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

Parasites to help fight cancer

Posted by Kasra

Research on parasites is important, even if most of them are not direct health concerns to the developed world! Millions of years of coevolution of parasites along with their hosts have made them masters in manipulation of the immune system and in coexistence with it. Many parasitic infections such as those with Toxoplasma, Trypanosoma and some Leishmania sp. elicit innate and adaptive immune responses that can result in life-long immunity to reinfection. However, the parasite might be carried chronically for life, keeping the antibody titers up.

The research team of Ricardo Gazzinelli have taken advantage of the stealth yet stimulatory property of parasites to target cancer. For their purpose, they expressed a cancer antigen in a strongly attenuated strain of Trypanosoma cruzi, the causative agent of Chagas disease in the Americas. This live vaccine showed great protection against melanoma in both prophylactic and therapeutic models.

T. cruzi was chosen as the vector for many reasons: it intrinsically possesses TLR ligands and thus induces a strong proinflammatory response; like many other parasites, it has ways of staying inside the body for a very long time; and it propagates inside the cytoplasm, therefore it can induce a Th1 type immune response and activation of cytotoxic CD8⁺ T cells, which are very important against cancer. It is interesting to me that although they did not observe any disease or parasitemia, such strong immune response and protection was observed. I think it is important to see if and how many residual parasites are sticking around and where and how long do they stay in the body. This might also teach us more about how this model actually works.

The study shows that if vaccinated before tumor induction, mice are completely protected from cancer. It is also shown that this antigen-carrying vector can delay tumor growth and lethality if given after. One might ask: what advantages does this vector provide over vaccination with traditional recombinant protein, or other vectors such as attenuated viruses? The authors compared the protection and immune response resulted from recombinant T. cruzi to the canonical recombinant antigen (NY-ESO1) with Alum or CpG adjuvants. Recombinant T. cruzi showed better protection and stronger immune response compared to canonical vaccination strategies. Doing a quick search through pubmed, I didn’t find other strategies such live or viral vectors rather than variations of recombinant protein being used so far. I might be wrong, but still this is a novel idea and this recombinant parasite deserves a chance of being further studied, especially for prophylactic uses. There are plenty of other cancer or maybe even infectious antigens that can be targeted by this method. But of course, there are plenty of biohazard issues that also need to be addressed with injecting an attenuated form a dangerous pathogenic parasite.

Here is the link to the article abstract on Pubmed.

Junqueira C, Santos LI, Galvão-Filho B, Teixeira SM, Rodrigues FG, Darocha WD, Chiari E, Jungbluth AA, Ritter G, Gnjatic S, Old LJ, & Gazzinelli RT (2011). Trypanosoma cruzi as an effective cancer antigen delivery vector. Proceedings of the National Academy of Sciences of the United States of America, 108 (49), 19695-700 PMID: 22114198