Leishmania; Toll-like Receptors; Innate immune response; PKR; ER-Stress Response; Kinases; Autophagy; Anti-Leishmania drugs
Hartley Mary-Anne, Eren Remzi O., Rossi Matteo, Prevel Florence, Castiglioni Patrik, Isorce Nathalie, Desponds Chantal, Lye Lon-Fye, Beverley Stephen M., Drexler Stefan K., Fasel Nicolas (2018), Leishmania guyanensis parasites block the activation of the inflammasome by inhibiting maturation of IL-1β, in Microbial Cell
, 5(3), 137-149.
Eren R.O. Kopelyanskiy D. Moreau D. Chapalay J.B. Chambon M. Turcatti G. Lye L.F. Beverley S. (2018), Development of a semi-automated image-based high-throughput drug screening system, in Frontiers in bioscience
, 10, 242-253.
Dias-Teixeira Karina Luiza, Calegari-Silva Teresa C., Medina Jorge M., Vivarini Áislan C., Cavalcanti Átila, Teteo Nataly, Santana Alynne Karen M., Real Fernando, Gomes Ciro M., Pereira Renata Meirelles Santos, Fasel Nicolas, Silva João S., Aktas Bertal H., Lopes Ulisses G. (2017), Emerging Role for the PERK/eIF2α/ATF4 in Human Cutaneous Leishmaniasis, in Scientific Reports
, 7(1), 17074-17074.
Rossi M. Castiglioni P. Hartley M.A. Eren R.O. Prével F. Desponds C. Utzschneider D.T. Zehn D (2017), Type I interferons induced by endogenous or exogenous viral infections promote metastasis and relapse of leishmaniasis., in PNAS
, 114(19), 4987-4992.
Kuhlmann F. Matthew, Robinson John I., Bluemling Gregory R., Ronet Catherine, Fasel Nicolas, Beverley Stephen M. (2017), Antiviral screening identifies adenosine analogs targeting the endogenous dsRNA Leishmania RNA virus 1 (LRV1) pathogenicity factor, in Proceedings of the National Academy of Sciences
, 114(5), E811-E819.
Eren RO Fasel N (2017), Macrophage Survival Assay Using High Content Microscopy, in Bio-Protocol
, 7(16), 2509.
Eren Remzi Onur, Reverte Marta, Rossi Matteo, Hartley Mary-Anne, Castiglioni Patrik, Prevel Florence, Martin Ricardo, Desponds Chantal, Lye Lon-Fye, Drexler Stefan K, Reith Walter, Beverley Stephen M, Ronet Catherine, Fasel Nicolas (2016), Mammalian Innate Immune Response to a Leishmania-Resident RNA Virus Increases Macrophage Survival to Promote Parasite Persistence., in Cell host & microbe
, 20(3), 318-28.
Calegari-Silva TC Vivarini ÁC Pereira RMS Dias-Teixeira KL Rath CT Pacheco ASS Silva GBL Pint, Leishmania amazonensis downregulates macrophage iNOS expression via Histone Deacetylase 1 (HDAC1): a novel parasite evasion mechanism, in Eur J Immunol
Patients infected with Leishmania protozoan parasites present either cutaneous lesions (CL) at the site of the sand fly bite or metastatic leishmaniases such as visceral (VL) and Post Kala-Azar dermal (PKDL), disseminated (DCL), diffuse (DL) and mucosal (ML) forms. The poor immunologic control can be due to susceptibilities of the host or parasite virulence factors influencing the host cell innate immune response and the survival of the infected cell. The signalling cascades, induced by the infection, are triggered by various Pattern Recognition Receptors such as the Toll-like Receptors (TLRs), many of them being intricately involved in leishmanial immune response.In South America, New World Leishmania (L.) species such as L. amazonensis and L. guyanensis can subvert the innate immune system of the host to survive and induce metastatic leishmaniasis. In both cases, the exacerbation was caused by the production of type I Interferons (IFNs-I). Thanks to the work of the two applicants, the signalling cascades triggering IFN-I have been linked to Leishmania RNA virus (LRV) present in L. guyanensis and activating the Toll-like Receptor 3 (TLR3) and to the dsRNA dependent Protein Kinase (PKR) in L. amazonensis infections respectively. These two immune evasion strategies leading to exacerbation of the disease could use convergent or different pathways.Results obtained in Switzerland demonstrated that the presence of a viral endosymbiont (LRV) found naturally inside L. guyanensis parasites triggered TLR3, induced IFN-beta secretion, pro-inflammatory chemokines and cytokines, exacerbated the pathology possibly by increasing survival of infected macrophages. Preliminary experimental evidence suggested that, in the infected macrophage, LRV-activated TLR3 induced AKT1, a pro-survival kinase, and thereby down-regulating apoptosis of the infected macrophage. Interestingly, LRV-activated TLR3 induces the microRNA (miR155), which is known to trigger autophagy in macrophages. Results obtained in Brazil with L. amazonensis (which causes CL and also disseminated leishmaniasis) demonstrated that the dsRNA-dependent kinase (PKR) is activated in L. amazonensis infected macrophages leading to the expression of IL-10 and IFN-beta. The PKR/IFN-beta axis plays a pivotal role on the parasite intracellular replication and results obtained in human biopsies from CL and ADCL patients revealed a dramatic increase of PKR and IFN1 expression in the latter group, thus indicating an important role in the severity of the disease. Moreover, our data suggests that ER stress is induced in L. amazonensis infected cells and may control the progression of the infection throughout the expression IFN-beta and the activation of the NF-E2-related factor 2 (Nrf2). The data obtained by Brazilian group shows that Nrf2, a transcription factor that control the expression of anti-oxidative responsive genes, is translocated to nuclei of infected macrophage, binds to the ARE (Antioxidant Responsive Elements) sequences of genes such as SOD1 and seems to relief the oxidative stress due to the infection. Importantly, PKR and AKT1 activation are required for Nrf2 signalling in the context of the infection.How these different kinases ending up with IFN-beta secretion modulate survival of the infected macrophage and are relevant to the clinical complications is not clear. This proposal aims at investigating the relevance of host cell kinases in L. guyanensis and L. amazonensis infections and to define how they program the host cell to the advantage of the parasites and infected macrophage survival. Both groups will investigate specific kinases, kinase signaling pathways and downstream targets in infected macrophages. Emphasis will be put on the pro-survival kinase, AKT1 which blocks apoptosis, induces an early glycolytic flux, regulates the mammalian Target of Rapamycin complex (mTORC1), and consequently autophagy (AIM 1) and on the Endoplasmic Reticulum (ER) stress response (AIM 2) in macrophages infected with LRV+ or LRV- L. guyanensis as well with L. amazonensis. A major obstacle in controlling leishmaniases is the variation in drug responsiveness across different species, thus, finding common ground in druggable pathways such as autophagy and ER stress response, brings much promise. Our results will not only improve our understanding of host-parasite interactions but should, at the end, propose new therapeutics to disrupt the pathogenic evasion strategies. It could have an impact not only on L. guyanensis and L. amazonensis infections but also on other types of Leishmania spp. infections. It will also give essential information on the changes induced on the metabolism of the host cell.