Abstract
Human angiotensin-II receptor type-I (hAT1R) over-expression may cause adverse pathological outcomes due to renin-angiotensin system overactivity. We have shown that transgenic (TG) mice containing Hap-I (hypertensive genotype) of hAT1R gene are more prone to develop metabolic syndrome (MetS) disorders as compared to the TG mice with Hap-II (normotensive genotype). Aging together with an increased risk of hypertension, can affect multiple organ systems, including increased susceptibility to various pathogenic infections. The current study, therefore, was designed to examine the potential role of aging and hypertension on lung pathology and altered transcriptome, in our TG mice, in response to
Francisella tularensis
live vaccine strain (LVS) intranasal infection. Our results showed that in comparison to Hap-II, aged Hap-I TG mice had a significantly higher mortality post-infection; elevated lung pathology; and altered gene expression profile. Consistent with worsened phenotype in aged Hap-I mice post LVS infection, RNA-seq data from their lungs revealed that >1400 genes (p <0.005) were significantly altered. Bioinformatics analysis identified major alterations in canonical pathways related to immune responses including interferon signaling, antigen presentation, agranulocyte adhesion and dendritic cell maturation. These alterations in turn resulted in disorders including, lung infection, inflammation, and immunological diseases. Importantly, IFNG, STAT1, STAT3 and TNF were among the top upstream regulators significantly affected by LVS infection. Overall, these results provide a deeper insight in molecular signaling associated with hypertension associated lung infections in aged subjects.