Baron et al. show that mycolactone, an immunosuppressive macrolide produced by the pathogen Mycobacterium ulcerans, operates by targeting the Sec61 translocon. This identifies the most potent Sec61 inhibitor reported to date and the potential of inhibiting Sec61 for immune modulation.
Depression is the leading cause of disability worldwide. Recent observations have revealed an association between mood disorders and alterations of the intestinal microbiota. Here, using unpredictable chronic mild stress (UCMS) as a mouse model of depression, we show that UCMS mice display phenotypic alterations, which could be transferred from UCMS donors to naïve recipient mice by fecal microbiota transplantation. The cellular and behavioral alterations observed in recipient mice were accompanied by a decrease in the endocannabinoid (eCB) signaling due to lower peripheral levels of fatty acid precursors of eCB ligands. The adverse effects of UCMS-transferred microbiota were alleviated by selectively enhancing the central eCB or by complementation with a strain of the Lactobacilli genus. Our findings provide a mechanistic scenario for how chronic stress, diet and gut microbiota generate a pathological feed-forward loop that contributes to despair behavior via the central eCB system.
Inflammation adversely affects the health of millions of people worldwide, and there is an unmet medical need for better anti-inflammatory drugs. We evaluated the therapeutic interest of mycolactone, a polyketide-derived macrolide produced by Mycobacterium ulcerans. Bacterial production of mycolactone in human skin causes a combination of ulcerative, analgesic, and anti-inflammatory effects. Whereas ulcer formation is mediated by the proapoptotic activity of mycolactone on skin cells via hyperactivation of Wiskott-Aldrich syndrome proteins, analgesia results from neuronal hyperpolarization via signaling through angiotensin II type 2 receptors. Mycolactone also blunts the capacity of immune cells to produce inflammatory mediators by an independent mechanism of protein synthesis blockade. In an attempt to isolate the structural determinants of mycolactone's immunosuppressive activity, we screened a library of synthetic subunits of mycolactone for inhibition of cytokine production by activated T cells. The minimal structure retaining immunosuppressive activity was a truncated version of mycolactone, missing one of the two core-branched polyketide chains. This compound inhibited the inflammatory cytokine responses of human primary cells at noncytotoxic doses and bound to angiotensin II type 2 receptors comparably to mycolactone in vitro. Notably, it was considerably less toxic than mycolactone in human primary dermal fibroblasts modeling ulcerative activity. In mouse models of human diseases, it conferred systemic protection against chronic skin inflammation and inflammatory pain, with no apparent side effects. In addition to establishing the anti-inflammatory potency of mycolactone in vivo, our study therefore highlights the translational potential of mycolactone core-derived structures as prospective immunosuppressants.
Mycolactone is a diffusible lipid toxin produced by Mycobacterium ulcerans, the causative agent of a necrotizing skin disease referred to as Buruli ulcer. Intriguingly, patients with progressive lesions display a systemic suppression of Th1 responses that resolves on surgical excision of infected tissues. In this study, we examined the effects of mycolactone on the functional biology of T cells and identified two mechanisms by which mycolactone suppresses cell responsiveness to antigenic stimulation. At noncytotoxic concentrations, mycolactone blocked the activation-induced production of cytokines by a posttranscriptional, mammalian target of rapamycin, and cellular stress-independent mechanism. In addition, mycolactone triggered the lipid-raft association and activation of the Src-family kinase, Lck. Mycolactone-mediated hyperactivation of Lck resulted in the depletion of intracellular calcium stores and downregulation of the TCR, leading to impaired T cell responsiveness to stimulation. These biochemical alterations were not observed when T cells were exposed to other bacterial lipids, or to structurally related immunosuppressors. Mycolactone thus constitutes a novel type of T cell immunosuppressive agent, the potent activity of which may explain the defective cellular responses in Buruli ulcer patients.
Summary
Mycobacteria are characterized by a complex cell wall, the lipid nature of which confers to the bacilli resistance to drying, acid or alkaline conditions, and to chemical disinfectants and therapeutic agents. Pathogenic species, such as Mycobacterium tuberculosis, M. leprae and M. ulcerans, have evolved various strategies to establish residence in their hosts and provoke long‐term infections. There is mounting evidence that the unique lipids composing their envelopes, strategically located at the host‐pathogen interface, contribute to their escape from immune surveillance. Here, the chemical structure, host cell receptors and biological actions of this emerging class of mycobacterial virulence factors are reviewed.
Mycolactones are complex macrolides responsible for a severe necrotizing skin disease called Buruli ulcer. Deciphering their functional interactions is of fundamental importance for the understanding, and ultimately, the control of this devastating mycobacterial infection. We report herein a diverted total synthesis approach of mycolactones analogues and provide the first insights into their structure-activity relationship based on cytopathic assays on L929 fibroblasts. The lowest concentration inducing a cytopathic effect was determined for selected analogues, allowing a clear picture to emerge by comparison with the natural toxins.
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