A phenomenon that is normally lethal to cells — the breakage of the double strand that forms DNA — appears to be important in the life cycle of trypanosomatids, a family of parasites that infects humans and causes diseases such as Chagas’, sleep and leishmaniasis.
The hypothesis was raised in a study supported by Fapesp and published in the journal 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 that the so-called double-stranded DNA breaks are harmful to any type of cell. But, when analyzing some trypanosomatids, we see that this does not apply”, says the study’s author, Marcelo Santos da Silva , researcher at the Botucatu Institute of Biosciences at the São Paulo State University (IBB-Unesp).
Double-stranded DNA breaks are normally fatal injuries to cells, caused by a wide range of conditions. They can be generated by complications of the organism itself, as failures occurred during the duplication of DNA or in the attempt to repair the oxidation in the genetic code.
They can also result from external stimuli, such as chemical changes caused by drugs or ionizing radiation — hence they are the mechanism of action of some antitumor treatments.
In the article, Silva reviews existing studies to date that show how trypanosomatids depend on the phenomenon, which is deadly in other cells, to continue their life cycle. None of this research, however, has delved into the importance of DNA breaks for parasites — knowledge that could lead to the development of new therapies.
different functions
“Trypanosoma brucei [causador da doença do sono, prevalente na África], for example, depends on a process in which one gene needs to be exchanged for another in order for it to escape the host’s immune system. In some populations of this parasite this occurs through the breakage of DNA in the form of a double strand. In this way, they manage to circumvent the immune system and perpetuate themselves”, explains Silva.
Causer of Chagas disease, which affects about 10 million people mainly in the Americas, Trypanosoma cruzi is known to reproduce asexually.
Studies in the last two decades, however, have shown the existence of material exchange between different strains of T. cruzi, which may indicate sexual reproduction and the consequent increase in genetic variability.
To reproduce in this way, parasites benefit from double-stranded DNA breakage. Another evidence of this exchange is that strains with hybrid genetic material have a higher expression of proteins linked to DNA breakage.
Finally, the parasites that cause leishmaniasis — a disease that can be visceral or cutaneous, causing different health problems — are known to have repeated elements in the genetic code. This characteristic is favored by the double-stranded DNA break and occurs, above all, under environmental stress conditions and as a way of resisting existing drugs against Leishmania species.
“There are three examples in which double-stranded DNA breakage appears to benefit trypanosomatids rather than harm them. The view that this process is necessarily harmful, therefore, needs to be rethought, as it may be a way to carry out new approaches to understand the life cycle of these parasites and, who knows, carry out specific actions to eliminate them”, points out Silva, who is currently investigating the phenomenon in depth.
These three diseases whose agents were the target of research are some of the 20 neglected tropical diseases (NTDs), which affect more than 1 billion people in the world. NTDs are characterized by the absence of effective treatments and by affecting mostly poor populations.
poison x medicine
Unraveling how double-stranded DNA breakage occurs in trypanosomatids could pave the way for the study of possible treatments for the diseases caused by them. Currently, the drugs used against diseases caused by parasites are ineffective or cause many side effects.
Among the many molecules currently tested in the laboratory that have the potential to become new drugs are phospholipases, present in snake venoms.
In another article, signed with a team of researchers from institutions in Brazil and France, Silva provides an overview of studies involving phospholipases and several families of parasites. In addition to trypanosomatids, helminths, Toxoplasma and Plasmodium were included.
Helminths are parasites better known as worms and are responsible for most neglected tropical diseases. Toxoplasma gondii is the protozoan that causes toxoplasmosis (which does not belong to the group of NTDs) and can attack all organs, causing generalized infection and various deficiencies. Plasmodia, in turn, cause malaria and are predominantly transmitted by mosquitoes.
A series of snakes have already had their phospholipases tested against these agents, including some of the genera Bothrops, of jararacas, and Crotalus, of rattlesnakes, present in Brazil, reveals the study.
“There is a great potential to be explored for snake venoms. One criticism that we make, however, is that many of these studies were carried out with the phases of the parasites that infect insects and not humans. However, the results give an good idea of the possibilities that these molecules offer. It is necessary to continue advancing”, says the researcher.
The work was supported by Fapesp through a project coordinated by Nilmar Silvio Moretti, professor at the Paulista School of Medicine at the Federal University of São Paulo (EPM-Unifesp).
The article “DNA Double-Strand Breaks: A Double-Edged Sword for Trypanosomatids” can be read here.
The publication “Panacea within a Pandora’s box: the antiparasitic effects of phospholipases A2 (PLA2s) from snake venoms” also in English, is available here.
