Infection & Immunity

The Leishmania Laboratory - Attachment & Infection

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Attachment and Infection

New candidate ligands for attachment and infection of macrophages

A few years back, Thomas Ilg, a post doctoral fellow in the lab, reasoned that secreted parasite molecules may be important messengers between the parasite and its two hosts, the sandfly and the macrophage. He set out to identify and isolate such secreted molecules. One of these was a totally new and unusual parasite mucin made up of repetitive units which polymerise into long filaments. We named this molecule filamentous proteophosphoglycan (fPPG) because it consists of a polypeptide backbone with a large repetitive sequence of [alanine-proline-serine] where most of the serines are phosphoglycosylated. In collaboration with colleagues in Tübingen, we went on to show that fPPG is secreted by the parasites in the gut of the sandfly, and that it is part of the “plug” which appears to block the fly foregut and prevents it from feeding. In that situation, the fly tends to probe repeatedly in its attempt to suck blood and in the process it transmits more parasites to its hapless hosts.Slide of scanning EM of PPG filaments around the parasites

It subsequently became apparent that PPG is a member of a large family of secreted and membrane-anchored proteins. With the cloning of a membrane-anchored member of the PPG family, we began a program of study aimed at defining the function of the membrane PPG in the mammalian host.

One of the discoveries made by Thomas Ilg was the surprising presence in PPG of glycans known to be present in a complex parasite glycolipid, the lipophosphoglycan or LPG. Some of these glycans had been shown in our earlier studies to be ligands for the host macrophage. Work of a post doctoral fellow in the lab, Aline Piani, showed that indeed, PPG bound to macrophages, was internalized and it was present in the macrophage phagolysosome. In the macrophage, it had interesting but complex immunomodulatory effects.

A PhD student, Jacqui Montgomery was intrigued by the presence of an amino terminal Leucine Rich Repeat (LRR)domain in the membrane PPG. LRRs are present in many proteins, they are all involved in protein-protein interaction and some are involved in signal transduction. Interestingly, they are present in all the proteins known to be responsible for pathogen resistance in plants, and are also involved in host cell invasion by Listeria monocytogenes. What is more surprising is the finding that this domain shared remarkable similarity to another surface protein, the parasite surface antigen-2 or PSA-2. Although we have studied the structure of PSA-2 and the developmental regulation of its expression over some years, and it has been our major candidate for a Leishmania vaccine, its function has eluded us. The LRRs may provide a clue and a handle on its function.

Currently, Lukasz Kedzierski is studying the function of the LRRs in PPG and PSA-2. We now wonder if PPG binds to macrophages not only through its glycans (which are shared with LPG), but also through its LRRs. Questions yet to be answered are the relative importance of the three surface molecules LPG, PPG and PSA-2 in host infection by the promastigote and the amastigote, the responses induced by the binding of these different molecules in the macrophage, and the potential role of PPG in the interaction of the parasite with dendritic cells.

Three molecules involved in Host-Parasite Interaction

We are interested in several issues that fall under this category.

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