Cytokines: Key Determinants of Resistance or Disease Progression in Visceral Leishmaniasis: Opportunities for Novel Diagnostics and Immunotherapy

Abstract

Leishmaniasis is a parasitic disease of humans, highly prevalent in parts of the tropics, subtropics, and southern Europe. The disease mainly occurs in three different clinical forms namely cutaneous, mucocutaneous, and visceral leishmaniasis (VL). The VL affects several internal organs and is the deadliest form of the disease. Epidemiology and clinical manifestations of VL are variable based on the vector, parasite (e.g., species, strains, and antigen diversity), host (e.g., genetic background, nutrition, diversity in antigen presentation and immunity) and the environment (e.g., temperature, humidity, and hygiene). Chemotherapy of VL is limited to a few drugs which is expensive and associated with profound toxicity, and could become ineffective due to the parasites developing resistance. Till date, there are no licensed vaccines for humans against leishmaniasis. Recently, immunotherapy has become an attractive strategy as it is cost-effective, causes limited side-effects and do not suffer from the downside of pathogens developing resistance. Among various immunotherapeutic approaches, cytokines (produced by helper T-lymphocytes) based immunotherapy has received great attention especially for drug refractive cases of human VL. Therefore, a comprehensive knowledge on the molecular interactions of immune cells or components and on cytokines interplay in the host defense or pathogenesis is important to determine appropriate immunotherapies for leishmaniasis. Here, we summarized the current understanding of a wide-spectrum of cytokines and their interaction with immune cells that determine the clinical outcome of leishmaniasis. We have also highlighted opportunities for the development of novel diagnostics and intervention therapies for VL.

Ursolic Acid Potentializes Conventional Therapy in Experimental Leishmaniasis

“…In respect to the immunological response, it has been observed that in visceral leishmaniasis, parasites downregulate IFN-γ, a Th1 related cytokine, and in contrast upregulate IL-10, a T regulatory associated cytokine [ 36 , 37 ]. Thus, a low or absent level of circulating IFN-γ will not activate macrophage to a leishmanicidal state; additionally, IL-10 is able to inhibit macrophage activation, and is associated with parasite persistence in the host tissues [ 38 ].…”

Cytokine profile and nitric oxide levels in peritoneal macrophages of BALB/c mice exposed to Fucose-Mannose Ligand of Leishmania infantum combined with Glycyrrhizin

“…with the control of disease caused by Leishmania donovani complex (35). In a recent study, we demonstrated that FML increases the levels of both IL-12p70 and IL-10 in activated macrophages (19).…”

“…VL is characterized by the absence of cytokines such as IFN-γ and IL-12 and cure of VL is associated with a restoration of these cytokines (34). Several reports have shown that IL-10 and IL-12 play opposite roles in control of VL infections (35). The IL-10 is associated with progression VL and IL-12…”

Engineering a vector-based pan-Leishmania vaccine for humans: proof of principle

“…The next step we will follow will be the evaluation of the vaccine candidate in the context of a visceral disease model (e.g. L. infantum transmission by L. longipalpis , the natural parasite-vector pairing from South America), with a certain degree of optimism, since also in visceral disease, a high IFN-γ response, together with a lower IL-10 response are essential for parasite elimination and disease resolution 67 , 68 .…”