Fatal Leishmaniasis in the Absence of TNF Despite a Strong Th1 Response.

Phillip D Fromm,Jessica C Kling,Heinrich Körner,Christian Bogdan,Annika Remke

doi:10.3389/fmicb.2015.01520

Abstract

Induction of inducible nitric oxide synthase in mononuclear phagocytes by IFN-γ and innate tumor necrosis factor (TNF) provide the basis for an effective immune response to the intracellular parasite Leishmania (L.) major. In previous experiments, we observed a fatal visceral form of leishmaniasis in L. major-infected C57BL/6 TNF-/- mice. To further delineate the protective function of TNF and its receptor requirements, we comparatively assessed L. major-infected C57BL/6 mice that were either deficient for membrane and soluble TNF (Tnf-/-), for soluble TNF alone (memTnfΔ/Δ), or the TNF receptors type 1 (Tnfr1-/-) or type 2 (Tnfr2-/-). We detected locally and systemically increased levels of the cytokine IFN-γ in the absence of the TNF-TNFR1-signaling pathway. An analysis of transcription factors and cytokines revealed that activated Tnf-/- CD4+ T cells displayed a highly active Th1 phenotype with a strong usage of the T cell receptor Vβ5.1/2. From these data we conclude that the fatal outcome of L. major infection in Tnf-/- mice does not result from a skewed or deficient Th1 differentiation.

Highlights

Cutaneous leishmaniasis is caused by different species of the protozoan parasite genus Leishmania (L.) such as the “old world” species of Leishmania major (Reithinger et al, 2007; Schonian et al, 2008), which are transferred by the bite of a sand fly (Sacks and Perkins, 1985)
The wildtype controls [C57BL/6, shown as B6.WT (Figure 1) and BALB/c] exhibited the expected symptoms with B6.Wt controlling the infection whereas BALB/c succumbing to a progressive infection
In the present study we have analyzed the clinical course of L. major infection in C57BL/6 mouse strains deficient for tumor necrosis factor (TNF), soluble TNF, TNFR1 or TNFR2 and could show that the outcome was fatal in the absence of TNF and TNFR1

Summary

Introduction

Cutaneous leishmaniasis is caused by different species of the protozoan parasite genus Leishmania (L.) such as the “old world” species of Leishmania major (Reithinger et al, 2007; Schonian et al, 2008), which are transferred by the bite of a sand fly (Sacks and Perkins, 1985). In the case of a L. major infection, the clinical manifestation is limited to a local skin lesion that heals without further treatment. The immune response to L. major in the skin and draining LNs has been analyzed extensively using high- or low-dose mouse infection models (Sacks and Noben-Trauth, 2002; Bogdan, 2008; Liese et al, 2008), but is still only partly understood. IFN-γ drives macrophages to upregulate the enzyme inducible nitric oxide synthase (iNOS, NOS2; Ding et al, 1998) to produce large amounts of the

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Conclusion