Caspase-mediated cleavage of murine norovirus NS1/2 potentiates apoptosis and is required for persistent infection of intestinal epithelial cells

Bridget A. Robinson, Jacob A. Van Winkle, Broc T. McCune, A. Mack Peters, Timothy Nice

Research output: Contribution to journalArticle

Abstract

Human norovirus (HNoV) is the leading cause of acute gastroenteritis and is spread by fecal shedding that can often persist for weeks to months after the resolution of symptoms. Elimination of persistent viral reservoirs has the potential to prevent outbreaks. Similar to HNoV, murine norovirus (MNV) is spread by persistent shedding in the feces and provides a tractable model to study molecular mechanisms of enteric persistence. Previous studies have identified non-structural protein 1 (NS1) from the persistent MNV strain CR6 as critical for persistent infection in intestinal epithelial cells (IECs), but its mechanism of action remains unclear. We now find that the function of CR6 NS1 is regulated by apoptotic caspase cleavage. Following induction of apoptosis in infected cells, caspases cleave the precursor NS1/2 protein, and this cleavage is prevented by mutation of caspase target motifs. These mutations profoundly compromise CR6 infection of IECs and persistence in the intestine. Conversely, NS1/2 cleavage is not strictly required for acute replication in extra-intestinal tissues or in cultured myeloid cells, suggesting an IEC-centric role. Intriguingly, we find that caspase cleavage of CR6 NS1/2 reciprocally promotes caspase activity, potentiates cell death, and amplifies spread among cultured IEC monolayers. Together, these data indicate that the function of CR6 NS1 is regulated by apoptotic caspases, and suggest that apoptotic cell death enables epithelial spread and persistent shedding.

Original languageEnglish (US)
Article numbere1007940
JournalPLoS pathogens
Volume15
Issue number7
DOIs
StatePublished - Jul 1 2019

Fingerprint

Norovirus
Caspases
Epithelial Cells
Apoptosis
Infection
Proteins
Cell Death
Mutation
Gastroenteritis
Myeloid Cells
Feces
Intestines
Disease Outbreaks
Cultured Cells

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

Caspase-mediated cleavage of murine norovirus NS1/2 potentiates apoptosis and is required for persistent infection of intestinal epithelial cells. / Robinson, Bridget A.; Van Winkle, Jacob A.; McCune, Broc T.; Peters, A. Mack; Nice, Timothy.

In: PLoS pathogens, Vol. 15, No. 7, e1007940, 01.07.2019.

Research output: Contribution to journalArticle

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