Abstract
Chemokines and chemokine receptor-mediated effects are important mediators of the immunological response and cure in human leishmaniasis. However, in addition to their signalling properties for leukocytes, many chemokines have also been shown to act directly as antimicrobial peptides on bacteria and fungi. We screened ten human chemokines (CXCL2, CXCL6, CXCL8, CXCL9, CXCL10, CCL2, CCL3, CCL20, CCL27, CCL28) for antimicrobial effects on the promastigote form of the protozoan parasite Leishmania mexicana, and observed direct parasiticidal effects of several, CCL28 being the most potent. Damage to the plasma membrane integrity could be visualised by entrance of propidium iodide, as measured with flow cytometry, and by scanning electron microscopy, which showed morphological changes and aggregation of cells. The findings were in concordance with parasiticidal activity, measured by decreased mitochondrial activity in an MTT-assay. This is the first report of direct antimicrobial activity by chemokines on parasites. This component of immunity against Leishmania parasites identified here warrants further investigation that might lead to new insight in the mechanisms of human infection and/or new therapeutic approaches.
Highlights
Cutaneous, mucocutaneous and visceral leishmaniasis in humans are caused by several species of the intracellular protozoan parasite Leishmania
CCL3 exerted a marginal effect, whereas CXCL8, CCL2 and CCL27 did not cause a statistically significant decrease in viability. These findings were in concordance with pilot studies in which cells were manually counted in a Neubauer chamber on days 0–3 after incubation with the chemokines, corresponding well to survival of cells on day 3 (Table S1)
Treatment with the limited number of drugs available against leishmaniasis is lengthy, costly, and frequently has side effects with considerable morbidity and risks, and healing requires an appropriate immune response evoked by the host, in which chemokines are likely to play an important part
Summary
Mucocutaneous and visceral leishmaniasis in humans are caused by several species of the intracellular protozoan parasite Leishmania. The clinical picture and outcome of disease depends on the particular Leishmania species that causes infection, immunological status, and possibly genetic factors of the host. When the promastigote form of the parasite enters the haemorrhagic pool caused by the bite of an infected sand fly, it is rapidly taken up by dermal macrophages, neutrophils and other antigen presenting cells. The promastigote transforms to the smaller amastigote form, which multiplies in the phagosome/parasitophorous vacuole of the macrophage. Throughout its life cycle, the Leishmania parasite has to withstand the immune systems of both vector and host long enough to secure further transmission through the bite. It has evolved different ways to modulate the immune response of the mammalian host outside and within the hostile environment of the phagosomes of macrophages
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