Toll-like receptors 2, 4, and 9 expressions over the entire clinical and immunopathological spectrum of American cutaneous leishmaniasis due to Leishmania (V.) braziliensis and Leishmania (L.) amazonensis

Farhat Afrin,Luciana Vieira do Rêgo Lima,Ana Carolina Stocco de Lima,Marliane Batista Campos,Claudia Maria de Castro Gomes,Patrícia Karla Santos Ramos,Thiago Vasconcelos dos Santos,Fernando Tobias Silveira

doi:10.1371/journal.pone.0194383

Farhat Afrin, Luciana Vieira do Rêgo Lima + Show 6 more

Open Access

https://doi.org/10.1371/journal.pone.0194383

Copy DOI

Journal: PloS one	Publication Date: Mar 15, 2018
Citations: 28	License type: CC BY 4.0

Affiliation: Ministry of Health

Abstract

Leishmania (V.) braziliensis and Leishmania(L.) amazonensis are the most pathogenic agents of American Cutaneous Leishmaniasis in Brazil, causing a wide spectrum of clinical and immunopathological manifestations, including: localized cutaneous leishmaniasis (LCLDTH+/++), borderline disseminated cutaneous leishmaniasis (BDCLDTH±), anergic diffuse cutaneous leishmaniasis (ADCLDTH-), and mucosal leishmaniasis (MLDTH++++). It has recently been demonstrated, however, that while L. (V.) braziliensis shows a clear potential to advance the infection from central LCL (a moderate T-cell hypersensitivity form) towards ML (the highest T-cell hypersensitivity pole), L. (L.) amazonensis drives the infection in the opposite direction to ADCL (the lowest T-cell hypersensitivity pole). This study evaluated by immunohistochemistry the expression of Toll-like receptors (TLRs) 2, 4, and 9 and their relationships with CD4 and CD8 T-cells, and TNF-α, IL-10, and TGF-β cytokines in that disease spectrum. Biopsies of skin and mucosal lesions from 43 patients were examined: 6 cases of ADCL, 5 of BDCL, and 11 of LCL caused byL. (L.) amazonensis; as well as 10 cases of LCL, 4 of BDCL, and 6 of ML caused byL. (V.) braziliensis. CD4+ T-cells demonstrated their highest expression in ML and, in contrast, their lowest in ADCL. CD8+ T-cells also showed their lowest expression in ADCL as compared to the other forms of the disease. TNF-α+showed increased expression from ADCL to ML, while IL-10+and TGF-β+ showed increased expression in the opposite direction, from ML to ADCL. With regards to TLR2, 4, and 9 expressions, strong interactions of TLR2 and 4 with clinical forms associated with L. (V.) braziliensis were observed, while TLR9, in contrast, showed a strong interaction with clinical forms linked to L. (L.) amazonensis. These findings strongly suggest the ability of L. (V.) braziliensis and L. (L.) amazonensis to interact with those TLRs to promote a dichotomous T-cell immune response in ACL.

Highlights

American cutaneous leishmaniasis (ACL) is a parasitic protozoan disease caused by different species of the genus Leishmania that are widely distributed throughout Latin America [1]
With regards to CD4+ T-cell densities in the relative spectrum of ACL caused by L. (L.) amazonensis, there were no differences (p> 0.05) between the central form localized cutaneous leishmaniasis (LCL) (1465 ± 194.3 cells/ mm2) and the subpolar borderline disseminated cutaneous leishmaniasis (BDCL) form (1198 ± 84.2 cells/mm2), both clinical forms showed higher cell densities (p< 0.05) than the polar form anergic diffuse cutaneous leishmaniasis (ADCL) (394 ± 159.3 cells/mm2): LCL/BDCL > ADCL
Considering the relative spectrum of ACL caused by L. (V.) braziliensis, an equivalence (p> 0.05) could be observed between the cell densities of the central LCL (1568 ± cells/mm2) and polar mucosal leishmaniasis (ML) (1741± 175.5 cells/mm2) forms, only the cell density of ML form was seen to be greater than the BDCL (1364 ± 179.6 cells/ mm2) form (p< 0.05)

Summary

Introduction

American cutaneous leishmaniasis (ACL) is a parasitic protozoan disease caused by different species of the genus Leishmania that are widely distributed throughout Latin America [1]. (L.) amazonensis may produce LCL (the most frequent form of the disease occupying the center of that spectrum, with moderate T-cell hypersensitivity), but principally ML andADCL, the most severe forms occupying the extreme pathogenicity poles of that spectrum; i.e., the highest and lowest T-cell hypersensitivity, respectively. Those Leishmania species may produce BDCL, an intermediary form showing partial inhibition of T-cell hypersensitivity between the central LCL and the two polar forms, ML and ADCL, which can occupy both sides of that spectrum It should be noted that the immunopathogenic abilities of L. (V.) braziliensis and L. (L.) amazonensis have been confirmed in experimental BALB/c mice model–which have shown that those Leishmania species are able to modulate differential expressions of dendritic cells and T-cell immune responses [5]

Methods

Results

Conclusion