Differential properties of CBA/J mononuclear phagocytes recovered from an inflammatory site and probed with two different species of Leishmania

Abstract

While CBA/J mice fail to be permissive to Leishmania amazonensis-driven pathogenic processes, they heal easily following Leishmania major infection. The early-phase events are crucial to the outcome of Leishmania infection and it is known that macrophages (Mphi) are important in infection control. In the present study we investigated the role of Mphi in driving CBA/J susceptibility to L. amazonensis. We performed kinetic studies and compared the capacity of L. amazonensis and L. major to infect Mphi. There was no difference in percentages of infection or parasite burden for 6 h between the two groups. In contrast, after 12 h we observed that infection was about twice as high in L. amazonensis- than in L. major-infected Mphi. In addition, rIFN-gamma added to the cultures induced nitric oxide (NO) production, and did not modify L. amazonensis infection, although the percentage of L. major infection was significantly reduced. This reduction in L. major infection is a TNF-alpha dependent mechanism as L. major-infected Mphi expressed twice as much TNF-alpha mRNA as L. amazonensis-infected cells, and anti-TNF-alpha reversed the IFN-gamma effect. Moreover, rTNF-alpha plus IFN-gamma were able to significantly reduce the percentage of L. amazonensis-infected cells but not to the same extent as in L. major infection. Despite having higher NO production than IFN-gamma-treated cells, AMG addition to IFN-gamma-plus TNF-alpha-treated cells only partially reversed the inhibition in L. major, but not in L. amazonensis infection. Thus, in this study, we demonstrated that L. amazonensis both inactivated and resisted innate and IFN-gamma-induced Mphi killing mechanisms, indicating that the nature of the parasite and its interaction with Mphi could determine immune response polarization.

IFN-β Impairs Superoxide-Dependent Parasite Killing in Human Macrophages: Evidence for a Deleterious Role of SOD1 in Cutaneous Leishmaniasis

“…Moreover, the same histopathological pattern was observed in CBA mice infected with L. amazonensis, but not with L. major (30), confirming the striking differences between New World and Old World Leishmania species. Additionally, when compared with L. major, L. amazonensis was highly resistant to NO-mediated leishmanicidal activity in murine macrophages in vitro (31,32), but Mukbel et al (32) found parasite killing to be dependent on superoxide production, in agreement with our findings. In parallel with New World leishmanial infection, killing of M. tuberculosis was shown to be NO-independent in human macrophages (33), and M. bovis bacterial load was significantly increased upon IFN-␣/␤ treatment (34).…”

Leukotrienes Are Essential for the Control ofLeishmania amazonensisInfection and Contribute to Strain Variation in Susceptibility

“…However, it has been reported that NO inhibition did not modify the course of L. amazonensis infection in vitro (42) or in vivo (24). Our results with L-NAME implicated NO as a major mediator of leishmanicidal activity of LTB 4 .…”

Low and high-dose intradermal infection with Leishmania majorand Leishmania amazonensis in C57BL/6 mice

“…It has been previously shown that macrophages from mice infected with L. major produce more TNF than do those from mice infected with L. amazonensis (Gomes et al 2003). Moreover, CBA mice produce less TNF when infected with L. amazonensis than when infected with L. major (Lemos de Souza et al 2000).…”