Deletion of carboxypeptidase N delays onset of experimental cerebral malaria.

Complement contributes to inflammation during pathogen infections; however, less is known regarding its role during malaria and in the severest form of the disease, cerebral malaria. Recent studies have shown that deletion of the complement anaphylatoxins receptors, C3aR and C5aR, does not alter disease susceptibility in experimental cerebral malaria (ECM). This does not, however, preclude C3a- and C5a-mediated contributions to inflammation in ECM and raises the possibility that carboxypeptidase regulation of anaphylatoxin activity rapidly over rides their functions. To address this question, we performed ECM using carboxypeptidase N-deficient (CPN(-/-)) mice. Unexpectedly, we found that CPN(-/-) mice survived longer than wild-type mice, but they were fully susceptible to ECM. CD4(+) and CD8(+) T cell infiltration was not reduced at the peak of disease in CPN(-/-) mice, and there was no corresponding reduction in pro-inflammatory cytokine production. Our results indicate that carboxypeptidases contribute to the pathogenesis of ECM and that studies examining the contribution of other carboxypeptidase families and family members may provide greater insight into the role these enzymes play in malaria.