Plasminogen alleles influence susceptibility to invasive aspergillosis

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.     

The effect of aging on OX40 agonist-mediated cancer immunotherapy

Agents that enhance T cell co-stimulatory signaling have emerged as promising cancer immunotherapies. Our laboratory has been evaluating the TNF receptor co-stimulatory molecule, OX40, which has the capacity to augment critical aspects of T cell function and induce tumor regression in animal models. Effective stimulation of OX40 expressing T cells was accomplished with agonist antibodies to OX40 that were eventually translated into a clinical trial for cancer patients. A recent attempt to assess the affect of immune senescence on OX40 therapy, revealed a dramatic loss of efficacy of the agonist therapy in older tumor-bearing mice. The deficiency in OX40-enhanced anti-tumor responses in older mice correlated with a decrease in the number of differentiated effector T cells. Further investigation suggests that the underlying age-related decline in the agonist OX40-mediated T cell responses was not inherent to the T cells themselves, but related to the host environment. Thus, effective use of immunotherapies based on T cell co-stimulatory molecules may require additional modifications, such as immune stimulants to increase innate immunity, to address age-related defects that reside outside of the T cell and within the host environment.     

A Computational Model of Aging and Calcification in the Aortic Heart Valve

The aortic heart valve undergoes geometric and mechanical changes over time. The cusps of a normal, healthy valve thicken and become less extensible over time. In the disease calcific aortic stenosis (CAS), calcified nodules progressively stiffen the cusps. The local mechanical changes in the cusps, due to either normal aging or pathological processes, affect overall function of the valve. In this paper, we propose a computational model for the aging aortic valve that connects local changes to overall valve function. We extend a previous model for the healthy valve to describe aging. To model normal/uncomplicated aging, leaflet thickness and extensibility are varied versus age according to experimental data. To model calcification, initial sites are defined and a simple growth law is assumed. The nodules then grow over time, so that the area of calcification increases from one model to the next model representing greater age. Overall valve function is recorded for each individual model to yield a single simulation of valve function over time. This simulation is the first theoretical tool to describe the temporal behavior of aortic valve calcification. The ability to better understand and predict disease progression will aid in design and timing of patient treatments for CAS.