Immunoregulation in human American leishmaniasis: balancing pathology and protection

Abstract

Leishmaniasis covers a broad spectrum of diseases with distinct, and sometimes overlapping, characteristics. The common thread in all forms of leishmaniasis is the infection by the parasite Leishmania belonging to the genus Leishmania. Upon infection of humans, there can be at least three outcomes, (i) control of Leishmania by the host immune response resulting in asymptomatic disease, (ii) patent infection and development of a relatively mild form of leishmaniasis and (iii) patent infection and development of severe clinical forms. The factors that determine the outcome of an initial inoculation with Leishmania are many, with the species of Leishmania representing one of the strongest predictive factors for the development of a given clinical form of disease. This is seen with L. braziliensis and L. amazonensis, infection leading mostly to tegumentary forms of disease, and L. infantum with the potential to induce visceral disease. However, it is also clear that the host immune response is a key factor in disease progression, not only responsible for control of Leishmania, but also playing an important role in disease progression and pathology. This duality between protective and pathogenic immune responses in individuals infected with Leishmania in the Americas is the focus of this review.

Keywords: CD4 T lymphocytes; cytokine; human; immunopathology; immunoregulation; leishmaniasis.

Figure 1. Parasite species and host responses influence disease outcome

Leishmania infects macrophages early during infection: 1) infection via the introduction of infective metacyclic promastigotes via an insect bite, 2) initial infection of host macrophages, 3) conversion to intracellular replicating form of the parasite (amastigote), and 4) progression to a complex host-parasite interaction culminating in diseases with distinct clinical forms.

Figure 2. T cell subsets and macrophage interactions in cellular responses to Leishmania

Effective cellular responses to combat Leishmania depend on the formation of CD4+ T cell subsets that are capable of activating leishmaniacidal responses by host macrophages and monocytes. The differentiation of CD4+ T cell subsets, Th1, Th2, Th3, Treg and Th17 all depend greatly on the cytokine microenvironment during the initial activation of naïve CD4+ T cells. Depending on the balance of these cytokines, co-stimulatory molecules, host genetics and antigenic stimuli, a given T cell will differentiate toward one of the Th subsets and produce the effector cytokines indicated in the figure. These cytokines in turn will act on host macrophages and monocytes to prime them for effective or ineffective control of Leishmania and subsequent control or not of immunopathology as well.

Figure 3. Protection - Pathology – Persistence, three way balancing act

After the initial introduction of the pathogen within the host, the infective form of the parasite quickly parasitizes host macrophages and converts to the amastigote, intracellular replicating form of the parasite. This initial interaction between the host and parasite is paramount for establishing the infection and directing the subsequent adaptive immune response. Both parasite and host factors interact to culminate in a beneficial or detrimental host-parasite interaction, which is dependent on multiple factors. However, it is clear that the macrophage itself will be more effective at killing Leishmania under a cytokine environment rich in IFN-gamma and TNF-alpha, and that IL-10 can act to reduce macrophage production of TNF-alpha and parasite killing.

Figure 4. Representation of the two clinical outcomes following infection with L. infantum

While an asymptomatic outcome is associated with lower levels cytokine production and a balance between the cytokines IFN-gamma and IL-10, patients with active VL are associated with higher production of both inflammatory (IFN-gamma and TNF-alpha) and the down regulatory cytokine IL-10. Thus, a suppression of an effective leishmaniacidal response in VL is correlated with disease development, as well as the presence of immunomodulatory molecules such as CTLA-4 leading to ineffective control of Leishmania.