O013 Metastatic leishmaniasis—An IL-17 mediated response to Leishmania-virus

Abstract

Introduction As veterans of infection, Leishmania guyanensis parasites have been plaguing humankind for centuries, provoking a deleterious hyper-inflammatory response, destroying host tissue and forming the ulcerating lesions, which typify most forms of the disease. About 15% of patients develop secondary lesions in the mouth and nose, where parasites metastasise to mucocutaneous tissues creating corrosive and exceptionally disfiguring inflammation. Our lab has recently linked disease severity in these infections to a virus naturally residing within the cytoplasm of some leishmania parasites. Here, Leishmania RNA virus (LRV) can act as an independently immunogenic entity, where its RNA-based nucleic acid acts as a potent innate immunogen, triggering a destructive hyper-inflammatory cascade through Toll-Like-Receptor 3 recognition [1] . The immune effectors underlying the devolution of stubborn and metastatic leishmaniasis of have largely focused on the Th1/Th2 (healing/non-healing) dogma: a paradigm, which neglects the role and interactions of other T-cell subsets, such as Th17. Methods Using Leishmania guyanensis clones, which are either naturally infected by LRV (V + ) or depleted in it (V − ), we set out to characterise the perpetrators of this chronic hyper-inflammation in a murine model of infection. These candidates were then used as targets for immunomodulatory intervention, with the aim of reaching a therapeutic end. Results Here, we found that V + parasites potently induced the production of IL-17A as compared to their V − equivalents, thus insinuating that this pro-inflammatory cytokine plays a destructive role in the devolution and severity of metastatic leishmaniasis. Indeed, IL-17A −/− mice infected with V + parasites have a significantly reduced disease severity and parasite burden compared to wild type controls. Further, in vitro studies revealed that IL-17A directly increases the parasitism of macrophages while simultaneously decreasing their ability to clear the infection. SR-1001: a recently described drug inhibiting the differentiation of Th17 cells, has been used in a pioneering study that inhibited the development of destructive inflammation in multiple sclerosis, we propose this immunomodulator (and its cheaper equivalent Digoxin), for trials in the treatment of complicated metastatic leishmaniasis. Conclusion Although IL-17 has a promiscuous role in immunity, stimulating both the innate and adaptive immune systems (as well as a plethora of non-immune cells), a major shared goal of these pathways is their self-propagation, where down-stream effects converge to create a hyper-inflammatory feedback loop. Indeed, the Th17 T-cell population has been thoroughly vilified as the architect of many chronic and destructive inflammatory processes. Determining the role of IL-17 in LRV-based virulence is essential to our understanding of its pathogenesis and would stand to guide and justify a much-needed immunotherapeutic revolution in the treatment of complicated leishmaniases.