Beschreibung:
<jats:title>Abstract</jats:title><jats:p>Protozoan parasites of the genus <jats:italic>Leishmania</jats:italic> adapt to their arthropod and vertebrate hosts through the development of defined life cycle stages. Stage differentiation is triggered by environmental stress factors and has been linked to parasite chaperone activities. Using a null mutant approach we previously revealed important, nonredundant functions of the cochaperone cyclophilin 40 in <jats:italic>L. donovani‐</jats:italic>infected macrophages. Here, we characterized in more detail the virulence defect of <jats:italic>cyp40</jats:italic>−/− null mutants. In vitro viability assays, infection tests using macrophages, and mixed infection experiments ruled out a defect of <jats:italic>cyp40</jats:italic>−/− parasites in resistance to oxidative and hydrolytic stresses encountered inside the host cell phagolysosome. Investigation of the CyP40‐dependent proteome by quantitative 2D‐Di<jats:styled-content style="fixed-case">GE</jats:styled-content> analysis revealed up regulation of various stress proteins in the null mutant, presumably a response to compensate for the lack of CyP40. Applying transmission electron microscopy we showed accumulation of vesicular structures in the flagellar pocket of <jats:italic>cyp40</jats:italic>−/− parasites that we related to a significant increase in exosome production, a phenomenon previously linked to the parasite stress response. Together these data suggest that <jats:italic>cyp40</jats:italic>−/− parasites experience important intrinsic homeostatic stress that likely abrogates parasite viability during intracellular infection.</jats:p>