Phosphatases for and against: Trichuris vs. Leishmania

Posted by Kasra

Trichuris trichiura adult male

Trichuris trichiura adult male – Image taken from DPDx

Trichuris, is an intestinal roundworm, also known as whipworm, that can be transmitted through ingestion of food contaminated with its eggs. The larvae hatch inside the small intestine and complete their life cycle to adults in the cecum. After maturation, which can take about 3 months, the female worm lays thousands of eggs per day. The parasite can stay in the intetine between 1-5 years. Trichuris trichiura is a parasite of humans, while Trichuris muris is a mouse parasite, used usually as the animal model to study its infection.

In contrast to intracellular pathogens, a Th1 response is non-protective in infection with large extracellular pathogens such as intestinal helminths. For instance, during infection with Trichuris muris, a Th2 response comprising IL-4 and Ig-E production leads to resolution of infection, while a Th1 response comprising IFN-gamma, IL-12 and IL-18 is not protective.

S Hadidi et al. look at regulation of the immune response to T. muris and focus on the importance of the macrophage lipid phosphatase Ship1. Ship1 or Sh-2 containing inositol 5′ phosphatase 1 is a regulator of the PI3K pathway. Hadidi et al. show that Ship1 expression is upregulated steadily following T. muris infection. Ship1-/- mice have higher parasite burden and IFN-gamma while lower levels of IL-13. Also, Ship1-/- macrophages produce more IL-12. Blocking IL-12 or IFN-gamma by blocking antibodies rescued the phenotype by reducing worm burden and increase in IL-13. Thus, they found how activity of this phosphatase can direct the immune response against T. muris infection. It would be very interesting now to see what stimuli induce upregulation of Ship1 and also what are this enzyme’s substrates, which are so important for production of IL-12 by macrophages.

Similar to this story, a few years ago, Abu-Dayyeh et al. and Gomez et al. showed that activating phosphatases is important for Leishmania to establish its infection. Being an intracellular parasite, a Th1 response, with large amounts of IFN-gamma would be protective against Leishmania. So in this context, Leishmania-mediated activation of many phosphatases (most importantly SHP-1) leading to inhibition of IL-12 production leads to disease progression, because it skews the immune response towards Th2. In this situation, Leishmania takes advantage of the phosphatase’s function.

Hadidi S, Antignano F, Hughes MR, Wang SK, Snyder K, Sammis GM, Kerr WG, McNagny KM, & Zaph C (2012). Myeloid cell-specific expression of Ship1 regulates IL-12 production and immunity to helminth infection. Mucosal immunology, 5 (5), 535-43 PMID: 22535180

Abu-Dayyeh I, Shio MT, Sato S, Akira S, Cousineau B, & Olivier M (2008). Leishmania-induced IRAK-1 inactivation is mediated by SHP-1 interacting with an evolutionarily conserved KTIM motif. PLoS neglected tropical diseases, 2 (12) PMID: 19104650
Gomez MA, Contreras I, Hallé M, Tremblay ML, McMaster RW, & Olivier M (2009). Leishmania GP63 alters host signaling through cleavage-activated protein tyrosine phosphatases. Science signaling, 2 (90) PMID: 19797268
ResearchBlogging.org

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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

ResearchBlogging.org

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!