New therapeutic targets uncovered for leishmaniasis

Researchers from the University of Pennsylvania (PA, USA) have elucidated the role of inflammasome activation in mediating leishmaniasis progression and severity; in addition, they demonstrated that therapies inhibiting the inflammasome and the cytokine IL-1β can protect against severe disease in mouse models.

The study, published recently in PLOS Pathogens, reported that NLRP3 inflammasome activation, as a consequence of CD8 T cell-mediated cytotoxicity, was a key component driving the formation of skin lesions in leishmaniasis. Moreover, the researchers identified two drugs, currently FDA-approved for other diseases, which block key components of this pathway and appear to significantly reduce disease severity.

Leishmaniasis is currently endemic in 98 countries with an estimated 1 million new cases reported each year. This study focused on the cutaneous form of the disease and the team hypothesized that major tissue damage from skin ulcers was not a direct effect of the Leishmania parasite, but instead the result of an aberrant immune response, specifically caused by CD8 T cells.

In a previous study, the group discovered that expression levels of the gene encoding IL-1β, a cytokine involved in inflammation, were elevated in human tissue samples of leishmaniasis skin lesions. First author Fernanda O. Novais (University of Pennsylvania) explained:  “In earlier work, we found that CD8 T cells lead to inflammation, but what we didn’t know was what was downstream from the CD8 T cells. Here we discover the pathway by which they cause inflammation.”

To further explore the role of IL-1β the researchers examined a mouse model of leishmaniasis, demonstrating that mice with CD8 T cells had higher levels of IL-1β, when compared with mice lacking T cells altogether. Moreover, mice with CD8 T cells developed skin lesions, whereas the control group did not.

In addition, the team demonstrated that capsase-1, the enzyme responsible for producing IL-1β, and the NLRP3 inflammasome, a protein complex responsible for producing capsase-1, were required to produce skin lesions. They discovered that treating mice with an IL-1β inhibitor significantly reduced leishmaniasis severity; moreover, blocking caspase-1 and NLRP3 inflammasome also prevented severe disease.

The researchers additionally tested these inhibitors in human cells in vitro, demonstrating these compunds reduced the production of IL-1β. “What we found was that drugs blocking either the inflammasome or IL-1β have the same effect in controlling disease,” commented Novais.

Author Phillip Scott, from the University of Pennsylvania, summarized:  “At this point, we have solid evidence in the mouse that blocking these pathways with a couple of different drugs blocks the pathology, and we have data from patients that this pathway is operating in humans. What we don’t have is information on whether blocking these pathways will clear up pathology in patients.”

Investigating the role of these pathways on disease pathology in humans will be priority for this research moving forwards, as the team hope that clinical trials testing the drug in leishmaniasis patients will be the next step.

Scott concluded:  “This is a neglected tropical disease, so it can be difficult to get the investment needed to develop new therapies. Our discoveries implicate the use of drugs in leishmaniasis that are already in use for other inflammatory diseases. This will be the foundation for clinical trials moving forward.”

Source: Novais FO, Caralho AM, Clark ML et al. CD8+ T cell cytotoxicity mediates pathology in the skin by inflammasome activation and IL-1β production. PLoS pathog. doi:10.1371/journal.ppat.1006196 (2017) (Epub ahead of print)


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