Interferon-gamma is required for the late but not early control of Leishmania amazonensis infection in C57Bl/6 mice

Abstract

The critical role of interferon-gamma (IFN-γ) in the resistance of C57Bl/6 mice to Leishmania major is widely established but its role in the relative resistance of these animals to L. amazonensis infection is still not clear. In this work we use C57Bl/6 mice congenitally deficient in the IFN-γ gene (IFN-γ KO) Leishmaniasis is a complex of diseases caused by the obligate intracellular protozoan parasites of the genus Leishmania. The various clinical forms of human leishmaniasis have been partially reproduced in different strains of mice. For example, C57Bl/6 mice infected with L. major develop cutaneous lesions that spontaneously heal, whereas BALB/c mice harbor non-healing cutaneous lesions. Such experimental models have earlier allowed definition of some of the immunological factors involved in resistance and susceptibility to L. major infection (Reiner & Locksley 1995). During L. major infection of mice, a polarized differentiation of Th1/Th2 CD4 + T cells occurs in resistant and susceptible mice and the Th1 cytokine interferon-γ (IFN-γ) plays an essential role in controlling parasite growth and disease progression (Scott 1991, Liew et al. 1997. Evidence for the critical role for IFN-γ in the control of L. major infection comes from the demonstration that IFN-γ knockout (KO) mice fail to cure infection (Wang et al. 1994).In contrast to L. major, the immunological mechanisms determining susceptibility and resistance to L. amazonensis have been less studied. This is of relevance since the pathogenesis caused by L. amazonensis in humans follows a pattern different from that described for L. major and has been associated not only with localized cutaneous lesions but also with diffuse cutaneous leishmaniasis and more rarely, fatal visceral leishmaniasis (Convit et al. 1993, Almeida et al. 1996. Notably, in IFN-γ production by CD8 + T cells has been associated with immunoregulatory responses induced by leishmanial antigens that elicit significant protection against L. amazonensis (Champsi & McMahon-Pratt 1988, Soong et al. 1997) and an overproduction of IFN-γ seems necessary for development of a resistant phenotype (Afonso & Scott 1993). The protective role of IFN-γ in L. amazonensis infection is further questioned in a more recent report showing that IFN-γ promotes the replication of L. amazonensis amastigotes in macrophages, as opposed to its inhibitory effect on L. major infected macrophages (Qi et al. 2004). In vivo, adoptive transfer of naïve splenocytes devoid of CD4 + CD25 + Treg cells into RAG1-/-mice before infection markedly exacerbated disease progression, and this effect was associated with a marked production of IFN-γ by the effector T cells (Ji et al. 2005). Since the role of IFN-γ during L. amazonensis infection is not a resolved issue, in the present work we proposed to evaluate the course of L. amazonensis infection in IFN-γ KO mice. MATERIALS AND METHODSMice -C57Bl/6-background IFN-γ KO mice were a kind gift of Dr Leda Quércia Vieira (Gnotobiology Laboratory, Federal University of Minas Gerais,...

IFN-γ-Dependent Recruitment of CD4+T Cells and Macrophages Contributes to Pathogenesis DuringLeishmania amazonensisInfection

“…The data are representative of 2 independent experiments. in vivo (Pinheiro and Rossi-Bergmann 2007), and the administration of recombinant IFN-g was not sufficient to induce protection from this parasite in BALB/c mice (Barral-Netto and others 1996). Moreover, the induction of a stronger level of Th1 polarization in a vaccine-treated experimental model (Carneiro and others 2014) or in IL-10-deficient mice ( Jones and others 2002) failed to reverse their susceptibility to this parasite.…”

“…In vitro experiments showed that IFNg stimulated the replication of the amastigote forms of the parasite in macrophages instead of killing them (Qi and others 2004). Additionally, during in vivo infections, IFN-g was not required for protection during the early stages of infection (Pinheiro and Rossi-Bergmann 2007).…”

Immunohistochemical evidence of stress and inflammatory markers in mouse models of cutaneous leishmaniosis

“…Indeed many stimuli for VEGF production have been identified which could be involved in leishmanial infection, including hypoxia, HIFs, cytokines and nitric oxide (NO) [18,50,66]. Of relevance to this work is the cytokine interferon-c (IFNc) [52], which is associated with host resistance to Leishmania [3], and produced by C57BL/6 mice infected with L. amazonensis [10,49]. In addition, endogenous NO enhances VEGF synthesis in in vitro models, including macrophages [52,66], and is associated with control of leishmaniasis, since high levels of NO are known to be leishmanicidal and are continuously produced by C57BL/6 mice infected with L. amazonensis [30].…”

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

“…The low IFN-γ production is, in our experience, at least partially responsible for the maintenance of parasites in tissues. Although IFN-γ has been shown to favor growth of L. amazonensis amastigotes in macrophages in vitro and in vivo (Qi et al 2004), this cytokine seems to participate in the late control of L. amazonensis (Pinheiro & Rossi-Bergmann 2007). Moreover, when IFN-γ production is elevated by vaccination, a small but significant decrease in parasite levels is seen (Vanloubbeeck & Jones 2004, Hernández et al 2006, Hernández Sanabria et al 2007, González-Lombana et al 2008.…”