title: Unc93b1 -Dependent Endosomal Toll-Like Receptor Signaling Regulates Inflammation and Mortality during Coxsackievirus B3 Infection.
abstract: Coxsackievirus strain B serotype 3 (CVB3)-induced myocarditis 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.
authors: Meakins-Christie Laboratories, McGill University, Montréal, Qué., Canada.
authors: Erin I
authors: EI
authors: Lafferty
authors: Sean A
authors: SA
authors: Wiltshire
authors: Isabelle
authors: I
authors: Angers
authors: Silvia M
authors: SM
authors: Vidal
authors: Salman T
authors: ST
authors: Qureshi
mesh_terms: D000209:Acute-Phase Proteins / Q000276:immunology; D000818:Animals; D003384:Coxsackievirus Infections / Q000276:immunology* / Q000473:pathology; D011992:Endosomes / Q000276:immunology* / Q000473:pathology; D029822:Enterovirus B, Human / Q000276:immunology*; D006367:HeLa Cells; D006801:Humans; D016899:Interferon-beta / Q000276:immunology; D000071068:Lipocalin-2; D054834:Lipocalins / Q000276:immunology; D026901:Membrane Transport Proteins / Q000276:immunology*; D051379:Mice; D009205:Myocarditis / Q000276:immunology* / Q000473:pathology; D015513:Oncogene Proteins / Q000276:immunology; D015843:Serpins / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D051193:Toll-Like Receptors / Q000276:immunology*
chemical_list: D000209:Acute-Phase Proteins; D000071068:Lipocalin-2; D054834:Lipocalins; D026901:Membrane Transport Proteins; D015513:Oncogene Proteins; C516624:Serpina3n protein, mouse; D015843:Serpins; D051193:Toll-Like Receptors; C512254:UNC93B1 protein, mouse; C071332:Lcn2 protein, mouse; D016899:Interferon-beta