Plasminogen Alleles Influence Susceptibility to Invasive Aspergillosis

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Abstract
Invasive aspergillosis (IA) is a common and life-threatening infection in immunocompromised individuals. A number of environmental and epidemiologic risk factors for developing IA have been identified. However, genetic factors that affect risk for developing IA have not been clearly identified. We report that host genetic differences influence outcome following establishment of pulmonary aspergillosis in an exogenously immune suppressed mouse model. Computational haplotype-based genetic analysis indicated that genetic variation within the biologically plausible positional candidate gene plasminogen (Plg; Gene ID 18855) correlated with murine outcome. There was a single nonsynonymous coding change (Gly110Ser) where the minor allele was found in all of the susceptible strains, but not in the resistant strains. A nonsynonymous single nucleotide polymorphism (Asp472Asn) was also identified in the human homolog (PLG; Gene ID 5340). An association study within a cohort of 236 allogeneic hematopoietic stem cell transplant (HSCT) recipients revealed that alleles at this SNP significantly affected the risk of developing IA after HSCT. Furthermore, we demonstrated that plasminogen directly binds to Aspergillus fumigatus. We propose that genetic variation within the plasminogen pathway influences the pathogenesis of this invasive fungal infection. Invasive aspergillosis (IA) is the most common invasive mould infection among highly immune compromised hosts. While exogenous immune suppression is the greatest risk factor for infection acquisition, polymorphic variation in key immune effector genes likely contributes to disease susceptibility as well. We hypothesized that susceptibility to invasive aspergillosis was, in part, due to host genetic variation. By screening strains of inbred mice, we demonstrated differential susceptibility to invasive aspergillosis. Using the Roche Mouse single nucleotide polymorphism (SNP) Database, we localized an area on murine chromosome 17 as a putative “quantitative trait locus” governing disease susceptibility. Within this interval, the gene encoding plasminogen (Plg) was found to have a coding change SNP in murine strains that were highly susceptible to disease. Many micro-organisms are recognized to hijack the plasminogen to be more prevalent in human hematopoietic stem cell transplant recipients who developed IA as compared to those who did not. Thus, we demonstrated a genetic basis for increased susceptibility to IA in both a murine model and human cohort, and implicated the fibrinolytic system in the pathogenesis of this disease.