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

2019 ◽  
Vol 15 (7) ◽  
pp. e1007940 ◽  
Author(s):  
Bridget A. Robinson ◽  
Jacob A. Van Winkle ◽  
Broc T. McCune ◽  
A. Mack Peters ◽  
Timothy J. Nice
Keyword(s):  
Epithelial Cells ◽  
Persistent Infection ◽  
Intestinal Epithelial Cells ◽  
Intestinal Epithelial ◽  
Murine Norovirus

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

2018 ◽  
Author(s):  
Bridget A. Robinson ◽  
Jacob A. Van Winkle ◽  
Broc T McCune ◽  
A. Mack Peters ◽  
Timothy J. Nice
Keyword(s):  
Cell Death ◽  
Epithelial Cells ◽  
Persistent Infection ◽  
Acute Gastroenteritis ◽  
Intestinal Epithelial Cells ◽  
Intestinal Epithelial ◽  
Murine Norovirus ◽  
Structural Protein ◽  
Human Norovirus ◽  
Caspase Cleavage

AbstractHuman 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 required for acute replication in extra-intestinal tissues or in cultured myeloid cells, indicating an IEC-specific role. Intriguingly, we find that caspase cleavage of 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.Author SummaryHuman Norovirus infection is highly contagious and the most common cause of acute gastroenteritis. Norovirus can be persistently shed after resolution of symptoms, perpetuating or initiating new outbreaks. Murine norovirus (MNV) is also persistently shed, enabling study of host and viral determinants of norovirus pathogenesis. We previously identified a critical role for MNV non-structural protein 1 (NS1), in persistence. Herein we find that regulation of NS1 by host apoptotic caspases is required for infection of intestinal epithelial cells, but not for extra-intestinal spread. Additionally, we demonstrate that NS1 reciprocally promotes cell death and spread among epithelial cells. These data identify regulation of NS1 by host proteases and suggest that apoptotic death is a determinant of epithelial spread and persistence.

scholarly journals Expression of Ifnlr1 on Intestinal Epithelial Cells Is Critical to the Antiviral Effects of Interferon Lambda against Norovirus and Reovirus

2017 ◽  
Vol 91 (7) ◽  
Author(s):  
Megan T. Baldridge ◽  
Sanghyun Lee ◽  
Judy J. Brown ◽  
Nicole McAllister ◽  
Kelly Urbanek ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Antiviral Activity ◽  
Viral Infections ◽  
Intestinal Epithelial Cells ◽  
Intestinal Epithelial ◽  
Murine Norovirus ◽  
Intestinal Tissue ◽  
Viral Pathogens ◽  
Fecal Shedding ◽  
Antiviral Effects

ABSTRACT Lambda interferon (IFN-λ) has potent antiviral effects against multiple enteric viral pathogens, including norovirus and rotavirus, in both preventing and curing infection. Because the intestine includes a diverse array of cell types, however, the cell(s) upon which IFN-λ acts to exert its antiviral effects is unclear. Here, we sought to identify IFN-λ-responsive cells by generation of mice with lineage-specific deletion of the receptor for IFN-λ, Ifnlr1. We found that expression of IFNLR1 on intestinal epithelial cells (IECs) in the small intestine and colon is required for enteric IFN-λ antiviral activity. IEC Ifnlr1 expression also determines the efficacy of IFN-λ in resolving persistent murine norovirus (MNoV) infection and regulates fecal shedding and viral titers in tissue. Thus, the expression of Ifnlr1 by IECs is necessary for the response to both endogenous and exogenous IFN-λ. We further demonstrate that IEC Ifnlr1 expression is required for the sterilizing innate immune effects of IFN-λ by extending these findings in Rag1-deficient mice. Finally, we assessed whether our findings pertained to multiple viral pathogens by infecting mice specifically lacking IEC Ifnlr1 expression with reovirus. These mice phenocopied Ifnlr1-null animals, exhibiting increased intestinal tissue titers and enhanced reovirus fecal shedding. Thus, IECs are the critical cell type responding to IFN-λ to control multiple enteric viruses. This is the first genetic evidence that supports an essential role for IECs in IFN-λ-mediated control of enteric viral infection, and these findings provide insight into the mechanism of IFN-λ-mediated antiviral activity. IMPORTANCE Human noroviruses (HNoVs) are the leading cause of epidemic gastroenteritis worldwide. Type III interferons (IFN-λ) control enteric viral infections in the gut and have been shown to cure mouse norovirus, a small-animal model for HNoVs. Using a genetic approach with conditional knockout mice, we identified IECs as the dominant IFN-λ-responsive cells in control of enteric virus infection in vivo. Upon murine norovirus or reovirus infection, Ifnlr1 depletion in IECs largely recapitulated the phenotype seen in Ifnlr1 −/− mice of higher intestinal tissue viral titers and increased viral shedding in the stool. Moreover, IFN-λ-mediated sterilizing immunity against murine norovirus requires the capacity of IECs to respond to IFN-λ. These findings clarify the mechanism of action of this cytokine and emphasize the therapeutic potential of IFN-λ for treating mucosal viral infections.

Three-dimensional organization and functional relationships of endocytotic compartments in pig intestinal epithelial cells

1992 ◽  
Vol 50 (1) ◽  
pp. 576-577
Author(s):  
Julian P. Heath ◽  
Buford L. Nichols ◽  
László G. Kömüves
Keyword(s):  
Electron Microscopy ◽  
Epithelial Cells ◽  
Intestinal Epithelial Cells ◽  
Three Dimensional ◽  
Intestinal Epithelial ◽  
Cell Surfaces ◽  
Basal Surface ◽  
Functional Relationships

The newborn pig intestine is adapted for the rapid and efficient absorption of nutrients from colostrum. In enterocytes, colostral proteins are taken up into an apical endocytotic complex of channels that transports them to target organelles or to the basal surface for release into the circulation. The apical endocytotic complex of tubules and vesicles clearly is a major intersection in the routes taken by vesicles trafficking to and from the Golgi, lysosomes, and the apical and basolateral cell surfaces.Jejunal tissues were taken from piglets suckled for up to 6 hours and prepared for electron microscopy and immunocytochemistry as previously described.

Thrombin enhances migration of intestinal epithelial cells

2001 ◽  
Vol 120 (5) ◽  
pp. A504-A504
Author(s):  
A NEUMANN ◽  
M DEPKAPRONDZINSKI ◽  
C WILHELM ◽  
K FELGENHAUER ◽  
T CASPRITZ ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Intestinal Epithelial Cells ◽  
Intestinal Epithelial
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