The Role of Neutrophils in the Interaction with <i>Leishmania</i>: Far beyond a Simple Trojan Horse?

Abstract

Neutrophils are the most numerous leukocyte in mammals and normally they are the first phagocyte observed in recently damaged or infected tissues. They play a key role in the innate immune responses to Leishmania and several other microorganisms, nonetheless an exacerbated neutrophils activity can generate a harmful response to the host, therefore its turnover rate is very important to maintain the homeostasis and averts the host tissue damage. Both apoptosis followed by phagocytosis by mononuclear phagocytes (eferocytosis) and reverse transmigration have been considered the main processes for the clearance of neutrophils from injured or infected tissues. However, the interaction with Leishmania and other microbes, as well as molecules produced by arthropod vectors such as sandflies saliva can modify the behavior of neutrophils, causing immediate lysis to prolong their life. In fact, as a result of a long course of coevolution, several microorganisms have developed skills to avoid neutrophil effector mechanisms and take advantage of neutrophil clearance pathways to promote their spread in the host's body. Leishmania, Chlamydia pneumoniae and Yersinia pestis for example use the efferocytic Trojan horse process for their dissemination and immune protection, in a different way vaccinia Ankara virus and Toxoplasma gondii exploit the neutrophil reverse transmigration for the same reason. Here we present an overview of some characteristics of neutrophils and their different destinations after interaction with several microorganisms, with an emphasis on Leishmania species. It was also suggested the probable role of neutrophils reverse transmigration as another possible route for the spreading of Leishmania in the visceral leishmaniasis.

CCR7/dendritic cell axis mediates early bacterial dissemination in Orientia tsutsugamushi-infected mice

“…Several microorganisms (e.g., Leishmania, Chlamydia pneumoniae, and Yersinia pestis) have developed capabilities to invade neutrophils and avoid neutrophil-mediated killing, or to take advantage of neutrophil clearance pathways, such as efferocytosis, to promote their dissemination in the host (55,56). However, the role of neutrophils in bacterial dissemination of Ot infection is not well defined.…”

“…Neutrophils are potent phagocytes and the first line of defense following infection; however, they can also serve as the Trojan horse in pathogen transmission from the initial bite site to visceral organs. Several microorganisms (e.g., Leishmania , Chlamydia pneumoniae , and Yersinia pestis ) have developed capabilities to invade neutrophils and avoid neutrophil-mediated killing, or to take advantage of neutrophil clearance pathways, such as efferocytosis, to promote their dissemination in the host ( 55 , 56 ). However, the role of neutrophils in bacterial dissemination of Ot infection is not well defined.…”

Th17 Cell and Inflammatory Infiltrate Interactions in Cutaneous Leishmaniasis: Unraveling Immunopathogenic Mechanisms

“…Additionally, some Leishmania parasites have developed countermeasures against neutrophil microbicidal mechanisms to the point of using the neutrophils as vehicles for infecting other cells ( 62 ). This phenomenon, described as the “Trojan horse” model, was first reported in 2003 and outlines a scenario in which Leishmania hijacks neutrophils, inhibits their effector mechanisms, proliferates within them, and then infects macrophages ( 67 68 ).…”

Eosinophils of patients with localized and diffuse cutaneous leishmaniasis: Differential response to Leishmania mexicana, with insights into mechanisms of damage inflicted upon the parasites by eosinophils

“…Early recruitment of neutrophils to the infection site mediated by IL-8 also leads to their activation and enhanced phagocytosis of the parasite. Neutrophils not only harbor the parasite, shielding it from the deleterious effects of complement, but they have also been described to aid in parasite spread through "silent" phagocytosis that occurs after apoptotic cells containing the parasites are phagocytosed by non-activated macrophages ("Trojan horse" strategy) [34][35][36]. Our results of enhanced production of this chemokine are in line with the literature, where infections by L. infantum, and L. major have all been shown to enhance the production of IL-8 [37][38][39].…”