A MITOGEN-ACTIVATED PROTEIN (MAP) KINASE HOMOLOG OF LEISHMANIA-MEXICANA IS ESSENTIAL FOR PARASITE SURVIVAL IN THE INFECTED HOST

The parasitic protozoon Leishmania mexicana undergoes two major develo pmental stages in its life cycle exhibiting profound physiological and morphological differences, the promastigotes in the insect vector and the amastigotes in mammalian macrophages. A deletion mutant, Delta lm sap1/2, for the secreted acid phosphatase (SAP) gene locus, comprising the two SAP genes separated by an intergenic region of similar to 11. 5 kb, lost its ability to cause a progressive disease in Balb/c mice. While in vitro growth of promastigotes, invasion of host cells and dif ferentiation from promastigotes to amastigotes was indistinguishable f rom the wild-type, the mutant parasites ceased to proliferate when tra nsformed to amastigotes in infected macrophages or in a macrophage-fre e in vitro differentiation system, suggesting a stage-specific growth arrest. This phenotype could be reverted by complementation with 6 kb of the intergenic region of the SAP gene locus. Sequence analysis iden tified two open reading frames, both encoding single copy genes; one g ene product shows high homology to mitogen-activated protein (MAP) kin ases, Complementation experiments revealed that the MAP kinase homolog ue, designated LMPK, is required and is sufficient to restore the infe ctivity of the Delta lmsap1/2 mutant. Therefore, LMPK is a kinase that is essential for the survival of L.mexicana in the infected host by a ffecting the cell division of the amastigotes.