A small heat shock protein is essential for thermotolerance and intracellular survival of Leishmania donovani

Abstract

Leishmania parasites must survive and proliferate in two vastly different environs – the guts of poikilothermic sandflies and the antigen-presenting cells of homeothermic mammals. The change of temperature during transmission from sandflies to mammals is both a key trigger for the progression of their life cycle and for elevated synthesis of heat shock proteins which have been implicated in survival at higher temperatures. While the main heat shock protein families have been studied for their function in the Leishmania life cycle, nothing is known about the roles played by small heat shock proteins. Here, we present first evidence for the pivotal role played by the Leishmania donovani 23-kD heat shock protein which is expressed preferentially in the mammalian stage where it assumes a perinuclear localisation. Loss of HSP23 causes increased sensitivity to chemical stressors, but renders L. donovani incapable of surviving at 37°C. Consequently, HSP23 null mutants are non-infectious to primary macrophages in vitro. All phenotypic effect can be abrogated by the introduction of a functional HSP23 transgene into the null mutant, confirming the specificity of the mutant phenotype. Thus, HSP23 expression is a prerequisite for L. donovani survival at mammalian host temperatures and a crucial virulence factor.