Phenomenon that normally leads to human cell death appears vital for parasites, study shows

Double-strand DNA breaks cause cell damage in several organisms, but apparently play a key role in the lifecycles of species that cause Chagas disease, sleeping sickness and leishmaniasis. The results of the study pave the way to the development of more effective treatment.

André Julião | Agência FAPESP – Double-strand breaks in DNA usually kill cells but appear to be important in the lifecycle of trypanosomatids, a family of parasites that infect humans and cause Chagas disease, sleeping sickness and leishmaniasis, among other conditions.

The hypothesis was raised in a study supported by FAPESP and reported in an article in Frontiers in Cell and Developmental Biology. If confirmed, it could pave the way for the development of more effective treatments than those currently available.

“Common sense says DNA double-strand breaks are severely harmful to any type of cell, but when we analyze some trypanosomatids, we find this doesn’t apply,” said Marcelo Santos da Silva, sole author of the review article. Silva is a researcher at São Paulo State University’s Botucatu Institute of Biosciences (IBB-UNESP) in Brazil.

DNA double-strand breaks are caused by a wide array of factors, including complications such as failures that occur during DNA replication or attempts to repair oxidative damage to the genetic code. 

They can also result from external stimuli, such as chemical alterations caused by medications or ionizing radiation, both of which are deliberately used to treat cancer for that very reason.

In the article, Silva reviews the studies conducted to date where trypanosomatids are found to depend on DNA breaks to survive. None of these studies investigated the phenomenon in depth, however. Deeper knowledge of the mechanism could lead to the development of novel therapies.

Different functions

“For example, Trypanosoma brucei [which causes sleeping sickness, prevalent in Africa] depends on a process in which a gene has to be substituted for another in order for it to escape the host’s immune system. In some populations of the parasite, this occurs via DNA double-strand breaks. That’s how it survives in the human organism,” Silva said.

T. cruzi, which causes Chagas, a disease that affects some 10 million people, mainly in the Americas, is known to reproduce asexually. Studies conducted in the past two decades, however, have revealed an exchange of material between different strains of T. cruzi, possibly indicating sexual reproduction and a resulting increase in genetic variability.

The parasite uses DNA double-strand breaks to reproduce in this manner. Further evidence of the exchange is that strains with hybrid genetic material express more proteins associated with DNA breaks.

In addition, the parasites that cause leishmaniasis – visceral or cutaneous, each with a range of different symptoms – have repeated elements in their genetic code, a feature largely due to DNA double-strand breaks occurring particularly under conditions of environmental stress and as a form of resistance to drugs that target species of Leishmania.

“These are three examples of how DNA double-strand breaks appear to benefit rather than hinder trypanosomatids. The view that this process is necessarily harmful needs to change. It could be a path to novel approaches and a better understanding of these parasites’ lifecycles, possibly leading to specific actions to eliminate them,” said Silva, who is currently investigating the phenomenon in detail.

The conditions on whose agents the review article focuses are among 20 neglected tropical diseases (NTDs) that affect over 1 billion people worldwide. NTDs are characterized by an absence of effective treatment and prevalence mainly among the poor (more at: https://agencia.fapesp.br/32265/ and https://agencia.fapesp.br/37434/). 

Snake venom medications

Finding out more about how DNA double-strand breaks occur in trypanosomatids could pave the way for the study of possible treatments for the diseases they cause. The drugs currently used against these conditions are ineffectual or have many adverse side effects.

Among the many molecules that are being laboratory-tested and show potential to become novel drugs are phospholipases derived from snake venom. 

A more recent article by a group of researchers affiliated with institutions in Brazil and France, including Silva, reviews studies of the anti-parasitic effects of snake venom phospholipases, covering helminths, Toxoplasma, and Plasmodium, as well as trypanosomatids.

Helminths are macroparasites popularly known as worms and cause several NTDs. Toxoplasma gondii is a protozoan that causes toxoplasmosis (not usually included among NTDs but considered a neglected disease in the US, for example) and can attack all organs, causing generalized infection and several life-threatening illnesses. Five mosquito-borne species of Plasmodium are known to infect humans, mainly causing malaria.

Several snake venom phospholipases have been tested against these parasites, including some from Bothrops pit vipers and Crotalus rattlesnakes found in Brazil, the study shows.

“Snake venom offers a lot of potentials,” Silva said. “We make the criticism that many of these studies involved parasite stages that infect insects and not humans. Nevertheless, our findings evidence the significant opportunities for drug development, and it’s necessary to continue advancing.”

The study was supported by FAPESP via a project led by Nilmar Silvio Moretti, a professor at the Federal University of São Paulo’s Medical School (EPM-UNIFESP).

The article “DNA double-strand breaks: A double-edged sword for trypanosomatids” is at: www.frontiersin.org/articles/10.3389/fcell.2021.669041. 

The article “Panacea within a Pandora's box: the antiparasitic effects of phospholipases A2 (PLA2s) from snake venoms” is at: www.sciencedirect.com/science/article/pii/S1471492221001690.