Balancing the functions of DNA extracellular traps in intracellular parasite infections: implications for host defense, disease pathology and therapy

Abstract

The release of DNA to the extracellular milieu is a biological process referred to as etosis, which is involved in both physiological and pathological functions. Although the release of DNA extracellular traps (ETs) was initially attributed to innate immune cells such as neutrophils, eosinophils, and macrophages, recent studies have shown that T cells, as well as non-immune cells, are capable of releasing ETs. These structures were described primarily for their potential to trap and kill pathogens, presenting an important strategy of host defense. Intriguingly, these functions have been associated with intracellular pathogens such as the parasites Leishmania sp. and Trypanosoma cruzi, causative agents of leishmaniasis and Chagas disease, respectively. These are two devastating tropical diseases that lead to thousands of deaths every year. In an apparent contradiction, ETs can also induce and amplify inflammation, which may lead to worsening disease pathology. This has prompted the concept of targeting ETs' release as a means of controlling tissue destruction to treat human diseases. What is the best approach to prevent disease severity: inducing ETs to kill pathogens or preventing their release? In this Perspective article, we will discuss the importance of understanding ETs released by different cell types and the need to balance their potentially complementary functions. In addition, we will explore other functions of ETs and their translational applications to benefit individuals infected with intracellular parasites and other pathogens. Ultimately, a better understanding of the role of ETs in disease pathogenesis will provide valuable insights into developing novel therapies for human diseases.

Fig. 1. Illustration of the etosis process, in which cells release extracellular traps to capture and eliminate microorganisms.

This process can be performed by several types of cells, including neutrophils and macrophages. Microorganisms that can activate this process include bacteria, viruses, fungi and protozoa. Extracellular traps are composed of DNA, histones, and various proteins depending on the cell type and stimulus. One of their functions is to capture and eliminate microorganisms such as Leishmania sp. and T. cruzi. However, extracellular traps can also cause inflammation and tissue damage by stimulating the local production of cytokines and other proinflammatory molecules. Understanding these processes may help identify targets for therapeutic intervention, offering new alternatives to treat human diseases.