Age-dependent roles of cardiac remodeling in sepsis defense and pathogenesis

Karina K Sanchez; Justin L McCarville; Sarah J Stengel; Jessica M Snyder; April E Williams; Janelle S Ayres

doi:10.1101/2023.03.14.532695

Age-dependent roles of cardiac remodeling in sepsis defense and pathogenesis

bioRxiv [Preprint]. 2023 Mar 15:2023.03.14.532695. doi: 10.1101/2023.03.14.532695.

Authors

Karina K Sanchez^{1

2

3}, Justin L McCarville^{1

2

3}, Sarah J Stengel^{1

2

3}, Jessica M Snyder⁴, April E Williams⁵, Janelle S Ayres^{1

2

3}

Affiliations

¹ Molecular and Systems Physiology Lab, University of Washington, Seattle WA.
² Gene Expression Lab, University of Washington, Seattle WA.
³ Nomis Center for Immunobiology and Microbial Pathogenesis, University of Washington, Seattle WA.
⁴ Department of Comparative Medicine, School of Medicine, University of Washington, Seattle WA.
⁵ The Razavi Newman Integrative Genomics and Bioinformatics Core Facility Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, CA 92037, USA.

Abstract

Disease tolerance is a defense strategy essential for survival of infections, limiting physiological damage without killing the pathogen. The disease course and pathology a pathogen may cause can change over the lifespan of a host due to the structural and functional physiological changes that accumulate with age. Since successful disease tolerance responses require the host to engage mechanisms that are compatible with the disease course and pathology caused by an infection, we predicted that this defense strategy would change with age. Animals infected with a lethal dose 50 (LD₅₀) of a pathogen often display distinct health and sickness trajectories due to differences in disease tolerance, and thus can be used to delineate tolerance mechanisms. Using a polymicrobial sepsis model, we found that despite having the same LD₅₀, old and young susceptible mice exhibited distinct disease courses. Young survivors employed a cardioprotective mechanism via FoxO1-mediated regulation of the ubiquitin-proteosome system that was necessary for survival and protection from cardiomegaly. This same mechanism was a driver of sepsis pathogenesis in aged hosts, causing catabolic remodeling of the heart and death. Our findings have implications for the tailoring of therapy to the age of an infected individual and suggest that disease tolerance alleles may exhibit antagonistic pleiotropy.

Publication types

Preprint