The Severity of Visceral Leishmaniasis Correlates with Elevated Levels of Serum IL-6, IL-27 and sCD14

Abstract

BackgroundVisceral leishmaniasis (VL) is a severe disease caused by infection with protozoa of the genus Leishmania. Classic VL is characterized by a systemic infection of phagocytic cells and an intense activation of the inflammatory response. It is unclear why 90% of infected individuals do not develop the disease while a minority develop the classical form. Furthermore, among those that develop disease, a small group progresses to more severe form that is unresponsive to treatment. The presence of inflammatory mediators in serum could theoretically help to control the infection. However, there is also a release of anti-inflammatory mediators that could interfere with the control of parasite multiplication. In this study, we took advantage of the spectrum of outcomes to test the hypothesis that the immune profile of individuals infected with Leishmania (L.) infantum is associated with the development and severity of disease.Methodology/Principal FindingsSera from patients with confirmed diagnosis of VL were evaluated for the presence of numerous molecules, and levels compared with healthy control and asymptomatic infected individuals.Conclusions/Principal FindingsAlthough differences were not observed in LPS levels, higher levels of sCD14 were detected in VL patients. Our data suggest that L. infantum may activate the inflammatory response via CD14, stimulating a generalized inflammatory response with production of several cytokines and soluble molecules, including IFN-γ, IL-27, IL-10, IL-6 and sCD14. These molecules were strongly associated with hepatosplenomegaly, neutropenia and thrombocytopenia. We also observed that IL-6 levels greater than 200 pg/ml were strongly associated with death. Together our data reinforce the close relationship of IFN-γ, IL-10, IL-6, TNF-α and IL-27 in the immune dynamics of VL and suggest the direct participation of sCD14 in the activation of the immune response against L. infantum.

Interleukin-27 Early Impacts Leishmania infantum Infection in Mice and Correlates with Active Visceral Disease in Humans

“…are expert in modulating immune activity through diverse strategies (4). Previous reports on human leishmaniasis indicate that IL-27 increases when the disease is active in both cutaneous (26–28) and visceral forms (7, 8). Here, for the first time, plasma levels of IL-27 were evaluated in L. infantum -infected individuals from Europe.…”

“…To address if the increase of systemic IL-27 is a common fact of VL among different endemic areas (7, 8), we determined this cytokine in the plasma of active L. infantum infected individuals from a current outbreak in Spain. Patients with active disease presented higher IL-27 levels than both cured ( p  ≤ 0.001) and negative controls ( p  ≤ 0.001) (Figure 1A).…”

“…Active visceral leishmaniasis (VL) patients from India (7) and Brazil (8) present increased IL-27 in plasma. In mice, IL-27 appears to be essential to prevent severe immunopathology after infection with both cutaneous (9) and visceral (10) strains, mainly through the effects of IL-10.…”

Interleukin-27 (IL-27) Mediates Susceptibility to Visceral Leishmaniasis by Suppressing the IL-17–Neutrophil Response

“…The production of IL-27 has been observed in the serum of patients with VL, which correlated with the severity of the disease (19). Thus, we hypothesized that IL-27 could mediate susceptibility to VL.…”

“…Therefore, the role of IL-27 in the regulation of the immune response can lead to higher parasite replication or to the control of infection. It was recently observed that visceral leishmaniasis patients present high levels of IL-27 in serum, which decreases after successful treatment (19). Thus, we hypothesized that IL-27 plays a role in the regulation of immune response during L. infantum infection, which could exacerbate the disease in a mouse model of visceral leishmaniasis.…”