The Dangerous Liaisons in the Oxidative Stress Response to Leishmania Infection

Abstract

Leishmania parasites preferentially invade macrophages, the professional phagocytic cells, at the site of infection. Macrophages play conflicting roles in Leishmania infection either by the destruction of internalized parasites or by providing a safe shelter for parasite replication. In response to invading pathogens, however, macrophages induce an oxidative burst as a mechanism of defense to promote pathogen removal and contribute to signaling pathways involving inflammation and the immune response. Thus, oxidative stress plays a dual role in infection whereby free radicals protect against invading pathogens but can also cause inflammation resulting in tissue damage. The induced oxidative stress in parasitic infections triggers the activation in the host of the antioxidant response to counteract the damaging oxidative burst. Consequently, macrophages are crucial for disease progression or control. The ultimate outcome depends on dangerous liaisons between the infecting Leishmania spp. and the type and strength of the host immune response.

Keywords: LRV1; Leishmania; NF-kB; NRF2; ROS; inflammation; macrophage.

Figure 1

Representation of the different pathways and enzymes leading to the production of parasitotoxic molecules and enzymes (red) and of detoxification enzymes (green) in macrophages infected by Leishmania parasites.

Figure 2

The oxidative stress and the inflammatory response in Leishmania infection. Independently of the presence of LRV1, the NRF2 pathway is activated upon contact between the parasite and the macrophage producing oxygen species generated by NOX2 permitting the release of NRF2 from its negative regulator KEAP1 and phosphorylation via SFK and PKC. This anti-oxidant response limits the NF-kB inflammatory and the production of inflammatory chemokines and cytokines. In the presence of LRV1 in Leishmania parasites, survival of infected macrophages is increased and production of Type-I interferon and inflammatory chemokines and cytokines are induced leading to accelerated dissemination of the infection via IL-17.