Host-Directed Therapies for Cutaneous Leishmaniasis

Abstract

Cutaneous leishmaniasis exhibits a wide spectrum of clinical presentations from self-resolving infections to severe chronic disease. Anti-parasitic drugs are often ineffective in the most severe forms of the disease, and in some cases the magnitude of the disease can result from an uncontrolled inflammatory response rather than unrestrained parasite replication. In these patients, host-directed therapies offer a novel approach to improve clinical outcome. Importantly, there are many anti-inflammatory drugs with known safety and efficacy profiles that are currently used for other inflammatory diseases and are readily available to be used for leishmaniasis. However, since leishmaniasis consists of a wide range of clinical entities, mediated by a diverse group of leishmanial species, host-directed therapies will need to be tailored for specific types of leishmaniasis. There is now substantial evidence that host-directed therapies are likely to be beneficial beyond autoimmune diseases and cancer and thus should be an important component in the armamentarium to modulate the severity of cutaneous leishmaniasis.

A Mouse Model of Ulcerative Cutaneous Leishmaniasis by Leishmania (Viannia) panamensis to Investigate Infection, Pathogenesis, Immunity, and Therapeutics

“…A significant in vivo leishmanicidal effect that induced subsequent resolution of lesions was evidenced both with Glucantime ® , the agent used to successfully treat the CL patient from whom the UA-946 L(V)p was isolated, and with Miltefosine, which has been increasingly used to treat CL in the New World ( Pinart et al, 2020 ). Likewise, since host-directed immunotherapeutic interventions have been used to treat leishmaniasis ( Mota et al, 2021 ) and are gaining special attention ( Novais et al, 2021 ), we also confirmed that low dose of the TLR9 agonist CpG protected mice clinically and parasitologically from L(V)p CL when co-delivered with the challenge or when used as an adjuvant of total L(V)p antigen in a vaccination setting ( Zimmermann et al, 1998 , 2008 ; Raman et al, 2012 ). Moreover, the model allowed us to identify a protective 28–30 kDa L(V)p subproteome (termed F9) via forward vaccinology and confirm that F9 induces a shift toward a Th1 response.…”

“…While the immunopathological mechanisms operating in L(V) infections have been enigmatic for many years, two relevant pathways have been recently described. In one, cytotoxic activities involving CD8+ T and NK cells linked to inflammatory executors such as NLRP3 inflammasome, IL-1β, and neutrophils mediate exacerbated tissue damage in response to L(V)b infection ( Novais et al, 2021 ; Carvalho et al, 2022 ). In the other, the innate immune recognition of the viral RNA present in L(V)g isolates harboring the Leishmania virus LRV1 (or via exogenous viral coinfections) triggers a type I IFN response, immunopathology, chronicity, and metastasis ( Rossi and Fasel, 2018b ).…”

Considerations about leishmaniasis and the current scenario for the development of new treatments

“…Studies report the role of T cellmediated immune responses to this parasitosis, with cytokines associated with a Th1 profile (IFN-gamma, TNF and IL-12) leading to the activation of macrophages and parasite death, as well as functioning as protective immunity, as well as the production of Th2 cytokines (IL-4, IL -5 and IL-10) causing the evolution of the disease with the replication and persistence of the parasite (Dayakar et al, 2019;Maspi et al, 2016;Scorza et al, 2017). Therefore, it is important to consider this response when developing new drugs, searching for new therapeutic strategies that aim to modulate these immune mechanisms positively in favor of the host (Novais et al, 2021). New drugs active against Leishmania species, must present efficacy against the parasite, and be planned for a short-term treatment model with safety and tolerability for patients.…”

Liposomal Amphotericin B for Treatment of Leishmaniasis: From the Identification of Critical Physicochemical Attributes to the Design of Effective Topical and Oral Formulations

“…In addition to drug toxicity, a major challenge in the treatment of leishmaniasis is that traditional antileishmanial drugs face specific difficulties penetrating inside the macrophages to reach parasites. This context has stimulated the search for strategies to target and improve drug delivery to the host cell [ 9 ], as well as to enhance drug efficacy through host-directed therapy [ 3 , 10 ].…”