Death for life – The Leishmania parasite needs dead competitors to outwit the immune system

The human body has a highly efficient immune system, which recognises bacteria, viruses or parasites that enter the organism as “non-self” and kills them. Leishmania escape this mechanism, thus being able to replicate in the human organism unrecognised by the immune system. The parasites are transmitted by sand flies and cause Leishmaniasis, a disease which above all occurs in tropical regions, the Mediterranean and Asia. However, sand flies are increasingly moving north and have in the meantime also been found in Germany.

Why the immune system is unable to stop the parasites has so far been unclear. The research team of Professor Dr Ger van Zandbergen, head of the Division Immunology at the Paul-Ehrlich-Institut (PEI) and of Peter Crauwels, who is also a member of this Division, found new mechanisms of immune evasion.

Living Leishmania parasites ensure their intracellular survival depending on simultaneous presence of dead Leishmania. In this context, a process called autophagy plays an important part. This process is a digestion mechanism in the human cell which normally serves to provide energy to this cell on a short-term basis in stress situations by degrading cell components. This mechanism can also serve to degrade viruses, bacteria, and foreign proteins.

The PEI researchers have now discovered that Leishmania are digested by the autophagy pathway, which, however, in this case is fatal to the human cell: The defence mechanism of the adaptive immune system against the Leishmania is deactivated. Another peculiarity is that only Leishmania which are already dead can be digested by autophagy thus being able to outwit the immune defence mechanism. If, on the other hand, only live Leishmania enter the cell, this inhibition of the immune system does not take place. In this case, strikingly more specific immune cells of the blood, so-called T cells, are formed which ascertain that the Leishmania are killed.

The researchers have also found out that the ratio of dead to live parasites is roughly 1:1. But where do the dead Leishmania come from? A possible explanation could be that the parasites are transmitted by sand flies which consume food only once a week. Only half the parasites may survive this interval in the stomach of the sand fly before the contents of the stomach with the dead and live parasites is transmitted by the bite of the sand fly.

Another intriguing result of this team’s research is that the specific T cell response against Leishmania was established without exception in blood samples of more than 80 healthy donors who never had any contact with Leishmania. This contradicts the central postulate that adaptive immune response triggering the formation of specific T cells is only set off after prior contact with a certain pathogenic agent. “We have found an existing immune response mechanism against a parasite with which no previous contact took place“, as Professor van Zandbergen summarised the surprising results of the research.

Can the research results be used therapeutically? “Autophagy is not only an interesting immune response mechanism for infections but also for tumours. Active substances are currently developed with which autophagy can be triggered or deactivated. Such medicinal products could also be effective in the case of Leishmaniasis infections” explained Zandbergen.

Original publication: Crauwels P, Bohn R, Thomas M, Gottwalt S, Jäckel F, Krämer S, Bank E, Tenzer S, Walther P, Bastian M, van Zandbergen G (2014): Apoptotic-like Leishmania exploit the host´s autophagy machinery to reduce T-cell 1 mediated parasite elimination. Autophagy (DOI:10.1080/15548627.2014.998904)

http://www.tandfonline.com/doi/abs/10.1080/15548627.2014.998904?journalCode=kaup… Link to the online abstract of this article
http://www.pei.de/EN/information/journalists-press/press-releases/2015/05-death-… Link to the press release of the Paul-Ehrlich-Institut