Leishmania protein KMP-11 modulates cholesterol transport and membrane fluidity to facilitate host cell invasion.

The first step of successful infection by any intracellular pathogen relies on its ability to invade its host cell membrane. However, the detailed structural and molecular understanding underlying lipid membrane modification during pathogenic invasion remains unclear. In this study, we show that a specific Leishmania donovani (LD) protein, KMP-11, forms oligomers that bridge LD and host macrophage (MΦ) membranes. This KMP-11 induced interaction between LD and MΦ depends on the variations in cholesterol (CHOL) and ergosterol (ERG) contents in their respective membranes. These variations are crucial for the subsequent steps of invasion, including (a) the initial attachment, (b) CHOL transport from MΦ to LD, and (c) detachment of LD from the initial point of contact through a liquid ordered (Lo) to liquid disordered (Ld) membrane-phase transition. To validate the importance of KMP-11, we generate KMP-11 depleted LD, which failed to attach and invade host MΦ. Through tryptophan-scanning mutagenesis and synthesized peptides, we develop a generalized mathematical model, which demonstrates that the hydrophobic moment and the symmetry sequence code at the membrane interacting protein domain are key factors in facilitating the membrane phase transition and, consequently, the host cell infection process by Leishmania parasites. Synopsis: The Leismhania membrane protein KMP-11 facilitates parasite invasion into macrophages through cholesterol transport from the macrophage membrane to Leishmania and subsequent phase transition in the host cell membrane. KMP-11 transports cholesterol from macrophage to Leishmania. KMP-11 increases macrophage membrane fluidity through liquid ordered to liquid disordered phase transition. KMP-11 depleted Leishmania cannot attach and invade macrophages. KMP-11 can form oligomers which can bridge two membranes containing different sterol molecules. The Leismhania membrane protein KMP-11 facilitates parasite invasion into macrophages through cholesterol transport from the macrophage membrane to Leishmania and subsequent phase transition in the host cell membrane. [ABSTRACT FROM AUTHOR]