Tissue Damage in Human Cutaneous Leishmaniasis: Correlations Between Inflammatory Cells and Molecule Expression

Saldanha, Maíra; Pagliari, Carla; Queiroz, Adriano; Machado, Paulo Roberto Lima; Carvalho, Lucas P.; Scott, Phillip; Carvalho, Edgar M.; Arruda, Sérgio

doi:10.3389/fcimb.2020.00355

Cited by 13 publications

(6 citation statements)

References 37 publications

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“…This disease, termed mucosal leishmaniasis, is most often caused by L. braziliensis parasites and is refractory to anti-parasitic treatment. While the parasites are largely controlled by the immune response, there is a large infiltration of inflammatory cells into the lesions, suggesting that the damage is due to an overexuberant inflammatory response rather than uncontrolled parasite growth ( 11 ). While mucosal leishmaniasis is the most severe form of the disease at the inflammatory end of the spectrum, single lesions in patients infected by L. braziliensis can also be chronic, resistant to drug treatment, and associated with a severe inflammatory response with a low parasite burden in the lesions.…”

Section: Spectrum Of Clinical Presentations In Cutaneous Leishmaniasismentioning

confidence: 99%

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Host-Directed Therapies for Cutaneous Leishmaniasis

2021

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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.

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Section: Spectrum Of Clinical Presentations In Cutaneous Leishmaniasismentioning

confidence: 99%

“…This is most clearly observed in DCL patients ( 9 ). In contrast, patients with a strong Th1 cell response also develop severe disease, but in this case due to inflammation rather than massive parasite numbers ( 11 ). This spectrum is not unique to cutaneous leishmaniasis.…”

Section: Spectrum Of Clinical Presentations In Cutaneous Leishmaniasismentioning

confidence: 99%

Host-Directed Therapies for Cutaneous Leishmaniasis

2021

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“…The exception was for IL-4, which presented much lower relative quantitation in the 10 4 group compared to the 10 5 and 10 6 groups. Meanwhile, the multivariate analysis demonstrated that the IFN-γ gene, which was highly expressed, was the only independent variable that directly influences lesion size, strengthening the role of imbalanced proinflammatory responses on CL pathogenesis ( 55 – 57 ). Although no cytokine influenced parasite loads, CL2B1 presented lower parasite loads than CL2B2.…”

Section: Discussionmentioning

confidence: 95%

A Cytokine Network Balance Influences the Fate of Leishmania (Viannia) braziliensis Infection in a Cutaneous Leishmaniasis Hamster Model

et al. 2021

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The golden hamster is a suitable model for studying cutaneous leishmaniasis (CL) due to Leishmania (Viannia) braziliensis. Immunopathological mechanisms are well established in the L. (L.) major-mouse model, in which IL-4 instructs a Th2 response towards progressive infection. In the present study, we evaluated the natural history of L. braziliensis infection from its first stages up to lesion establishment, with the aim of identifying immunological parameters associated with the disease outcome and parasitism fate. To this end, hamsters infected with 104, 105, or 106 promastigotes were monitored during the first hours (4h, 24h), early (15 days, 30 days) and late (50 days) post-infection (pi) phases. Cytokines, iNOS and arginase gene expression were quantified in the established lesions by reverse transcription-quantitative PCR. Compared to the 105 or 106 groups, 104 animals presented lower lesions sizes, less tissue damage, and lower IgG levels. Basal gene expression in normal skin was high for TGF-β, and intermediary for TNF, IL-6, and IL-4. At 4hpi, no cytokine induction was observed in the 104 group, while an upregulation of IL-6, IL-10, and IL-4 was observed in the 106 group. At 15dpi, lesion appearance was accompanied by an increased expression of all assessed cytokines, markedly in the 105 and 106 groups. Upregulation of all investigated cytokines was observed in the late phase, although less expressive in the 104 group. IFN-γ was the depending variable influencing tissue damage, while IL-6 was associated to parasite load. The network correlating gene expression and clinical and laboratorial parameters indicated inoculum-independent associations at 15 and 30dpi. A strong positive network correlation was observed in the 104 group, but not in the 105 or 106 groups. In conclusion, IL-4, IL-6, IL-10, and TGF-β are linked o L. braziliensis progression. However, a balanced cytokine network is the key for an immune response able to reduce the ongoing infection and reduce pathological damage.

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“…In mice models, and more especially in humans, 31 lesion evolution depends on parasite burden but it is also influenced by the inflammatory response. 32 Therefore, the immune response could affect parasite survival and critically determine tissue damage and healing of lesions as well as response to treatment.…”

Section: Discussionmentioning

confidence: 99%

Effect of topical berberine in murine cutaneous leishmaniasis lesions

Calvo

Moreno

Aldalur

et al. 2022

Journal of Antimicrobial Chemotherapy

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Objectives More effective topical treatments remain an unmet need for the localized forms of cutaneous leishmaniasis (CL). The aim of this study was to evaluate the efficacy and safety of a topical berberine cream in BALB/c mice infected with Leishmania major parasites. Methods A cream containing 0.5% berberine-β-glycerophosphate salt and 2.5% menthol was prepared. Its physicochemical and stability properties were determined. The cream was evaluated for its capacity to reduce lesion size and parasitic load as well as to promote wound healing after twice-a-day administration for 35 days. Clinical biochemical profile was used for estimating off-target effects. In vitro time-to-kill curves in L. major-infected macrophages and skin and plasma pharmacokinetics were determined, aiming to establish pharmacokinetic/pharmacodynamic relationships. Results The cream was stable at 40°C for 3 months and at 4°C for at least 8 months. It was able to halt lesion progression in all treated mice. At the end of treatment, parasite load in the skin was reduced by 99.9% (4 log) and genes involved in the wound healing process were up-regulated compared with untreated mice. The observed effects were higher than expected from in vitro time-to-kill kinetic and plasma berberine concentrations, which ranged between 0.07 and 0.22 μM. Conclusions The twice-a-day administration of a topical berberine cream was safe, able to stop parasite progression and improved the appearance of skin CL lesions. The relationship between drug plasma levels and in vivo effect was unclear.

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Tissue Damage in Human Cutaneous Leishmaniasis: Correlations Between Inflammatory Cells and Molecule Expression

Cited by 13 publications

References 37 publications

Host-Directed Therapies for Cutaneous Leishmaniasis

Host-Directed Therapies for Cutaneous Leishmaniasis

A Cytokine Network Balance Influences the Fate of Leishmania (Viannia) braziliensis Infection in a Cutaneous Leishmaniasis Hamster Model

Effect of topical berberine in murine cutaneous leishmaniasis lesions

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