Protection from Lethal Coxsackievirus-Induced Pancreatitis by Expression of Gamma Interferon

Abstract

Coxsackievirus infection causes severe pancreatitis and myocarditis in humans, often leading to death in young or immunocompromised individuals. In susceptible strains of mice, coxsackievirus strain CB4 causes lethal hypoglycemia. To investigate the potential of gamma interferon (IFN-γ) in protection and clearance of the viral infection, IFN-γ knockout mice and transgenic (Tg) mice specifically expressing IFN-γ in their pancreatic β cells were infected with CB4. Lack of IFN-γ in mice normally resistant to CB4-mediated disease resulted in hypoglycemia and rapid death. However, expression of IFN-γ in the β cells of Tg mice otherwise susceptible to lethal infection allowed for survival and protected them from developing the accompanying hypoglycemia. While all the mice had high levels of viral replication in their pancreata and comparable tissue pathology following viral infection, the Tg mice had significantly lower levels of virus at the peak of infection, significantly higher numbers of activated macrophages before and after infection, and less damage to their acinar tissue. Additionally, despite having increased levels of inducible nitric oxide synthetase (iNOS) expression, treatment of Tg mice with the iNOS inhibitor aminoguanidine did not alter the level of protection afforded by IFN-γ expression. In conclusion, IFN-γ protects from lethal coxsackievirus infection by activating macrophages in an iNOS-independent manner.

Enhanced Antiviral Activity against Foot-and-Mouth Disease Virus by a Combination of Type I and II Porcine Interferons

“…Other studies have demonstrated that IFN-␥ has antiviral activity against another member of the picornavirus family, i.e., coxsackievirus (36,37,39), and that there is a correlation with the IFN-␥-induced protection and induction of iNOS (37). Our results indicate that iNOS mRNA is only minimally induced in treated cells compared to the induction of INDO and IP-10 mRNAs and not induced in swine treated with type I or II IFNs.…”

IFN-γ production dominates the early human natural killer cell response to Coxsackievirus infection

“…Interferon (IFN)‐γ has well‐documented antiviral effects (Guidotti and Chisari, 2001; Chesler and Reiss, 2002; Flodstrom et al ., 2002; Schroder et al ., 2004; Flodstrom‐Tullberg et al ., 2005) and has been shown to protect mice from CVB‐induced myocardits and pancreatitis (Horwitz et al ., 1999; 2000; Eriksson et al ., 2001). In addition, NK and NKT cell‐derived IFN‐γ protects mice from chronic pancreatitis (Potvin et al ., 2003).…”

Presented antigen from damaged pancreatic β cells activates autoreactive T cells in virus-mediated autoimmune diabetes

“…CB4 was originally isolated from patients with IDDM, passaged through murine pancreatic β cells, and subsequently found to induce a diabetes-like disease in mice (3,4). Virus stocks of CB4 strain E2 were prepared and titered as previously described (18). Mice were infected at 12 weeks of age intraperitoneally with 100 plaqueforming units (pfu) of CB4.…”