Exploitation of host microvesicles by Trypanosoma cruzi

Posted by Kasra

Studying mechanisms of parasitism teaches us a lot about the host physiology as well as parasite pathogenicity. Millions of years of co-evolution have adapted the parasites to exploit various homeostatic and pathologic processes of the host for their benefit. A nice example is recent study on the protozoan parasite Trypanosoma cruzi and its exploitation of host microvesicles. T. cruzi, is the causative agent of Chagas disease in Southern America’s and similar to other parasites has a complicated life-cycle. Once injected into the mammalian host, it toggles between an intracellular and bloodstream stage. In the blood-stream, among all, the parasite should fight complement-mediated lysis and inside the host cells it should avoid being killed by activated immune cells. Cestari et al. show how the parasite is able to get help from host-released microvesicles for survival in both of these stages.

Microvesicles or plasma membrane vesicles or (PMVs) are relatively large (between 200-500nm, compared to exosomes that are between 40-100nm) exovesicles released by eukaryotic cells. Not much is known about their part in homeostasis, but they have been shown to play roles in cancer and infections. More research on their role in disease can help us tell what they do in normal conditions.

Microvesicles released from THP-1 cells, Cestari et al. 2012, J Immunology

Cestari et al. show that contact between T. cruzi metacyclic trypomastigotes and THP-1 induces a rapid augmentation in release of microvesicles from THP-1 cells in an apoptosis independent manner. They suggest that the cytoplasmic trigger for release of microvesicles is a transient increase in Ca2+ levels. Interestingly, they show that these vesicles are able to save the parasite from complement mediated lysis by binding C3 convertase on the parasite surface and inhibiting C3 cleavage.

Although they do not look at the complete content of the microvesicles, Cestari et al. show that microvesicles contain TGF-β, a generally antiproliferative and antiactivatory cytokine. Levels of TGF- β are not surprisingly different in microvesicles from different cell origins. However, once present together with the parasite, they allow a stronger infection of Vero cells (an epithelial cell line). They show that pre-incubation with microvesicles allows for a stronger T. cruzi infection and this effect is specifically due to TGF- β. This can be important for parasitism, since they have also suggested that mice infected with T. cruzi have higher levels of microvesicles in their bloodstream compared to normal mice.

Like any other exciting piece of research, this study raises a lot of questions. For instance, why is there an increase in microvesicle release following contact with T. cruzi? Is this a common effect with other pathogens or eukaryotic parasites? What is the role of these vesicles when they are not being exploited? What other cytokines/signaling proteins do they contain? What do they do? What are their target cells? And so on. I am very eager to read the follow-up papers and learn more about this method of cell-cell communication.

Cestari I, Ansa-Addo E, Deolindo P, Inal JM, & Ramirez MI (2012). Trypanosoma cruzi Immune Evasion Mediated by Host Cell-Derived Microvesicles. Journal of immunology (Baltimore, Md. : 1950), 188 (4), 1942-52 PMID: 22262654

Leishmania-induced IRAK-1 inactivation via host SHP-1 activation

Posted by Issa Abu-Dayyeh

I will hereby post the author summary of my most recent publication regarding modulation of macrophage signaling by the Leishmania parasite. The paper has been published on the 23rd of December 2008 in the Public Library of Science (PLoS) Neglected Tropical Diseases, and demonstrates for the first time the ability of Leishmania to inactivate IRAK-1 through its ability to activate host PTP-SHP-1.

Citation: Abu-Dayyeh I, Shio MT, Sato S, Akira S, Cousineau B, et al. (2008) Leishmania-Induced IRAK-1 Inactivation Is Mediated by SHP-1 Interacting with an Evolutionarily Conserved KTIM Motif. PLoS Negl Trop Dis 2(12): e305. doi:10.1371/journal.pntd.0000305

Here is the author summary of the paper:

Leishmania developed several methods to seize control of macrophage signalling pathways in an effort to inactivate their killing abilities. One effective method utilized by the parasite is the activation of host protein tyrosine phosphatases, specifically SHP-1. This increased phosphatase activity contributes to the inactivation of signalling molecules involved in critical macrophage functions such as NO and cytokine production. Interestingly, the absence of SHP-1 results in stronger macrophage inflammatory responses to a bacterial cell wall component known as LPS, a molecule detected by macrophages through Toll-like receptors (TLRs). This observation suggested a role for SHP-1 in the regulation of TLR signalling. Our study reveals that upon Leishmania infection, SHP-1 is able to rapidly bind to and inactivate a critical kinase (IRAK-1) in this pathway. This regulatory binding was shown to be mediated by an evolutionarily conserved motif identified in the kinase. This motif was also present in other kinases involved in Toll signalling and therefore could represent a regulatory mechanism of relevance to many kinases. This work not only reports a unique mechanism by which Leishmania can avoid harmful TLR signalling, but also provides a platform on which extensive investigation on host evasion mechanisms and regulation of cellular kinases can be gained.

For further information please check the citation below to read the whole paper. PLoS is an open-access journal and therefore offers free access to its contents to anybody anywhere in the world!

P.S.: Abstract translations are also available in the following languages: Arabic, French, Spanish, and Farsi.

Dawkin’s “extended phenotype”, an extension or a revolution?

Posted by: Issa Abu-Dayyeh

The extended phenotype, a relatively longer and a more difficult reading than Dawkin’s “The selfish gene”, is in my opinion a book worth the reading effort for several reasons:

1-Although a big portion of the book was dedicated to rebuttal critics that showered Dawkins with accusations of being a genetic determinist and a reductionist (Based on his views in the Selfish gene), Dawkin’s replies to those criticisms are pretty logical and organised. In fact, Dawkins almost did not have to retract any of the claims he made 6 years before “the extended phenotype” was written.

2-The rest of the book sets to establish a new vision on the extent to which a gene can act.

Many of us would agree that an organisms’ behaviour is selected to maximize the success of the replication of the genes residing inside this organism. As tempting as this statement might be, this vision definitely pictures the body as the gene’s prison. It is the boundary, the wall,the farthest limit upon which a gene can act.

Dawkins suggests in “the extended phenotype” that the action of genes goes way beyond their ability to produce proteins for the bodies they reside in. In fact, genes can have effects on inaminate objects (such as the type of house an animal would build) or on other living beings. An example given by Dawkins is a trematode that lives in snails. This trematode codes for proteins that drive the snail to produce thicker shells than ususal. This provides greater protection for the trematode while diverting the snail’s energy from practices that could benefit the snail but not the trematode such as: reproduction. The author goes on and on giving examples of how genes can act at a distance!

But how influential is this extended phenotype argument? After reading the book, my initial thought was that it is really no revolution! This is simply an extension of our vision of how far genes should be seen to go. On a deeper thought, I believe this book is revolutionary from a different perspective. First, it places more emphasis on the interactions of genes (regardless of the organism that carries them) on the overall evolution of complex traits and the natural selection they undergo. The principle also explains how a parasite can alter the host’s behaviour to its advantage (therefore suggesting what was formerly thought as mal-adaptation of a host gene as good adaptation of the parasite gene), and how some parasites can end up as symbionts and ultimately interested in increasing the reproductive success of the host and, soon, very difficult to even be seen as  parasites (ex: the mitochondria and chloroplast endosymbiont theory).

This book simply modifies a vision: from behaviour maximizing the success of the genes inside the organism to behaviour maximizing the success of genes that code for that specific behaviour, no matter in whose body those genes are found. This definition reorganizes the genetic vision in a way highly compatible with dawkins’ selfish gene view of evolution and natural selection. Is he right about the extended phenotype or is he wrong? I think most of us would agree it is a logical extension of what we perceive as a direct effect of a gene, but what really matters is that it is different… and a different view is sometimes what we need to reevaluate our current vision and devise new experiments to expand our knowledge. Not to mention the importance of such a vision on the mathematics of genetic contributions to phenotypes. In a nutshell, this is a book worth reading!