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.

Therapeutic effect of oral quercetin in hamsters infected with Leishmania Viannia braziliensis

“…The authors showed that treatment with quercetin was able to decrease labile iron in macrophages through the regulation of Nrf2/HO-1 expression, resulting in a decrease in the iron available to the parasite and consequently inducing its death (Cataneo et al, 2019). Although the production of toxic radicals by macrophages (such as ROS and NO) is crucial for the control of infection by intracellular microorganisms, such as Leishmania, the excess of these mediators is also associated with tissue damage and pathogenesis (revised by Bogdan, 2020;Reverte et al, 2022) Several studies have demonstrated the anti-inflammatory effects of quercetin involving the inhibition of nitric oxide production as well as the production of proinflammatory cytokines (Kim et al, 2004;Tsai et al, 2022). In this sense, quercetin appears to be an interesting drug candidate for leishmaniasis since it has both direct antileishmanial activity and the potential to modulate the microbicidal and inflammatory activity of macrophages.…”

Dissection of the macrophage response towards infection by the Leishmania-viral endosymbiont duo and dynamics of the type I interferon response

“…On one hand, Ifi202b, also known as IFNactivated gene 202B and encoding for the P202 protein, belongs to the pyrin and HIN domain-containing (PYHIN) proteins, as AIM2 and IFI16 (Wang et al, 2018). In several studies, Ifi202b has been associated with sex differences in autoimmune diseases (Panchanathan et al, 2011;Cao et al, 2018) and this question has recently been addressed in the Leishmania inflammation context (Lockard et al, 2019;Snaka et al, 2022). Likewise, Ifi202b has been shown to be upregulated upon L. major footpad infection in C57BL/6 mice (Ehrchen et al, 2010) and its corresponding P202 protein to exert an inhibitory effect on the AIM2 inflammasome (Wang et al, 2018).…”

“…One of such processes includes the recognition and ultimately elimination of pathogens. In order to achieve that, macrophages employ a plethora of mechanisms such as oxidative burst, inflammation, or antigen presentation ( Shapouri-Moghaddam et al., 2018 ; Rossi and Fasel, 2018a ; Ferrari, 2019 ; Sheu and Hoffmann, 2022 ; Reverte et al., 2022 ). However, these responses are not always straightforward nor unidirectional as pathogens use different strategies to hijack the macrophage machinery and ultimately exploit it to their advantage.…”

“…However, these responses are not always straightforward nor unidirectional as pathogens use different strategies to hijack the macrophage machinery and ultimately exploit it to their advantage. This is particularly true for intracellular pathogens such as Leishmania that have evolved over thousands of years to counteract the microbicidal power of macrophages ( Gupta et al., 2013 ; Rossi and Fasel, 2018a ; Reverte et al., 2022 ).…”

“…Moreover, it has been shown that Leishmania are able to block AIF1 (allograft inflammatory factor-1) expression in macrophages and degrade CXCL1 to inhibit the pro-inflammatory responses and the recruitment of neutrophils, respectively ( Yorek et al., 2019 ; da Silva et al., 2021 ). Parasites can also inhibit the inflammasome through the upregulation of the A20 protein ( Hartley et al., 2018 ; Zamboni and Sacks, 2019 ) or interfere with the oxidative stress response ( Reverte et al., 2021 ; Reverte et al., 2022 ).…”