Th17 cells and neutrophils: Close collaborators in chronic <i>Leishmania mexicana</i> infections leading to disease severity

Pedraza-Zamora, C. P.; Delgado-Domínguez, José; Zamora‐Chimal, Jaime; Becker, Ingeborg

doi:10.1111/pim.12420

Cited by 31 publications

(32 citation statements)

References 64 publications

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“…Neutrophils, through the release of inflammatory mediators and the formation of NETs, can drive inflammation [41]. L. mexicana was reported to elicit locally the formation of NETs and to favor the differentiation of Th17 cells recruiting more neutrophils to the lesion [7,42]. These 2 processes may participate in the development and persistence of L. mexicana lesions.…”

Section: Discussionmentioning

confidence: 99%

Frontline Science: Leishmania mexicana amastigotes can replicate within neutrophils

Hurrell

Beaumann

Heyde

et al. 2017

Journal of Leukocyte Biology

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Cutaneous leishmaniasis is a neglected tropical disease, causing a spectrum of clinical manifestations varying from self-healing to unhealing lesions that may be very difficult to treat. Emerging evidence points to a detrimental role for neutrophils during the first hours following infection with many distinct species (spp.) at a time when the parasite is in its nonreplicative promastigote form. Neutrophils have also been detected at later stages of infection in unhealing chronic cutaneous lesions. However, the interactions between these cells and the replicative intracellular amastigote form of the parasite have been poorly studied. Here, we show that amastigotes are efficiently internalized by neutrophils and that this process has only a low impact on neutrophil activation and apoptosis. In neutrophils, the amastigotes were found in acidified vesicles. Furthermore, within cutaneous unhealing lesions, heavily infected neutrophils were found with up to 6 parasites per cell. To investigate if the amastigotes could replicate within neutrophils, we generated photoconvertible fluorescent parasites. With the use of flow cytometry imaging and time-lapse microscopy, we could demonstrate that a subset of parasites replicated within neutrophils. Overall, our data reveal a novel role for neutrophils that can act as a niche for parasite replication during the chronic phase of infection, thereby contributing to disease pathology.

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Section: Discussionmentioning

confidence: 99%

Frontline Science: Leishmania mexicana amastigotes can replicate within neutrophils

Hurrell

Beaumann

Heyde

et al. 2017

Journal of Leukocyte Biology

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“…The disease is categorized as cutaneous (CL), mucocutaneous (MCL) and visceral leishmaniasis (VL), which is caused by over 20 species of the Leishmania (L) parasites . Cutaneous leishmaniasis (CL) with an estimated incidence of 1.5‐2 million cases annually is the most prevalent form of leishmaniasis . Although it is an endemic disease in 98 countries, approximately 75% of human CL cases are reported in only 10 countries including Afghanistan, Algeria, Brazil, Colombia, Costa Rica, Ethiopia, Iran, Sudan, Peru and Syria …”

Section: Introductionmentioning

confidence: 99%

Arginase activity of Leishmania isolated from patients with cutaneous leishmaniasis

Badirzadeh

Taheri

Abedi-Astaneh

et al. 2017

Parasite Immunology

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Cutaneous leishmaniasis (CL) is one of the most important vector-borne parasitic diseases, highly endemic in Iran, and its prevalence is increasing all over the country. Arginase (ARG) activity in isolated Leishmania parasites from CL patients is yet to be explored. This study aimed to compare the ARG activity of isolated Leishmania promastigotes from CL patients with a standard strain of Leishmania major and its influences on the disease pathogenesis. We recruited 16 confirmed CL patients from Qom Province, in central Iran; after detection of Leishmania species using PCR-RFLP, we assessed the levels of ARG in the isolated promastigotes and determined the parasites' growth rate. Only L. major was identified from CL patients. The level of ARG activity in the isolated Leishmania promastigotes from CL patients was significantly higher than that obtained from the standard strain of L. major. No significant correlations between ARG activity and lesion size, number or duration were observed; in contrast, a significant negative correlation was seen between ARG level and Leishmania' growth rate. The obtained results suggest that increased ARG expression and activity in the isolated Leishmania promastigotes might contribute to the higher parasite infectivity and play a major role in the pathogenicity of the CL.

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“…Although some reports have suggested that IL-17 plays a pathogenic role in leishmaniasis (11-13), others showed that they play a protective role (7, 9, 10). Because we found that enhanced resistance of PTX3 -/- mice to L. major was not associated with superior IFN-γ response, we postulated that the enhanced resistance was mediated by increased IL-17 response.…”

Section: Resultsmentioning

confidence: 99%

“…In contrast, susceptibility has been associated with IL-4 and IL-10 production by Th2 cells, which are cytokines that deactivate macrophages and inhibit their ability to kill intracellular parasites (2, 6). Besides Th1 and Th2 cells, IL-17A-secreting Th17 cells have also been shown to mediate either host protection (7-10) or susceptibility (11-13) to leishmaniasis. However, the series of events that leads to the induction of Th17 responses in CL are unknown.…”

Section: Introductionmentioning

confidence: 99%

The Long Pentraxin 3 (PTX3) Suppresses Immunity to Cutaneous Leishmaniasis by Negatively Regulating Th17 Response

Gupta

Jia

Sharma

et al. 2019

Preprint

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25 26 2 27 Abstract:28 The long Pentraxin 3 (PTX3), a soluble pattern recognition molecule, plays a critical role 29 in inflammation, tissue repair and wound healing. Here, we show that PTX3 regulates 30 disease pathogenesis in cutaneous leishmaniasis (CL). PTX3 expression is increased in 31 active skin lesions in patients and mice during CL, with higher levels being expressed in 32 individuals with severe disease. PTX3 deficient (PTX3 -/-) mice were highly resistant to L.33 major infection and the enhanced resistance was associated with increased IL-17 34 response. Neutralization of IL-17A abolished this enhanced resistance while treatment 35 with recombinant PTX3 resulted in reduced IL-17A response and increased susceptibility 36 to L. major infection. Naïve CD4 + T cells from PTX3 -/mice displayed increased 37 differentiation into Th17 cells, which was reversed in the presence of recombinant PTX3. 38 The enhanced Th17 response observed in PTX3 -/cells was associated with increased 39 Leishmania specific IL-6 production from dendritic cells along with enhanced expression 40 of Th17-specific transcription factors including RORt, AhR and STAT3. Addition of 41 recombinant PTX3 significantly inhibited the expression of Th17-specific transcription 42 factors and dramatically reduced the frequency of Th17 cells in Th17-polarizing cultures 43 of PTX3 -/-CD4 + T cells. Collectively, our results show that PTX3 contributes to the 44 pathogenesis of CL by suppressing Th17 differentiation and IL-17A production. 45 46 Author Summary:47 Cutaneous leishmaniasis (CL) is caused by several species of Leishmania. Currently, 48 there is no approved vaccine against human CL because of the poor understanding of 49 the mechanisms that regulate disease pathogenesis and correlates of protective 50 immunity. Because the long pentraxin 3 (PTX3, a soluble pattern recognition molecule 51 that forms an integral part of the host innate immunity), regulates inflammation and 3 52 tissue repair, which are critical physiological events associated with resolution of skin 53 lesions during CL, we investigated its role in disease pathogenesis.54 Here, we show that PTX3 levels were elevated in skin-lesions in patients and mice 55 during CL. Using a loss of function approach, we showed that PTX3 contributes to 56 pathogenesis, and this was associated with increased IL-17A responses. Neutralization 57 and recombinant cytokine treatment studies showed that the increased resistance of 58 PTX3 deficient mice to L. major is due to enhanced Th17 response in these mice. We 59 further show that PTX3 negatively regulates IL-6 production by dendritic cells and the 60 expression of IL-17A-specific transcription factors (including RORT, STAT3, IRF4, 61 BATF and AhR) in CD4 + T cells. Collectively, these findings show that PTX3 is a 62 negative regulator of Th17 response and protective immunity during L. major infection. 4 64 Introduction: 65 66 Cutaneous leishmaniasis (CL) is caused by several species of protozoan parasites that 67 belong to the genus Leishman...

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Th17 cells and neutrophils: Close collaborators in chronic Leishmania mexicana infections leading to disease severity

Cited by 31 publications

References 64 publications

Frontline Science: Leishmania mexicana amastigotes can replicate within neutrophils

Frontline Science: Leishmania mexicana amastigotes can replicate within neutrophils

Arginase activity of Leishmania isolated from patients with cutaneous leishmaniasis

The Long Pentraxin 3 (PTX3) Suppresses Immunity to Cutaneous Leishmaniasis by Negatively Regulating Th17 Response

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