Keratins provide virus-dependent protection or predisposition to injury in coxsackievirus-induced pancreatitis

DM Toivola¹, SE Ostrowski², H Baribault³, TM Magin⁴, AI Ramsingh², MB Omary⁵

¹Åbo Akademi University, Dept. Biology, BioCity, Turku, Finland and Stanford University School of Medicine and Digestive Disease Center; ²New York State Department of Health, Albany, NY, USA; ³Amgen, South San Francisco, CA, USA; ⁴University of Bonn, Bonn, Germany; ⁵Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Mi, USA

Abstract: Keratins 8 and 18 (K8/K18) are the two major intermediate filament proteins in hepatocytes and pancreatic acinar cells. Acinar cell keratins are organized as cytoplasmic and apicolateral filaments. An important role of hepatocyte K8/K18 is to maintain cellular integrity, while this cytoprotective function of K8/K18 is not evident in the pancreas since keratin-deficient mice cope well with pancreatitis models. To further study the roles of keratins in the exocrine pancreas, we used coxsackievirus B4-models, CVB4-V and CVB4-P, to induce severe acute/chronic pancreatitis and acute pancreatitis, respectively, in K8-null (which lack acinar keratins) and K18-null (which lack cytoplasmic keratins) mice. Despite similar virus titers in all mice, CVB4-V resulted in 40% mortality of the K8-null mice 14 days post-infection compared to no lethality of WT and K18-null mice. In contrast, K8-null mice were far less susceptible to CVB4-P-induced damage as determined by histology and serology analysis, and they recover faster than WT and K18-null mice. After CVB4 virus infection, keratins aggregated during acinar degranulation, and K8/K18 site-specific phosphorylation was observed during degranulation and recovery. Hence, keratins significantly affect CVB4 virulence, positively or negatively, depending on the virus subtype and keratin makeup, in a virus replication-independent manner.

Keywords: keratin, pancreatitis, coxsackievirus