Can We Harness Immune Responses to Improve Drug Treatment in Leishmaniasis?

Abstract

Leishmaniasis is a vector-borne parasitic disease that has been neglected in priority for control and eradication of malaria, tuberculosis, and HIV/AIDS. Collectively, over one seventh of the world's population is at risk of being infected with 0.7-1.2 million new infections reported annually. Clinical manifestations range from self-healing cutaneous lesions to fatal visceral disease. The first anti-leishmanial drugs were introduced in the 1950's and, despite several shortcomings, remain the mainstay for treatment. Regardless of this and the steady increase in infections over the years, particularly among populations of low economic status, research on leishmaniasis remains under funded. This review looks at the drugs currently in clinical use and how they interact with the host immune response. Employing chemoimmunotherapeutic approaches may be one viable alternative to improve the efficacy of novel/existing drugs and extend their lifespan in clinical use.

Keywords: chemotherapy; host directed therapy; immunity; immunochemotherapy; leishmaniasis.

Figure 1

Proposed outcome of management of leishmaniasis using chemoimmunotherapeutic approach. (A): Therapeutic success can be achieved via three possible routes. Administration of drugs achieves clinical cure which inhibits parasite replication within host cells. In parallel, the host immune response could be activated by immune-mediators and directly or indirectly disrupt parasite growth or magnify drug uptake in host cells via upregulation of a specific Th1 response. This drives the activation of macrophages. Since both of these approaches are associated with different levels of success, a third approach is to combine the drug with a host-directed therapeutic or therapeutics in a chemo-immunotherapeutic approach, where host immune responses are targeted in conjunction with the drug, overall, potentiating an enhanced Th1 response and leishmanicidal effect. (B): Therapeutic failure occurs if an antileishmanial drug does not reach the appropriate sites of infection. Alternatively, this occurs if the drug induces genetic changes by selecting for “fitter” parasites that are resistant to the drug and/or oxidative stress or if intracellular parasites induce modifications to alter drug uptake and/or efflux from infected host cells, both of which render parasites less responsive to treatment. In parallel, Leishmania parasites are immunosuppressive; hijacking host immunity and impairing Th1 differentiation by inducing factors that enable disease by reducing the efficacy of the host immune responses such as, downregulating macrophage-derived nitric oxide whilst concomitantly, enhancing IL-10 to deactivate macrophage killing effector functions. An expert understanding of the host immune response is needed to implement the third approach as a chemoimmunotherapeutic regimen could exacerbate inflammatory responses. Enhanced inflammation could enhance recruitment of host-cells for parasite replication, select for fitter parasites, which are drug-resistant and unresponsive to host antileishmanicidal products, or induce a cytokine storm that is ultimately detrimental to the host.

Figure 2

Host-directed therapies and immunochemotherapies and the protective roles they play in the mammalian host. (1) Various organs (A, infected spleen; B, infected skin; C, infected bone marrow; D, infected liver; and E, infected lymph node) are infected with Leishmania, the site depending on the infecting spp. (2) Administration of a drug in combination with an immunomodulator e.g., cytokines, co-stimulatory/inhibitory molecules, immune cells, which increase the antileishmanial Th1 population and boosts subsequent parasite clearance (3–5), represents a host-directed therapeutic drug target. (3) The administration of statins (an inhibitor of hydroxy-3-methylglutaryl coenzyme A reductase) enhanced host macrophage phagosome and killing effector function by lowering host cholesterol. (4) Inhibiting the cytotoxic T lymphocyte Ag-4 led to increased granuloma formation and IFN-γ and IL-4 production by the liver and spleen, which induced host-protective immunity. (5) Fucoidan activated p38 and ERK1/2 pathways leading to increased iNOS production, whereby p38 increased IL-12 levels and ERK1/2 enhanced TNF-α and NF-κB signal transduction for host-protective immunity. (6) Combination of drugs and HDTs leads to parasite clearance. Figure was created in BioRender.com.