Clinical and immunological spectra of human cutaneous leishmaniasis in North Africa and French Guiana

Abstract

Cutaneous leishmaniasis (CL) caused by infection with the parasite Leishmania exhibits a large spectrum of clinical manifestations ranging from single healing to severe chronic lesions with the manifestation of resistance or not to treatment. Depending on the specie and multiple environmental parameters, the evolution of lesions is determined by a complex interaction between parasite factors and the early immune responses triggered, including innate and adaptive mechanisms. Moreover, lesion resolution requires parasite control as well as modulation of the pathologic local inflammation responses and the initiation of wound healing responses. Here, we have summarized recent advances in understanding the in situ immune response to cutaneous leishmaniasis: i) in North Africa caused by Leishmania (L.) major, L. tropica, and L. infantum, which caused in most cases localized autoresolutives forms, and ii) in French Guiana resulting from L. guyanensis and L. braziliensis, two of the most prevalent strains that may induce potentially mucosal forms of the disease. This review will allow a better understanding of local immune parameters, including cellular and cytokines release in the lesion, that controls infection and/or protect against the pathogenesis in new world compared to old world CL.

Keywords: L. braziliensis; L. guyanensis; L. infantum; L. major; L. tropica; clinical manifestation; cutaneous leishmaniasis (CL); local immune response.

Figure 1

The pathogenesis of CL and the evolution of lesions are multifactorial; it depends on the complex interactions between the Leishmania parasite, the immune system, and the skin environment, including the vector-injected particles and the microbial skin communities. Sandfly saliva contains potent vasodilators, maxadilan, and adenosine, described respectively in Lutzomyia longipalpis and P. papatasi, that prevent clotting at the biting site (12), in addition of proteins that trigger a host immune response (–15). As clearly demonstrated by several investigators, sandfly saliva contains immunomodulatory molecules that have been shown to enhance disease progression (–18). Some of them, such as the parasite secretory gel (PSG), afford Leishmania protection from a hostile pro-inflammatory environment. They may directly regulate macrophages activation in dampening the early pro-inflammatory response and orchestrating wound repair and re-epithelialization (19). In fresh wounds, a robust pro-inflammatory response is required to sterilize the damaged tissue of potentially pathogenic bacteria. The skin microbiota plays a fundamental role in the host immune system’s induction, education, and function. In turn, the host immune system has evolved multiple means to maintain its homeostatic relationship with the microbiota. It has been shown that Staphylococcus spp., Streptococcus spp., Enterococcus spp, Pseudomonas spp, and other opportunistic bacteria are present in CL lesions (–22). It was proven using a Leishmania-infected mouse with dysbiotic skin microbiota that naturally acquired dysbiosis can cause a change in inflammatory responses and disease progression. It has been demonstrated that the skin microbiome could modulate the skin’s immune response by enhancing IL17 production, which is essential in mediating inflammation in CL. While Th17 cells are a source of IL-17, it is possible that IL-17 produced by innate lymphoid cells present in the skin could contribute to disease progression. In effect, Scoot’s team has suggested that following infection by L. major, RORγt+ILCs produced IL-17 in the skin may contribute to disease progression.

Figure 2

Clinical features of cutaneous leishmaniasis caused by L. major, L. tropica and L. infantum (Old world) (A) compared to L. braziliensis and L. guyanensis (New World) (B). Case photos were provided by the laboratory of Medical Parasitology and Mycology. Institute Pasteur of Tunis. and Dermatology Department, Centre Hospitalier de Cayenne, French Guiana. ^*Risk for mucosal involvement is about 6% for L. braziliensis and 1% for L. guyanensis. Reference: North Africa; French Guiana (, –57).

Figure 3

The T helper 1 (Th1)-type T helper 2 (Th2)-type balance across the cutaneous leishmaniasis severity. Mucosal and disseminated CL caused by L. guyanensis and L. braziliensis are the most severe form of the disease. They are on opposite sides of the Th1 and Th2 response, which enhances disease severity in an exaggerated response. An uncontrolled Th1 response in mucocutaneous leishmaniasis can cause an exaggerated cellular response, in which Leishmania amastigotes spread to the nasopharyngeal mucosa and cause tissue damage resulting in disfiguring lesions. For localized cutaneous leishmaniasis, mixed T_H1 and T_H2 responses have been observed during the active stage of infection; the Th1 profile is mainly associated with the healing of lesions.

Figure 4

Immune responses and skin cytokine profile during cutaneous leishmaniasis infection. Pro-inflammatory cytokines are produced primarily to amplify the immune response to Leishmania infection. The major proinflammatory cytokines include TNF-α, IFN-γ, IL-1, IL-8, IL-12, IL-17 and Granzyme β. In contrast, anti-inflammatory cytokines are immunoregulatory molecules that counteract the effects of pro-inflammatory cytokines to limit the inflammation. These major anti-inflammatory cytokines include IL-5, IL-6, IL-4, IL-10, IL-13, and TGF-β. It has been proposed that the existence of Tregs in infected tissues could be an immune response from the host to maintain the balance to control Leishmania infection and reduce excessive inflammation that supports parasite survival. This is achieved by Tregs inhibiting Th17 cells through the production of IL-10. The role of the local humoral response to amastigote spreading and tissue destruction is still uncompletely understood.

Figure 5

The in situ immune response against L. guyanensis contains a dsRNA virus called (LRV-1). The response to the virus is mediated by TLR 3 in the endosomal macrophage compartment, where the parasite lives and divides. A hypothesis is that after the infection, the viral RNA is released after parasite death and binds to TLR-3 (143), promoting pro-inflammatory cytokines and chemokines production such as IL-6, TNF-α, CXCL-10, and CCL-5 and controlling the severity of the disease (144). Generally, L. guyanensis infection induces a mixed Th1/Th2/Th17 immune response. Th-17 cells appear to predominate in lesions in the presence of Leishmania RNA with high production of IL17-A. TGF-β is essential for establishing infection and, together with IL-10, leads to therapeutic failures and increased disease severity. The stimulation of TLR3 results in the downregulating of IFN-γ receptor expression, reducing macrophage activation, which explains the high level of IFN-γ observed in lesions produced by Th-1. Indeed, via Akt (Protein kinase B) signaling, TLR3 activation by LRV1 promoted parasite persistence (145). Altogether, it enhances inflammation and thus exacerbates disease.

Figure 6

Comparison between the in situ immune profiles in lesions of patients infected with the five Leishmania species (L. major, L. infantum, L. tropica, L. guyanensis, L. braziliensis) and the implication for pathogenesis and the control of the diseases.