Infection & Immunity

Leismania Laboratory - The role of cytokines

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Cancer & Haematology | Molecular Genetics of Cancer | Immunology | Infection & Immunity
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The role of cytokines and their regulation in determining the disease phenotype

As discussed above, the availability of a mouse model for disease has elucidated many aspects of the T cell immune responses in leishmaniasis. However, the existing animal models are a blunt instrument. With the development of gene knock out technology, mice can be produced with very precise genetic lesions. One such mouse lacking the gene encoding the suppressor of cytokine signaling 1(SOCS1) has been generated by our collaborators in the Division of Cancer and Hematology. SOCS1 is a negative regulator of signaling by several cytokines, prominent among them is IFN-gamma . Our earlier work showed that macrophages from these mice were hyper sensitive to the effects of IFN-gamma and were activated to kill intracellular L. major at much lower concentrations of IFN-gamma compared to wild type mice. Since IFN-gamma is a critical mediator of host protective Th1 immune responses in leishmaniasis and is a critical mediator of disease promoting Th1 responses in malaria, Denise Bullen, a PhD student, set out to examine the role of SOCS1in both diseases. In mice lacking SOCS1, the IFN-gamma responses would be uncontrolled and the mice would be expected to be more resistant to leishmaniasis. In contrast, since Th1 immune responses are involved in the pathology of cerebral malaria caused by Plasmodium berghei ANKA, SOCS1 null mice would be expected to be more susceptible to disease. To our surprise, Denise found that mice lacking one copy of the SOCS1 gene were more susceptible to leishmaniasis. Also unexpectedly, the SOCS1 knock out mice were protected from cerebral malaria. Moreover, there was no correlation between the severity of disease and the cytokine pattern. These effects are most likely due to the complex and pleiotropic effects of SOCS1 in vivo.

The challenge for the future is the identification of the sites and mechanisms of action of SOCS1. These studies will be aided by the availability of newly produced SOCS1 conditional knock out mice where SOCS1 is turned off in T cells only or in myeloid cells.

The role of proteophosphoglycan in the subversion of macrophage function and the establishment of infection

As discussed earlier, PPG has several functions in the vector and the mammalian host. Several years ago, Aline Piani showed that PPG has complex immuno modulatory effects on the macrophage, inhibiting TNF-a production and synergising with IFN-gamma to stimulate production of nitric oxide. L. mexicana PPG causes the formation of huge vacuoles, much like those induced by infection with this organism. L. mexicana amastigote PPG is present in large amounts in the parasitophorous vacuole and in the extracellular space in lesions in infected mice. With our collaborators, Bernardo Foth and Malcolm McConville from the University of Melbourne, we have shown that L. major amastigote PPG is also detected in the parasitophorous vacuole and in additional vacuoles (possibly lysosomes) in the infected macrophage. PPG from L. mexicana amastigotes has the remarkable property of activating complement and mice injected with PPG lose their ability to activate complement, suggesting a role for PPG in protecting parasites from complement killing.

In summary, there is a large body of evidence that PPG plays an important role in the interaction of Leishmania with the mammalian host. Our current studies carried out by Tracey Baldwin, aim to elucidate the function of the species and stage-specific PPGs in the macrophage and their contribution to virulence and disease pathogenesis.

I would like to include in this category of host-parasite interaction our quest for anti-Leishmania drugs because metabolic pathways that are good targets for drugs are also the ones responsible for the survival of the parasite in the host cell.

Next: The Mannose biosynthetic pathway and its enzymes as novel drug targets...

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