Interferon-γ Is a Crucial Activator of Early Host Immune Defense against Mycobacterium ulcerans Infection in Mice

Abstract

Buruli ulcer (BU), caused by infection with Mycobacterium ulcerans, is a chronic necrotizing human skin disease associated with the production of the cytotoxic macrolide exotoxin mycolactone. Despite extensive research, the type of immune responses elicited against this pathogen and the effector functions conferring protection against BU are not yet fully understood. While histopathological analyses of advanced BU lesions have demonstrated a mainly extracellular localization of the toxin producing acid fast bacilli, there is growing evidence for an early intra-macrophage growth phase of M. ulcerans. This has led us to investigate whether interferon-γ might play an important role in containing M. ulcerans infections. In an experimental Buruli ulcer mouse model we found that interferon-γ is indeed a critical regulator of early host immune defense against M. ulcerans infections. Interferon-γ knockout mice displayed a faster progression of the infection compared to wild-type mice. This accelerated progression was reflected in faster and more extensive tissue necrosis and oedema formation, as well as in a significantly higher bacterial burden after five weeks of infection, indicating that mice lacking interferon-γ have a reduced capacity to kill intracellular bacilli during the early intra-macrophage growth phase of M. ulcerans. This data demonstrates a prominent role of interferon-γ in early defense against M. ulcerans infection and supports the view that concepts for vaccine development against tuberculosis may also be valid for BU.

Author Summary

Mycobacterium ulcerans is the causative agent of Buruli ulcer (BU), a slow progressing ulcerative skin disease. The mode of transmission of M. ulcerans remains unknown and only little is known about the early stages of the disease and the nature of protective immune responses against this pathogen. Given the increasing evidence for an early intracellular growth phase of M. ulcerans, we aimed at evaluating the impact of cell-mediated immunity for immunological defense against M. ulcerans infections. By comparing wild-type and interferon-γ-deficient mice in a BU mouse model, we could demonstrate that interferon-γ is a critical regulator of early host immune defense against M. ulcerans infections, indicative for an important role of early intracellular multiplication of the pathogen. In mice lacking interferon-γ the bacterial burden increased faster, resulting in accelerated pathogenesis. The observed differences between the two mouse strains were most likely due to differences in the capacity of macrophages to kill intracellular bacilli during the early stages of infection.