Early Cutaneous Leishmaniasis Patients Infected With Leishmania braziliensis Express Increased Inflammatory Responses After Antimony Therapy

Costa, Rúbia; Carvalho, Lucas P.; Campos, Taís M.; Magalhães, Ana Paula Nogueira de; Passos, Sara; Schriefer, Albert; Silva, Juliana Almeida; Lago, Ednaldo; Paixão, Camilla S.; Machado, Paulo Roberto Lima; Scott, Phillip; Carvalho, Edgar M.

doi:10.1093/infdis/jix627

Cited by 25 publications

(30 citation statements)

References 47 publications

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“…But, until now it has not been possible to accomplish a new treatment with less toxicity and at least the same efficacy of the old available drugs. It is important to note that, in parallel to treatment failure, the literature has also evidenced the possibility of an early spontaneous healing without treatment ( Oliveira-Ribeiro et al, 2017 ; Costa et al, 2018 ). In this context, understanding why leishmaniasis is becoming difficult to treat and control can help to develop new approaches to improve the healing of this infection.…”

Section: The Problemmentioning

confidence: 99%

The Binomial Parasite-Host Immunity in the Healing Process and in Reactivation of Human Tegumentary Leishmaniasis

2018

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Leishmaniasis is a vector-borne infectious disease caused by different species of protozoa from the Leishmania genus. Classically, the disease can be classified into two main clinical forms: Visceral (VL) and Tegumentary (TL) leishmaniasis. TL is a skin/mucosal granulomatous disease that manifests mainly as cutaneous localized or disseminated ulcers, papules diffusely distributed, mucosal lesions or atypical lesions. Once the etiology of the infection is confirmed, treatment can take place, and different drugs can be administered. It has already been shown that, even when the scar is clinically evident, inflammation is still present in the native tissue, and the decrease of the inflammatory process occurs slowly during the 1st years after clinical healing. The maintenance of residual parasites in the scar tissue is also well documented. Therefore, it is no longer a surprise that, under some circumstances, therapeutic failure and/or lesion reactivation occurs. All over the years, an impressive amount of data on relapses, treatment resistance and lesion reactivation after healing has been collected, and several factors have been pointed out as having a role in the process. Different factors such as Leishmania species, parasite variability, Leishmania RNA virus 1, parasite load, parasite persistence, age, nutritional status, gender, co-morbidities, co-infection, pregnancy, immunosuppression, lesion duration, number and localization of lesions, drug metabolism, irregular treatment and individual host cellular immune response were described and discussed in the present review. Unfortunately, despite this amount of information, a conclusive understanding remains under construction. In addition, multifactorial influence cannot be discarded. In this context, knowing why leishmaniasis has been difficult to treat and control can help the development of new approaches, such as drugs and immunotherapy in order to improve healing maintenance. In this sense, we would like to highlight some of the findings that may influence the course of Leishmania infection and the therapeutic response, with an emphasis on TL.

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Section: The Problemmentioning

confidence: 99%

The Binomial Parasite-Host Immunity in the Healing Process and in Reactivation of Human Tegumentary Leishmaniasis

2018

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“…The performance of adaptive immune responses in the cicatrization processes is well studied . However, the role of innate immunity in response to antimony treatment needs to be better investigated . Monocytes play an intriguing role in CL because they are host cells for the parasites and at the same time immune response regulating cells equipped to destroy Leishmania .…”

Section: Introductionmentioning

confidence: 99%

“…Monocytes play an intriguing role in CL because they are host cells for the parasites and at the same time immune response regulating cells equipped to destroy Leishmania . It has been described that, after treatment, these cells are activated by IFN‐γ produced by CD4 + and CD8 + T lymphocytes and NK cells and induced to produce TNF that, in synergy with IFN‐γ, activate iNOS to produce NO, which is responsible for the destruction of amastigote forms . Studies have focused on determining important aspects of the immune response in CL as mechanisms associated with natural resistance, the presence of active lesions, and healing after treatment .…”

Section: Introductionmentioning

confidence: 99%

Fcγ‐RI, Fcγ‐RII and IL‐10 as predictive biomarkers for post‐therapeutic cicatrization time in monocytes from cutaneous leishmaniasis patients

Rodrigues-Alves

Melo-Júnior

Coelho-dos-Reis³

et al. 2018

Parasite Immunology

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Cutaneous leishmaniasis (CL) treatment is based on therapy with Glucantime , yet, there are few laboratory methods to monitor its success. In this study, ex vivo and in vitro evaluations of peripheral blood monocytes were performed in a longitudinal study to characterize the impact of Glucantime on overall phenotypic/functional features of these cells from CL patients to identify predictive biomarkers for post-therapeutic monitoring by flow cytometry. The ex vivo evaluation from CL patients demonstrated a modulatory profile before treatment, with a decrease in TLR-2, FcγRII, HLA-DR, CD86, IFN-γR, TNF, IL-12, NO, and an increase in FcγRIII and IL-10R. Conversely, treatment changes some of these biomarker expressions by decreasing FcγRIII and IL-10R and increasing IFN-γR, IL-12 and NO. Moreover, an in vitro analysis of these patients showed a reduced phagocytic capacity of Leishmania braziliensis and higher levels of IL-10 and TGF-β modulating functional profile. Regardless of the compromised L. braziliensis phagocytic capacity, treatment re-established the production of IL-12, IL-10, TGF-β and NO at the basal level. Notably, monocytes from patients with early cicatrization showed enhanced FcγRI and FcγRII expressions and reduced IL-10, which was further corroborated by a baseline fold change analysis. Finally, the logistic regression model emphasized the performance of FcγRI, FcγRII and IL-10 as robust predictive biomarkers for post-therapeutic cicatrization during cutaneous leishmaniasis.

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“…The percentage of failure to therapy was lower than we have usually observed that similar to previous studies. We believe that the limited number of participants of the study was responsible for these differences ( 28 – 30 ).…”

Section: Discussionmentioning

confidence: 99%

“…Between the years 2012 and 2017, 6,597 cases of ATL were reported in the region of Corte de Pedra. As other endemic foci , the cure rates of antimonial pentavalent (Sbv) declined from 90 to 50% in the last 30 years ( 28 – 30 ).…”

Section: Methodsmentioning

confidence: 99%

The miRNA 361-3p, a Regulator of GZMB and TNF Is Associated With Therapeutic Failure and Longer Time Healing of Cutaneous Leishmaniasis Caused by L. (viannia) braziliensis

et al. 2018

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L. (viannia) braziliensis infection causes American Tegumentary Leishmaniasis (ATL), with prolonged time to healing lesions. The potent inflammatory response developed by the host is important to control the parasite burden and infection however an unbalanced immunity may cooperate to the tissue damage observed. The range of mechanisms underlying the pathological responses associated with ATL still needs to be better understood. That includes epigenetic regulation by non-coding MicroRNAs (miRNAs), non-coding sequences around 22 nucleotides that act as post-transcriptional regulators of RNAs encoding proteins. The miRNAs have been associated with diverse parasitic diseases, including leishmaniasis. Here we evaluated miRNAs that targeted genes expressed in cutaneous leishmaniasis lesions (CL) by comparing its expression in both CL and normal skin obtained from the same individual. In addition, we evaluated if the miRNAs expression would be correlated with clinical parameters such as therapeutic failure, healing time as well as lesion size. The miR-361-3p and miR-140-3p were significantly more expressed in CL lesions compared to normal skin samples (p = 0.0001 and p < 0.0001, respectively). In addition, the miR-361-3p was correlated with both, therapeutic failure and healing time of disease (r = 0.6, p = 0.003 and r = 0.5, p = 0.007, respectively). In addition, complementary analysis shown that miR-361-3p is able to identify with good sensitivity (81.2%) and specificity (100%) patients who tend to fail initial treatment with pentavalent antimonial (Sbv). Finally, the survival analysis considering “cure” as the endpoint showed that the higher the expression of miR-361-3p, the longer the healing time of CL. Overall, our data suggest the potential of miR-361-3p as a prognostic biomarker in CL caused by L. braziliensis.

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Early Cutaneous Leishmaniasis Patients Infected With Leishmania braziliensis Express Increased Inflammatory Responses After Antimony Therapy

Abstract: The enhanced production of proinflammatory cytokines, due in part to the decreased ability of IL-10 to down-modulate immune response during therapy in ECL, promotes the development and persistence of leishmania ulcer despite antimony therapy.

Cited by 25 publications

References 47 publications

The Binomial Parasite-Host Immunity in the Healing Process and in Reactivation of Human Tegumentary Leishmaniasis

The Binomial Parasite-Host Immunity in the Healing Process and in Reactivation of Human Tegumentary Leishmaniasis

Fcγ‐RI, Fcγ‐RII and IL‐10 as predictive biomarkers for post‐therapeutic cicatrization time in monocytes from cutaneous leishmaniasis patients

The miRNA 361-3p, a Regulator of GZMB and TNF Is Associated With Therapeutic Failure and Longer Time Healing of Cutaneous Leishmaniasis Caused by L. (viannia) braziliensis

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