al. (2008) [55] | Polymorphisms of CPT2 were found in patients suffering from IAE; results of overexpression of CPT2 variants in vitro suggested that the variants were heat-labile and failed to perform optimally |
Mak CM, et. al. (2011) [56] | CPT2 variants (F352C/V368I) were found in two Chinese patients who were among individuals infected with IAV who demonstrated IAE. The F352C mutation has not been reported in Caucasian populations, suggesting an Asian-specific phenotype of heat-labile CPT2-associated IAE. | ||
CD55 | CD55 molecule; decay accelerating factor for complement | Zhou J, et. al. (2012) [58]. | The CD55 SNP (rs2564978, genotype T/T) showed significant association with severe IAV infection (p=0.011). Patients who carry the T/T genotype may not control complement activation as well during IAV infection, resulting in worse disease outcomes. |
IFITM3 | Interferon-induced transmembrane protein-3; restricts mutiple viral infections | Everitt AR, et. al. (2012) [66] | A minor allele, SNP rs12252-C, was significantly enriched for in patients hospitalized due to H1N1/09 infection. |
Zhang YH, et. al. (2013) [68]. | Although the rs12252-genotype C/C SNP is a minor allele in Caucasians it is more prevalent in Han Chinese populations, where it was independently found to be present in 69% of patients with severe IAV infection, as compared to only 25% of patients with mild disease [68]. When compared with patients carrying the C/T or T/T genotypes, subjects with the C/C genotype were estimated to have six-fold higher risk of developing severe disease after IAV infection [68]. |
Polymorphisms within the carnitine palmitoyltransferase II (CPT2) gene, which encodes for a mitochondrial protein that oxidizes long chain fatty acids, were also found to be enriched in patients suffering from IAE [55]. In vitro, these CPT2 variants demonstrated reductions in both enzymatic activity and thermal stability when compared to the wildtype allele. Cells which were transiently transfected with these CPT2 variants also showed reduced fatty acid β-oxidation (30–59% of controls) and diminished intracellular ATP levels (48–79% of controls) in comparison to controls. Moreover, cells expressing CPT2 variants possessed decreased mitochondrial potential at both 37°C and 41°C when compared to the controls. Two additional CPT2 variants (F352C, V368I) were also isolated from two Chinese patients who were among individuals infected with IAV who demonstrated IAE [56]. Although likely not specific to IAV infection, these results suggest that such CPT2 variants are unstable during febrile periods and thus individuals expressing these variants may be at increased risk for IAE.
CD55 is a complement pathway regulatory protein which inhibits the formation of C3 and C5 convertase, two proteases involved in complement activation and inflammation [57]. A recent study identified SNPs in the CD55 genes of Chinese patients with severe influenza disease outcomes [58]. The CD55 SNP (rs2564978, genotype T/T) showed significant association with severe IAV infection (p=0.011). The rs2564978 SNP of CD55 resides in the minimal promoter region [59], and individuals with this genotype showed significantly lower levels of CD55 expression compared to those with the more common allele. Therefore, patients who carry the T/T genotype may have more robust complement activation during IAV infection, resulting in worse outcomes secondary to enhanced inflammation.
IFITM3 was identified as a host restriction factor that inhibits multiple viruses, including IAV, using several orthologous genetic approaches [60–63]. Although the mechanism of IFITM3 inhibition against virus infection is under active investigation, it has been reported that IFITM3 blocks IAV infection at the early stage of virus life cycle, and likely at the late endosomes where virus and endosomal membranes fuse [60, 64–65]. As an ISG, IFITM3 is induced by IFN and has been shown to be essential in restricting IAV infection in a mouse model [66–67]. When examining the role of IFITM3 in human IAV infection, a minor allele, SNP rs12252-C, was found to be enriched in patients hospitalized due to H1N1/09 infection [66]. Although the exact mechanism underlying these events remains to be determined, the rs12252-genotype C/C SNP affects a splice acceptor site suggesting several possibilities [66]. Furthermore, although the rs12252-genotype C/C SNP is a minor allele in Caucasians it is more prevalent in Han Chinese populations, where it was independently found to be present in 69% of patients with severe IAV infection, as compared to only 25% of patients with mild disease [68]. When compared with patients carrying the C/T or T/T genotypes, subjects with the C/C genotype were estimated to have six-fold higher risk of developing severe disease after IAV infection [68]. Therefore, host IFITM3 genetic heterogeneity may play an important role in IAV pathogenicity and the establishment of pandemics [66, 69], especially in populations expressing higher percentages of the rs12252 allele as seen in many regions of China and Japan [68]. These data suggest that risk assessment based on IFITM3 genotyping may aid clinical management in the appropriate populations. Moreover, these results suggest that modulation of IFITM3 levels and/or actions may also have therapeutic utility in disease prevention and treatment.
Conclusion
Despite the advances of modern medicine and the availability of effective vaccines, influenza remains a major global health concern because of the morbidity and mortality caused by seasonal epidemics, as well as the emergence of pandemics and the transmission of avian influenza viruses to humans. Currently, reports of an H7N9 avian influenza virus outbreak in China have again focused global attention on this pathogen [70–71]. As noted, murine and human susceptibility to severe disease outcome is the result of a combination of both viral and host genetic determinants. Researchers have successfully focused on elucidating the viral determinants of IAV pathogenicity such as HA variability and the immune-evasive actions of IAV's NS1 protein [11–15]. On the other hand, human genetic determinants are comparatively unknown, with the above noted studies shedding light on this area of active investigation (Table 1). With the availability of greatly enhanced genome sequencing technology and super-computing capability, the tools for determining host genetic determinants that modulate influenza infection have greatly improved. The recent 2009 H1N1 pandemic also has provided an excellent opportunity to elucidate the contribution of host alleles in altering disease outcome in the absence of naturally acquired or vaccine-induced humoral immunity [66, 68]. Therefore given the continual threat posed by IAV, and the recent advances in technology, a compelling case can now be made for the creation and funding of a large-scale research initiative to fully delineate the role of host genetic determinants in IAV pathogenicity.
Highlights.
Influenza’s clinical course is dictated by the struggle between viral and host genetic determinants.
This review primarily covers studies investigating human genetic determinants of influenza infection.
The roles of the human genes, MxA, CPT2, CD55, TLR3 and IFITM3, in influenza pathogenicity are discussed.
Footnotes
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References
- 1.Palese P, Shaw ML. In: Orthomyxoviridae: The Viruses and Their Replication, in Fields Virology. Fields BN, Knipe DM, Howley PM, editors. Wolters kluwer/Lippincott Williams & Wilkins; Philadelphia: 2007. pp. 1648–1689. [Google Scholar]
- 2.Zhu X, et al. Hemagglutinin homologue from H17N10 bat influenza virus exhibits divergent receptor-binding and pH-dependent fusion activities. Proc Natl Acad Sci U S A. 2013;110(4):1458–1463. doi: 10.1073/pnas.1218509110. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Claas EC, et al. Human influenza A H5N1 virus related to a highly pathogenic avian influenza virus. Lancet. 1998;351(9101):472–477. doi: 10.1016/S0140-6736(97)11212-0. [DOI] [PubMed] [Google Scholar]
- 4.Aditama TY, et al. Avian influenza H5N1 transmission in households, Indonesia. PLoS One. 2012;7(1):e29971. doi: 10.1371/journal.pone.0029971. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Belser JA, et al. Past, present, and possible future human infection with influenza virus A subtype H7. Emerg Infect Dis. 2009;15(6):859–865. doi: 10.3201/eid1506.090072. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Lin YP, et al. Avian-to-human transmission of H9N2 subtype influenza A viruses: relationship between H9N2 and H5N1 human isolates. Proc Natl Acad Sci U S A. 2000;97(17):9654–9658. doi: 10.1073/pnas.160270697. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Wilson PC, Andrews SF. Tools to therapeutically harness the human antibody response. Nat Rev Immunol. 2012;12(10):709–719. doi: 10.1038/nri3285. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Fukuyama S, Kawaoka Y. The pathogenesis of influenza virus infections: the contributions of virus and host factors. Curr Opin Immunol. 2011;23(4):481–486. doi: 10.1016/j.coi.2011.07.016. A review article covering both IAV factors and host factors that contribute to IAV pathogenicity. The authors summarized reported mutations on IAV-encoded proteins that impact virus pathogenicity.
- 9.Shinya K, et al. Avian flu: influenza virus receptors in the human airway. Nature. 2006;440(7083):435–6. doi: 10.1038/440435a. [DOI] [PubMed] [Google Scholar]
- 10.van Riel D, et al. Human and avian influenza viruses target different cells in the lower respiratory tract of humans and other mammals. Am J Pathol. 2007;171(4):1215–1223. doi: 10.2353/ajpath.2007.070248. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Glaser L, et al. A single amino acid substitution in 1918 influenza virus hemagglutinin changes receptor binding specificity. J Virol. 2005;79(17):11533–11536. doi: 10.1128/JVI.79.17.11533-11536.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Yamada S, et al. Haemagglutinin mutations responsible for the binding of H5N1 influenza A viruses to human-type receptors. Nature. 2006;444(7117):378–382. doi: 10.1038/nature05264. [DOI] [PubMed] [Google Scholar]
- 13.Imai M, Kawaoka Y. The role of receptor binding specificity in interspecies transmission of influenza viruses. Curr Opin Virol. 2012;2(2):160–167. doi: 10.1016/j.coviro.2012.03.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Xiong X, et al. Receptor binding by a ferret-transmissible H5 avian influenza virus. Nature. 2013 doi: 10.1038/nature12144. [DOI] [PubMed] [Google Scholar]
- 15.Paulson JC, de Vries RP. H5N1 receptor specificity as a factor in pandemic risk. Virus Res. 2013 doi: 10.1016/j.virusres.2013.02.015. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Shope RE. The Infection of Mice with Swine Influenza Virus. J Exp Med. 1935;62(4):561–672. doi: 10.1084/jem.62.4.561. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Hirst GK. Studies on the Mechanism of Adaptation of Influenza Virus to Mice. J Exp Med. 1947;86(5):357–366. doi: 10.1084/jem.86.5.357. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Lindenmann J. Resistance of mice to mouse-adapted influenza A virus. Virology. 1962;16:203–204. doi: 10.1016/0042-6822(62)90297-0. [DOI] [PubMed] [Google Scholar]
- 19.Lindenmann J. Inheritance of Resistance to Influenza Virus in Mice. Proc Soc Exp Biol Med. 1964;116:506–509. doi: 10.3181/00379727-116-29292. [DOI] [PubMed] [Google Scholar]
- 20.Horisberger MA, Staeheli P, Haller O. Interferon induces a unique protein in mouse cells bearing a gene for resistance to influenza virus. Proc Natl Acad Sci U S A. 1983;80(7):1910–1914. doi: 10.1073/pnas.80.7.1910. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Holzinger D, et al. Induction of MxA gene expression by influenza A virus requires type I or type III interferon signaling. J Virol. 2007;81(14):7776–7785. doi: 10.1128/JVI.00546-06. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Ding M, Lu L, Toth LA. Gene expression in lung and basal forebrain during influenza infection in mice. Genes Brain Behav. 2008;7(2):173–183. doi: 10.1111/j.1601-183X.2007.00335.x. [DOI] [PubMed] [Google Scholar]
- 23.Pavlovic J, Haller O, Staeheli P. Human and mouse Mx proteins inhibit different steps of the influenza virus multiplication cycle. J Virol. 1992;66(4):2564–2569. doi: 10.1128/jvi.66.4.2564-2569.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Haller O, Staeheli P, Kochs G. Interferon-induced Mx proteins in antiviral host defense. Biochimie. 2007;89(6 – 7):812–818. doi: 10.1016/j.biochi.2007.04.015. A comprehensive review article that summarizes the function and mechanism of the Mx protein family.
- 25.Staeheli P, et al. Influenza virus-susceptible mice carry Mx genes with a large deletion or a nonsense mutation. Mol Cell Biol. 1988;8(10):4518–4523. doi: 10.1128/mcb.8.10.4518. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Cilloniz C, et al. Molecular signatures associated with Mx1-mediated resistance to highly pathogenic influenza virus infection: mechanisms of survival. J Virol. 2012;86(5):2437–2446. doi: 10.1128/JVI.06156-11. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Seyama T, et al. Population research of genetic polymorphism at amino acid position 631 in chicken Mx protein with differential antiviral activity. Biochem Genet. 2006;44(9 – 10):437–448. doi: 10.1007/s10528-006-9040-3. [DOI] [PubMed] [Google Scholar]
- 28.Palm M, et al. Differential anti-influenza activity among allelic variants at the Sus scrofa Mx1 locus. J Interferon Cytokine Res. 2007;27(2):147–155. doi: 10.1089/jir.2006.0119. [DOI] [PubMed] [Google Scholar]
- 29.Nakajima E, et al. A naturally occurring variant of porcine Mx1 associated with increased susceptibility to influenza virus in vitro. Biochem Genet. 2007;45(1 – 2):11–24. doi: 10.1007/s10528-006-9045-y. [DOI] [PubMed] [Google Scholar]
- 30. Trammell RA, Toth LA. Genetic susceptibility and resistance to influenza infection and disease in humans and mice. Expert Rev Mol Diagn. 2008;8(4):515–529. doi: 10.1586/14737159.8.4.515. The authors discussed host genetic factors that can contribute to susceptibility to IAV infection. The ariticle reviewed both human and mouse factors but with strong emphasis on mouse genetic factors that render the animal model susceptible or resistant to IAV infection.
- 31. Horby P, et al. The role of host genetics in susceptibility to influenza: a systematic review. PLoS One. 2012;7(3):e33180. doi: 10.1371/journal.pone.0033180. The authors screened published literatures and systematically reviewed key studies of mouse and human heritability and genetic susceptibility to IAV infection.
- 32. Ferris MT, et al. Modeling host genetic regulation of influenza pathogenesis in the collaborative cross. PLoS Pathog. 2013;9(2):e1003196. doi: 10.1371/journal.ppat.1003196. To overcome the potential caveats of the genetic homogeneity of inbred mouse models, the authors used the genetically diverse incipient lines of the pre-CC population to study the relationship between host genetic variation and IAV infection. The Mx1 gene was confirmed to be a key host factor modulating IAV infection. Sequencing of the respective Mx1 coding regions of the eight CC founder mouse strains revealed a novel Mx1 allele that is attenuated in inhibiting IAV replication..
- 33.Aylor DL, et al. Genetic analysis of complex traits in the emerging Collaborative Cross. Genome Res. 2011;21(8):1213–1222. doi: 10.1101/gr.111310.110. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Chesler EJ, et al. The Collaborative Cross at Oak Ridge National Laboratory: developing a powerful resource for systems genetics. Mamm Genome. 2008;19(6):382–389. doi: 10.1007/s00335-008-9135-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Philip VM, et al. Genetic analysis in the Collaborative Cross breeding population. Genome Res. 2011;21(8):1223–1238. doi: 10.1101/gr.113886.110. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Collaborative Cross C. The genome architecture of the Collaborative Cross mouse genetic reference population. Genetics. 2012;190(2):389–401. doi: 10.1534/genetics.111.132639. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37. Park HS, et al. Cutting edge: direct interaction of TLR4 with NAD(P)H oxidase 4 isozyme is essential for lipopolysaccharide-induced production of reactive oxygen species and activation of NF-kappa B. J Immunol. 2004;173(6):3589–3593. doi: 10.4049/jimmunol.173.6.3589. The authors conducted an epidemiological study using genealogic databases of families in the state of Utah to investigate heritable susceptibility to severe IAV infection. They compared the influenza-associated mortality rate for consanguineal relatives of persons who died of influenza, with the mortality rates of spouses for such individuals. The results indicated that both close and distant relatives of persons who died of IAV had significantly higher risk of dying from IAV infection than those of spouses for such individuals, suggesting that genetic similarities may underlie this susceptibility.
- 38.Ma W, et al. Leukocyte-specific adaptor protein Grap2 interacts with hematopoietic progenitor kinase 1 (HPK1) to activate JNK signaling pathway in T lymphocytes. Oncogene. 2001;20(14):1703–1714. doi: 10.1038/sj.onc.1204224. [DOI] [PubMed] [Google Scholar]
- 39.Albright FS, et al. Evidence for a heritable predisposition to death due to influenza. J Infect Dis. 2008;197(1):18–24. doi: 10.1086/524064. [DOI] [PubMed] [Google Scholar]
- 40.Kandun IN, et al. Three Indonesian clusters of H5N1 virus infection in 2005. N Engl J Med. 2006;355(21):2186–2194. doi: 10.1056/NEJMoa060930. [DOI] [PubMed] [Google Scholar]
- 41.Sedyaningsih ER, et al. Epidemiology of cases of H5N1 virus infection in Indonesia, July 2005-June 2006. J Infect Dis. 2007;196(4):522–527. doi: 10.1086/519692. [DOI] [PubMed] [Google Scholar]
- 42.Wang H, et al. Probable limited person-to-person transmission of highly pathogenic avian influenza A (H5N1) virus in China. Lancet. 2008;371(9622):1427–1434. doi: 10.1016/S0140-6736(08)60493-6. [DOI] [PubMed] [Google Scholar]
- 43.Van Kerkhove MD, et al. Frequency and patterns of contact with domestic poultry and potential risk of H5N1 transmission to humans living in rural Cambodia. Influenza Other Respi Viruses. 2008;2(5):155–163. doi: 10.1111/j.1750-2659.2008.00052.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Aditama TY, et al. Risk factors for cluster outbreaks of avian influenza A H5N1 infection, Indonesia. Clin Infect Dis. 2011;53(12):1237–1244. doi: 10.1093/cid/cir740. [DOI] [PubMed] [Google Scholar]
- 45.Pitzer VE, et al. Little evidence for genetic susceptibility to influenza A (H5N1) from family clustering data. Emerg Infect Dis. 2007;13(7):1074–1076. doi: 10.3201/eid1307.061538. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 46.Horby P, et al. What is the evidence of a role for host genetics in susceptibility to influenza A/H5N1? Epidemiol Infect. 2010;138(11):1550–1558. doi: 10.1017/S0950268810000518. [DOI] [PubMed] [Google Scholar]
- 47.Reeves RH, et al. Genetic mapping of the Mx influenza virus resistance gene within the region of mouse chromosome 16 that is homologous to human chromosome 21. J Virol. 1988;62(11):4372–4375. doi: 10.1128/jvi.62.11.4372-4375.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48.Frese M, et al. Inhibition of bunyaviruses, phleboviruses, and hantaviruses by human MxA protein. J Virol. 1996;70(2):915–923. doi: 10.1128/jvi.70.2.915-923.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49.Dittmann J, et al. Influenza A virus strains differ in sensitivity to the antiviral action of Mx-GTPase. J Virol. 2008;82(7):3624–3631. doi: 10.1128/JVI.01753-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 50.Zimmermann P, et al. The viral nucleoprotein determines Mx sensitivity of influenza A viruses. J Virol. 2011;85(16):8133–8140. doi: 10.1128/JVI.00712-11. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51. Manz B, et al. Pandemic influenza A viruses escape from restriction by human MxA through adaptive mutations in the nucleoprotein. PLoS Pathog. 2013;9(3):e1003279. doi: 10.1371/journal.ppat.1003279. In this report the authors identified mutations in the nucleoprotein (NP) of pandemic IAV strains from 1918 and 2009 that confer MxA resistance. The exact NP mutations vary between the two strains but none-the-less cluster in the same surface-exposed cluster of amino acids, suggesting that the mechanism of MxA resistance may be similar. Introducing this cluster into the NP of the MxA-sensitive H5N1 virus resulted in MxA-resistance. The authors argue that human MxA is a barrier for cross-species transmission of avian IAV and that adaptive mutations in the viral NP should be carefully monitored.
- 52. Zuniga J, et al. Genetic variants associated with severe pneumonia in A/H1N1 influenza infection. Eur Respir J. 2012;39(3):604–610. doi: 10.1183/09031936.00020611. The authors identified four SNPs that are associated with worse IAV disease outcome. Among the SNP-containing genes, C1QBP and GCGR2A were associated with formation of immune complexes and complement activation, suggesting that the observed outcomes may result from an overly activated immune response.
- 53.Hidaka F, et al. A missense mutation of the Toll-like receptor 3 gene in a patient with influenza-associated encephalopathy. Clin Immunol. 2006;119(2):188–194. doi: 10.1016/j.clim.2006.01.005. [DOI] [PubMed] [Google Scholar]
- 54.Esposito S, et al. Toll-like receptor 3 gene polymorphisms and severity of pandemic A/H1N1/2009 influenza in otherwise healthy children. Virol J. 2012;9:270. doi: 10.1186/1743-422X-9-270. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 55.Yao D, et al. Thermal instability of compound variants of carnitine palmitoyltransferase II and impaired mitochondrial fuel utilization in influenza-associated encephalopathy. Hum Mutat. 2008;29(5):718–727. doi: 10.1002/humu.20717. [DOI] [PubMed] [Google Scholar]
- 56. Mak CM, et al. Fatal viral infection-associated encephalopathy in two Chinese boys: a genetically determined risk factor of thermolabile carnitine palmitoyltransferase II variants. J Hum Genet. 2011;56(8):617–621. doi: 10.1038/jhg.2011.63. The CPT2 variants (F352C and V368I) were found in two Chinese patients who were among individuals infected with IAV who demonstrated IAE. The authors reported that F352C has not been reported in Caucasian populations, suggesting an Asian-specific phenotype of heat-labile CPT2-associated IAE.
- 57.Kim DD, Song WC. Membrane complement regulatory proteins. Clin Immunol. 2006;118(2 – 3):127–136. doi: 10.1016/j.clim.2005.10.014. [DOI] [PubMed] [Google Scholar]
- 58.Zhou J, et al. A functional variation in CD55 increases the severity of 2009 pandemic H1N1 influenza A virus infection. J Infect Dis. 2012;206(4):495–503. doi: 10.1093/infdis/jis378. [DOI] [PubMed] [Google Scholar]
- 59.Ewulonu UK, Ravi L, Medof ME. Characterization of the decay-accelerating factor gene promoter region. Proc Natl Acad Sci U S A. 1991;88(11):4675–4679. doi: 10.1073/pnas.88.11.4675. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 60.Brass AL, et al. The IFITM proteins mediate cellular resistance to influenza A H1N1 virus, West Nile virus, and dengue virus. Cell. 2009;139(7):1243–1254. doi: 10.1016/j.cell.2009.12.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 61.Shapira SD, et al. A physical and regulatory map of host-influenza interactions reveals pathways in H1N1 infection. Cell. 2009;139(7):1255–1267. doi: 10.1016/j.cell.2009.12.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 62.Jiang D, et al. Identification of five interferon-induced cellular proteins that inhibit west nile virus and dengue virus infections. J Virol. 2010;84(16):8332–8341. doi: 10.1128/JVI.02199-09. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 63.Schoggins JW, et al. A diverse range of gene products are effectors of the type I interferon antiviral response. Nature. 2011;472(7344):481–485. doi: 10.1038/nature09907. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 64.Huang IC, et al. Distinct patterns of IFITM-mediated restriction of filoviruses, SARS coronavirus, and influenza A virus. PLoS Pathog. 2011;7(1):e1001258. doi: 10.1371/journal.ppat.1001258. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 65.Feeley EM, et al. IFITM3 inhibits influenza A virus infection by preventing cytosolic entry. PLoS Pathog. 2011;7(10):e1002337. doi: 10.1371/journal.ppat.1002337. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 66. Everitt AR, et al. IFITM3 restricts the morbidity and mortality associated with influenza. Nature. 2012;484(7395):519–523. doi: 10.1038/nature10921. This work was the first to report that IFITM3 was required for the in vivo control of IAV infection in a mouse model and that the IFITM3 SNP rs12252-C was strongly associated with worse clinical outcomes for patients infected with 2009 pandemic IAV.
- 67.Bailey CC, et al. Ifitm3 limits the severity of acute influenza in mice. PLoS Pathog. 2012;8(9):e1002909. doi: 10.1371/journal.ppat.1002909. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 68. Zhang YH, et al. Interferon-induced transmembrane protein-3 genetic variant rs12252-C is associated with severe influenza in Chinese individuals. Nat Commun. 2013;4:1418. doi: 10.1038/ncomms2433. Building on the work by Everitt et al. 2012, this effort reported that the IFITM3 rs12252 SNP is present in 69% of Han Chinese patients with severe IAV infection, as compared to only 25% of patients with less severe disease. The authors estimate that individuals homozygous for the rs12252 have a six-fold greater risk for developing severe IAV infection suggesting that screening for rs12252 homozygosity may aid in risk assessment, and that modulating IFITM3 activity may be protective and/or therapeutic.
- 69.John SP, et al. The CD225 Domain of IFITM3 is Required for both IFITM Protein Association and Inhibition of Influenza A Virus and Dengue Virus Replication. J Virol. 2013 doi: 10.1128/JVI.00481-13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 70.Gao R, et al. Human Infection with a Novel Avian-Origin Influenza A (H7N9) Virus. N Engl J Med. 2013 doi: 10.1056/NEJMoa1304459. [DOI] [PubMed] [Google Scholar]
- 71.Li Q, et al. Preliminary Report: Epidemiology of the Avian Influenza A (H7N9) Outbreak in China. N Engl J Med. 2013 [Google Scholar]