Protection from lethal coxsackievirus-induced pancreatitis by expression of gamma interferon

Coxsackievirus infection causes severe pancreatitis and myocarditis in huma ns, often leading to death in young or immunocompromised individuals. In su sceptible strains of mice, coxsackievirus strain CB4 causes lethal hypoglyc emia. To investigate the potential of gamma interferon (IFN-gamma) in prote ction and clearance of the viral infection, IFN-gamma knockout mice and tra nsgenic (Tg) mice specifically expressing IFN-gamma in their pancreatic bet a cells were infected with CB4, Lack of IFN-gamma in mice normally resistan t to CB4-mediated disease resulted in hypoglycemia and rapid death. However , expression of IFN-gamma in the beta cells of Tg mice otherwise susceptibl e to lethal infection allowed for survival and protected them from developi ng the accompanying hypoglycemia, While all the mice had high levels of vir al replication in their pancreata and comparable tissue pathology following viral infection, the Tg mice had significantly lower levels of virus at th e peak of infection, significantly higher numbers of activated macrophages before and after infection, and less damage to their acinar tissue. Additio nally, despite having increased levels of inducible nitric oxide synthetase (iNOS) expression, treatment of Tg mice with the iNOS inhibitor aminoguani dine did not alter the level of protection afforded by IFN-gamma expression . In conclusion, IFN-gamma protects from lethal coxsackievirus infection by activating macrophages in an iNOS-independent manner.