<b><i>Unc93b1</i></b>-Dependent Endosomal Toll-Like Receptor Signaling Regulates Inflammation and Mortality during Coxsackievirus B3 Infection

Abstract

Coxsackievirus strain B serotype 3 (CVB3)-inducedmyocarditis is an important human disease that causes permanent tissue damage and can lead to death from acute infection or long-term morbidity caused by chronic inflammation. The timing and magnitude of immune activation following CVB3 infection can mediate a positive host outcome or increase tissue pathology. To better elucidate the role of endosomal Toll-like receptor (TLR) signaling in acute CVB3 infection, we studied mice with a loss-of-function mutation, known as Letr for ‘loss of endosomal TLR response', in Unc93b1, which is a chaperone protein for TLR3, TLR7 and TLR9. Using Unc93b1^Letr/^Letr mice, we determined that Unc93b1-dependent TLR activation was essential for the survival of acute CVB3-induced myocarditis. We also determined that a lack of endosomal TLR signaling was associated with a higher viral load in target organs and that it increased inflammation, necrosis and fibrosis in cardiac tissue. Loss of Unc93b1 function was also associated with increased cardiac expression of Ifn-b and markers of tissue injury and fibrosis including Lcn2 and Serpina3n early after CVB3 infection. These observations establish a significant role for Unc93b1 in the regulation of the host inflammatory response to CVB3 infection and also reveal potential mediators of host tissue damage that merit further investigation in acute viral myocarditis.

Inhibition of SERPINA3N‐dependent neuroinflammation is essential for melatonin to ameliorate trimethyltin chloride–induced neurotoxicity

“…In various neurological diseases, the expression of SERPINA3N in the brain has been found to be significantly upregulated . Recent studies have also shown that SERPINA3N is clearly related to many inflammation‐related diseases, such as hypothalamic inflammation, retinal neuroinflammation, allergic airway inflammation, myocarditis, and atherosclerosis . Strikingly, the underlying mechanisms of SERPINA3N‐mediated inflammation have still not been clarified.…”

Unc93b Induces Apoptotic Cell Death and Is Cleaved by Host and Enteroviral Proteases

“…Taken together, these data suggest that TLR3 senses the dsRNA intermediate produced during CVB replication, and that this sensing and subsequent activation of innate immune signaling is key to the control of CVB infection. Indeed, recent work has shown that Unc93b1 LETR/LETR mice, which have a loss of function mutation in the gene encoding Unc93b, exhibit increased mortality upon CVB-induced myocarditis due to higher viral titers and dysregulation of inflammation in these mice [ 20 ].…”

“…Interestingly, analysis of microarray data [ 20 ] using DAVID [ 26 , 27 ] from cardiac tissue of wild-type mice versus Unc93b1 LETR/LETR mice found that there was a significant enrichment in the expression of genes involved in cell death pathways in CVB-infected wild-type animals (p = 0.0051), suggesting that Unc93b might play a role in cell death signaling during CVB infection. In addition, given that Unc93b has been directly linked to CVB-induced pathogenesis in vivo , we examined whether Unc93b was involved in cell death signaling during infection.…”

A Protective Role for Interleukin-1 Signaling during Mouse Adenovirus Type 1-Induced Encephalitis

“…UNC93B is a transmembrane protein localized to the ER that is required for this trafficking (40,41). Mice with a nonfunctional UNC93B fail to respond to TLR3, TLR7, or TLR9 ligands, and mice and humans deficient in UNC93B are highly susceptible to viral infection (42)(43)(44).…”