Abstract

Leishmania mexicana can cause both localized (LCL) and diffuse (DCL) cutaneous leishmaniasis, yet little is known about factors regulating disease severity in these patients. We analyzed if the disease was associated with single nucleotide polymorphisms (SNPs) in IL-1β (−511), CXCL8 (−251) and/or the inhibitor IL-1RA (+2018) in 58 Mexican mestizo patients with LCL, 6 with DCL and 123 control cases. Additionally, we analyzed the in vitro production of IL-1β by monocytes, the expression of this cytokine in sera of these patients, as well as the tissue distribution of IL-1β and the number of parasites in lesions of LCL and DCL patients. Our results show a significant difference in the distribution of IL-1β (−511 C/T) genotypes between patients and controls (heterozygous OR), with respect to the reference group CC, which was estimated with a value of 3.23, 95% CI = (1.2, 8.7) and p-value = 0.0167), indicating that IL-1β (−511 C/T) represents a variable influencing the risk to develop the disease in patients infected with Leishmania mexicana. Additionally, an increased in vitro production of IL-1β by monocytes and an increased serum expression of the cytokine correlated with the severity of the disease, since it was significantly higher in DCL patients heavily infected with Leishmania mexicana. The distribution of IL-1β in lesions also varied according to the number of parasites harbored in the tissues: in heavily infected LCL patients and in all DCL patients, the cytokine was scattered diffusely throughout the lesion. In contrast, in LCL patients with lower numbers of parasites in the lesions, IL-1β was confined to the cells. These data suggest that IL-1β possibly is a key player determining the severity of the disease in DCL patients. The analysis of polymorphisms in CXCL8 and IL-1RA showed no differences between patients with different disease severities or between patients and controls.

Highlights

  • Leishmania mexicana can cause a wide spectrum of clinical diseases, ranging from a localized cutaneous ulcer at the infection site, which is characteristic for patients with localized cutaneous leishmaniasis (LCL), to a disseminating disease, where intensely parasitized macrophages form nodules that spread throughout the skin and invade the oropharyngeal and nasal mucosae, which is characteristic for patients with diffuse cutaneous leishmaniasis (DCL)

  • Leishmania mexicana is an intracellular parasite that causes two polarly opposed diseases: One is a self-limited disease, characterized by ulcerative lesions associated with a low infectious load, as found in patients with localized cutaneous leishmaniasis (LCL)

  • The other pole is characterized by a progressive disease where abundant parasites spread uncontrollably throughout the skin inside heavily infected phagocytic cells, as occurs in patients with diffuse cutaneous leishmaniasis (DCL)

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Summary

Introduction

Leishmania mexicana can cause a wide spectrum of clinical diseases, ranging from a localized cutaneous ulcer at the infection site, which is characteristic for patients with localized cutaneous leishmaniasis (LCL), to a disseminating disease, where intensely parasitized macrophages form nodules that spread throughout the skin and invade the oropharyngeal and nasal mucosae, which is characteristic for patients with diffuse cutaneous leishmaniasis (DCL). Whereas LCL patients have a cellular immune response associated with macrophage-activating cytokines such as IFN-c, DCL patients lack an effective cellular immune response, permitting an uncontrolled replication of the parasites within macrophages and other phagocytic cells. Little is known regarding the factors involved in modulating the disease outcome; one of the possible factors are early inflammatory mediators [1,2,3,4,5]. An excessive inflammatory response can lead to increased neutrophil infiltration, which has been associated with disease progression [6,7]. One of factors responsible for neutrophil infiltration is IL-1b [9] This cytokine induces other innate mediators such as acute phase proteins and chemokines such as IL-6 and CXCL8 (IL-8), respectively [10]

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