Cytokines and Their STATs in Cutaneous and Visceral Leishmaniasis

Cytokines play a critical role in shaping the host immune response to Leishmania infection and directing the development of protective and non-protective immunities during infection. Cytokines exert their biological activities through the activation and translocation of transcription factors into the nucleus whether they drive the expression of specific cytokine-responsive genes. Signal transducer and activator of transcription (STATs) are transcription factors which play a critical role in mediating signaling downstream of cytokine receptors and are important for shaping the host immune response during Leishmania infection. Here we discuss the signature cytokines and their associated STATs involved in the host immune response during cutaneous and visceral leishmaniasis

Host-Directed Drug Therapies for Neglected Tropical Diseases Caused by Protozoan Parasites

The neglected tropical diseases (NTDs) caused by protozoan parasites are responsible for significant morbidity and mortality worldwide. Current treatments using anti-parasitic drugs are toxic and prolonged with poor patient compliance. In addition, emergence of drug-resistant parasites is increasing worldwide. Hence, there is a need for safer and better therapeutics for these infections. Host-directed therapy using drugs that target host pathways required for pathogen survival or its clearance is a promising approach for treating infections. This review will give a summary of the current status and advances of host-targeted therapies for treating NTDs caused by protozoa

Interleukin 21 Is a T Helper (Th) Cell 2 Cytokine that Specifically Inhibits the Differentiation of Naive Th Cells into Interferon γ–producing Th1 Cells

The cytokine potential of developing T helper (Th) cells is directly shaped both positively and negatively by the cytokines expressed by the effector Th cell subsets. Here we find that the recently identified cytokine, interleukin (IL)-21, is preferentially expressed by Th2 cells when compared with Th1 cells generated in vitro and in vivo. Exposure of naive Th precursors to IL-21 inhibits interferon (IFN)-γ production from developing Th1 cells. The repression of IFN-γ production is specific in that the expression of other Th1 and Th2 cytokines is unaffected. IL-21 decreases the IL-12 responsiveness of developing Th cells by specifically reducing both signal transducer and activator of transcription 4 protein and mRNA expression. These results suggest that Th2 cell-derived IL-21 regulates the development of IFN-γ–producing Th1 cells which could serve to amplify a Th2 response

Lymphocytes influence Leishmania major pathogenesis in a strain-dependent manner

Cutaneous leishmaniasis (CL) is the most common form of leishmaniasis and is caused byseveral species of Leishmania parasite. Clinical presentation of CL varies from a self-healinginfection to a chronic form of the disease determined by the virulence of infecting Leishmaniaspecies and host immune responses to the parasite. Mouse models of CL showcontradictory roles of lymphocytes in pathogenesis, while acquired immune responses areresponsible for host protection from diseases. To reconcile the inconclusive roles ofacquired immune responses in pathogenesis, we infected mice from various genetic backgroundswith two pathogenic strains of Leishmania major, Friedlin or 5ASKH, and assessedthe outcome of the infections. Our findings showed that the genetic backgrounds of L. majordetermine the impact of lymphocytes for pathogenesis. In the absence of lymphocytes, L.major Friedlin induced the lowest inflammatory reaction and pathology at the site of infection,while 5ASKH infection induced a strong inflammatory reaction and severe pathology.Lymphocytes ameliorated 5ASKH mediated pathology, while it exacerbated pathology duringFriedlin infection. Excess inflammatory reactions, like the recruitment of macrophages,neutrophils, eosinophils and production of pro-inflammatory cytokines, together with uncontrolledparasite growth in the absence of lymphocytes during 5ASKH infection may inducesevere pathology development. Taken together our study provides insight into the impact ofdifferences in the genetic background of Leishmania on CL pathogenesis