No abstract

The role of nitric oxide (NO) in the genesis of cerebral malaria is controversial. Most investigators propose that the unfortunate consequence of the high concentrations of NO produced to kill the parasite is the development of cerebral malaria. Here we have tested this high NO bioavailability hypothesis in the setting of experimental cerebral malaria (ECM), but find instead that low NO bioavailability contributes to the genesis of ECM. Specifically, mice deficient in vascular NO synthase showed parasitemia and mortality similar to that observed in control mice. Exogenous NO did not affect parasitemia but provided marked protection against ECM; in fact, mice treated with exogenous NO were clinically indistinguishable from uninfected mice at a stage when control infected mice were moribund. Administration of exogenous NO restored NO-mediated signaling in the brain, decreased proinflammatory biomarkers in the blood, and markedly reduced vascular leak and petechial hemorrhage into the brain. Low NO bioavailability in the vasculature during ECM was caused in part by an increase in NO-scavenging free hemoglobin in the blood, by hypoargininemia, and by low blood and erythrocyte nitrite concentrations. Exogenous NO inactivated NO-scavenging free hemoglobin in the plasma and restored nitrite to concentrations observed in uninfected mice. We therefore conclude that low rather than high NO bioavailability contributes to the genesis of ECM.

No abstract

The Plasmodium berghei-infected mouse model is a well-recognized model for human cerebral malaria. Mice infected with P. berghei exhibit (i) metabolic acidosis (pH < 7.3) associated with elevated plasma lactate concentrations, (ii) significant (P < 0.05) vascular leakage in their lungs, hearts, kidneys, and brains, (ii) significantly (P < 0.05) higher cell and serum glutamate concentrations, and (iv) significantly (P < 0.05) lower mean arterial blood pressures. Because these complications are similar to those of septic shock, the simplest interpretation of these findings is that the mice develop shock brought on by the P. berghei infection. To determine whether the immune system and specifically CD8 ؉ T cells mediate the key features of shock during P. berghei malaria, we depleted CD8 ؉ T cells by monoclonal antibody (mAb) treatment and assessed the complications of malarial shock. P. berghei-infected mice depleted of CD8 ؉ T cells by mAb treatment had significantly reduced vascular leakage in their hearts, brains, lungs, and kidneys compared with infected controls treated with rat immunoglobulin G. CD8-depleted mice were significantly (P < 0.05) protected from lactic acidosis, glutamate buildup, and diminished HCO 3 ؊ levels. Although the blood pressure decreased in anti-CD8 mAb-treated mice infected with P. berghei, the cardiac output, as assessed by echocardiography, was similar to that of uninfected control mice. Collectively, our results indicate that (i) pathogenesis similar to septic shock occurs during experimental P. berghei malaria, (ii) respiratory distress with lactic acidosis occurs during P. berghei malaria, and (iii) most components of circulatory shock are ameliorated by depletion of CD8 ؉