Date Published: February 10, 2016
Publisher: Public Library of Science
Author(s): Raphael Bieri, Miriam Bolz, Marie-Thérèse Ruf, Gerd Pluschke, Christian Johnson. http://doi.org/10.1371/journal.pntd.0004450
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.
Partial Text: Buruli ulcer (BU), caused by infection with Mycobacterium ulcerans (M. ulcerans), is a progressive disease of the skin and subcutaneous tissue. The disease is primarily affecting West African rural communities, but has also been reported from America, Australia and Asia. The pathogenesis of BU is mainly attributed to mycolactone, a macrolide exotoxin produced by M. ulcerans . Mycolactone is essential for bacterial virulence and is highly cytotoxic for a wide range of mammalian cell types in vitro and in vivo, including fibroblasts, keratinocytes and adipocytes [1–4]. Injection of the toxin induces the formation of necrotic non-inflammatory lesions similar to BU lesions. In addition to the induction of apoptosis, mycolactone possesses immunosuppressive characteristics and has been demonstrated to downregulate local and systemic immune responses [5,6], by interfering with the activation of immune cells such as T-cells, dendritic cells, monocytes and macrophages [7–10]. Furthermore, exposure to mycolactone results in complete inhibition of tumor necrosis factor alpha (TNFα) production by monocytes and macrophages, affects T-cell homing and interferes with the expression of T-cell receptors as well as co-stimulatory molecules including CD40 and CD86 [6–12].
Evidence for an early intra-macrophage growth phase of M. ulcerans has led to the suggestion that the immune effector mechanisms protecting against M. ulcerans infection are similar to those active against M. tuberculosis [41–43]. However, in contrast to this closely related pathogen, M. ulcerans has the capacity to produce the cytotoxic macrolide mycolactone, which eventually kills the host cells and causes the characteristic necrotizing pathology of BU [1,40]. In the case of M. tuberculosis infection, the host immune response involves cell-mediated immunity (CMI) accompanied by a delayed type hypersensitivity (DTH) reaction . Similarly, several reports showed that CMI and DTH responses are frequently induced in BU patients [43,45–50].