EFFECT OF IN-VIVO INHIBITION OF NITRIC-OXIDE PRODUCTION IN MURINE LEISHMANIASIS

In vitro experiments suggest that cytokine induced nitric oxide (NO) s ynthesis from L-arginine is a major effector mechanism against prokary otic and eukaryotic intracellular pathogens. N(omega) monomethyl L-arg inine (MLA), an active site inhibitor of the cytokine induced NO synth ase, inhibits cytokine induced resistance of mammalian cells to intrac ellular microbes in vitro. In our experiments, we show that Leishmania infection markedly increases NO synthesis in the genetically resistan t C3H/HeN mouse strain. In addition, administration of 50 mM MLA in th e drinking water inhibits endogenous NO synthesis as well as natural r esistance to footpad Leishmania infections in both susceptible BALB/c and resistant C3H/HeN mice. Leishmania parasites continued to prolifer ate in MLA-treated C3H/HeN mice after footpad inoculation. Similarly C 3H/HeN mice treated for 3 wk with MLA had an increased parasite load a nd sloughing of the footpad. Footpad size of C3H/HeN mice not treated with MLA returned to base-line diameter and the regional nodes contain ed few amastigotes. These in vivo effects were paralleled by endogenou s NO synthesis (high when Leishmania was controlled and low when Leish mania was not controlled). In addition, inhibition of NO synthesis in Leishmania-infected mice leads to a cachectic state not caused by infe ction alone or inhibition of NO synthesis alone. The cachexia appeared to be due to decreased food intake that occurs when NO synthesis is i nhibited in Leishmania-infected mice. Our results show that cytokine i nduced NO has a major effect or role in resistance of murine hosts to Leishmania infection.