DEVELOPMENTAL DIFFERENCES DETERMINE LARVAL SUSCEPTIBILITY TO NITRIC OXIDE-MEDIATED KILLING IN A MURINE MODEL OF VACCINATION AGAINST SCHISTOSOMA-MANSONI

A persistent paradox in our understanding of protective immunity again st Schistosoma mansoni infection in animals vaccinated with attenuated parasites has been that attrition of challenge parasites occurs durin g migration through the lungs in vivo, although parasites recovered fr om the lungs appear to be relatively resistant to cytotoxic effector m echanisms in vitro. We have compared the susceptibilities of different stages of larvae to killing by nitric oxide (NO), which was previousl y shown to be involved in the larvicidal function of cytokine-activate d cytotoxic effector cells, Lung-stage larvae obtained 1 week after in fection were not killed in vitro by NO generated either by a chemical NO donor or by activated cells, In contrast, parasites obtained from t he portal system of control mice or from the lungs of vaccinated mice 2.5 weeks following challenge infection were killed by NO. As previous ly shown for mammalian cell targets, the effects of NO in susceptible larval stages may involve enzymes required for aerobic energy metaboli sm, since similar cytotoxicity was demonstrated by chemical inhibitors of the citric acid cycle or mitochondrial respiration, Taken together with previous observations of enhanced Th1 activity and expression of NO synthase in the lungs of vaccinated mice at 2.5 weeks after challe nge infection, these observations elucidate the immune mechanism of va ccine-induced resistance to S, mansoni infection, Moreover, they sugge st that conversion to a less metabolically active state may allow path ogens to escape the effects of the important effector molecule NO.