Influenza A virus (IAV) is a significant threat to human health, affecting ~15% of the world's population annually. Most people who develop IAV recover in less than 2 weeks. However, a number of infected patients become critically ill and require intensive care. A subset of these patients exhibit severe progressive respiratory failure, often associated with multi-organ failure, and/or marked worsening of underlying airways disease and death. Epidemiological studies on IAV-associated deaths in Utah over the past 100 years provide strong evidence of host genetics as a risk factor. In vivo genetic studies using classical inbred strains of laboratory mice have contributed to our understanding of IAV pathogenesis and disease severity. However, as a consequence of undergoing extensive selection and domestication before and during inbreeding, classical inbred laboratory strains have a serious genetic limitation compared to human populations; they do not exhibit the same degree of genetic variation. The limited genetic diversity which distinguishes classical inbred laboratory strains used to study the genetics of IAV in vivo can be overcome by incorporating into the experimental design inbred wild-derived strains whose genetic diversity more accurately reflects the greater evolutionarily selected genetic diversity seen in humans. With respect to IAV, this is exemplified by the identification of functional Mx1 alleles segregating among inbred wild-derived stains that are quantitatively distinct, and exhibit background dependent epistasis. Taken together, this suggests that inbred wild-derived strains such as PWD and CAST (PWD; M. mus musculus and CAST; M. mus castaneus were separated ~0.8 Myr ago from each other, and from M. mus domesticus, the ancestry from which most classical inbred laboratory strains derived) may possess unique IAV-quantitative trait loci (IAV-QTL) that contribute to disease susceptibility and resistance as a function of either direct viral cytopathicity and/or immunopathologic damage. To test this hypothesis we will pursue two specific aims.
In Specific Aim 1 we will perform genome-wide physical mapping using B6-ChrPWD and B6-ChrCAST consomic and conplastic strains of mice, which cover all 19 autosomes, X and Y chromosomes, and mitochondrial genome, to identify novel IAV-QTL underling susceptibility and/or resistance to IAV.
In Specific Aim 2 we will determine the relative contribution that PWD and CAST IAV-QTL play in survival as a function of direct viral cytopathicity vs. immunopathologic damage.
Influenza A virus (IAV) affects ~15% world's population annually, resulting in large numbers of deaths with repeated pandemics occurring each century. The prevalence and fatality rates associated with IAV are believed to be determined primarily by viral virulence and acquired protective immunity. Most people who get IAV recover in less than 2 weeks. However, a number of infected patients become critically ill and require intensive care. A subset of patients rapidly develop severe progressive respiratory failure that is often associated with multi-organ failure and/or marked worsening of underlying airways disease and death. Epidemiological studies on IAV-associated deaths in Utah over the past 100 years provide strong evidence for host genetics as a risk factor. In vivo genetic studies using classical inbred strains of laboratory mice have contributed to our understanding of the genetics of IAV pathogenesis. However, the limited genetic diversity which distinguishes the classical inbred laboratory strains used in these studies is a limiting factor in understanding the genetic architecture of human disease since it does not reflect the greater genetic diversity seen within the human population. The relative lack of genetic diversity among classical inbred laboratory strains can, however, be overcome by incorporating into the experimental design wild-derived inbred strains whose genetic diversity more accurately reflects the greater evolutionarily selected genetic diversity seen in humans. In this application, we will take advantage of this greater genetic diversity to physically map within the genomes of inbred wild-derived PWD and CAST mice novel genes that influence susceptibility to IAV.
| Spear, E T; Holt, E A; Joyce, E J et al. (2018) Altered gastrointestinal motility involving autoantibodies in the experimental autoimmune encephalomyelitis model of multiple sclerosis. Neurogastroenterol Motil 30:e13349 |
| Paquette, Jackie K; Ma, Ying; Fisher, Colleen et al. (2017) Genetic Control of Lyme Arthritis by Borrelia burgdorferi Arthritis-Associated Locus 1 Is Dependent on Localized Differential Production of IFN-? and Requires Upregulation of Myostatin. J Immunol 199:3525-3534 |
