Meta-transcriptome Profiling of the Human-Leishmania braziliensis Cutaneous Lesion

Christensen, Stephen M; Dillon, Laura A. L.; Carvalho, Lucas P.; Passos, Sara; Novais, Fernanda O.; Hughitt, V. K.; Beiting, Daniel P.; Carvalho, Edgar M.; Scott, Phillip; El-Sayed, Najib M.; Mosser, David M.

doi:10.1371/journal.pntd.0004992

Cited by 57 publications

(76 citation statements)

References 31 publications

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“…In human disease, this has largely focused on cutaneous leishmaniasis 35– 37 . A single study has reported on transcriptional changes in the draining lymph node of Sudanese patients with VL before and after treatment with sodium stibogluconate, identifying a potential role for nuclear factor of activated T cells (NFAT)-regulated immune responses in treatment response 38 .…”

Section: Introductionmentioning

confidence: 99%

Tissue and host species-specific transcriptional changes in models of experimental visceral leishmaniasis

Ashwin¹,

Seifert²,

Forrester³

et al. 2018

Wellcome Open Res

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Background: Human visceral leishmaniasis, caused by infection with Leishmania donovani or L. infantum, is a potentially fatal disease affecting 50,000-90,000 people yearly in 75 disease endemic countries, with more than 20,000 deaths reported. Experimental models of infection play a major role in understanding parasite biology, host-pathogen interaction, disease pathogenesis, and parasite transmission. In addition, they have an essential role in the identification and pre-clinical evaluation of new drugs and vaccines. However, our understanding of these models remains fragmentary. Although the immune response to Leishmania donovani infection in mice has been extensively characterized, transcriptomic analysis capturing the tissue-specific evolution of disease has yet to be reported. Methods: We provide an analysis of the transcriptome of spleen, liver and peripheral blood of BALB/c mice infected with L. donovani. Where possible, we compare our data in murine experimental visceral leishmaniasis with transcriptomic data in the public domain obtained from the study of L. donovani-infected hamsters and patients with human visceral leishmaniasis. Digitised whole slide images showing the histopathology in spleen and liver are made available via a dedicated website, www.leishpathnet.org. Results: Our analysis confirms marked tissue-specific alterations in the transcriptome of infected mice over time and identifies previously unrecognized parallels and differences between murine, hamster and human responses to infection. We show commonality of interferon-regulated genes whilst confirming a greater activation of type 2 immune pathways in infected hamsters compared to mice. Cytokine genes and genes encoding immune checkpoints were markedly tissue specific and dynamic in their expression, and pathways focused on non-immune cells reflected tissue specific immunopathology. Our data also addresses the value of measuring peripheral blood transcriptomics as a potential window into underlying systemic disease. Conclusions: Our transcriptomic data, coupled with histopathologic analysis of the tissue response, provide an additional resource to underpin future mechanistic studies and to guide clinical research.

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Section: Introductionmentioning

confidence: 99%

Tissue and host species-specific transcriptional changes in models of experimental visceral leishmaniasis

Ashwin¹,

Seifert²,

Forrester³

et al. 2018

Wellcome Open Res

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“…Recently, RNA-seq of LCL patient biopsies revealed lesional skin containing detectable L. ( V. ) braziliensis transcripts had a unique transcriptional signature compared with lesional skin that did not contain L. ( V. ) braziliensis transcripts [ 80 ]. Although inflammatory gene transcripts (IFNG and TNF) were increased in these lesions indicative of an active adaptive response, there was a concomitant increase in transcripts encoding inhibitory molecules (IL10, CTLA4, PD1, PDL1, and LAG3).…”

Section: Localized Cutaneous Leishmaniasismentioning

confidence: 99%

“…Although inflammatory gene transcripts (IFNG and TNF) were increased in these lesions indicative of an active adaptive response, there was a concomitant increase in transcripts encoding inhibitory molecules (IL10, CTLA4, PD1, PDL1, and LAG3). Interestingly, parasite transcript-positive skin was also associated with a significant increase in B cell transcripts (CD79A, CD19, and CD20), suggesting B cell infiltration during active infection [ 80 ]. This is supported by another study showing an increase in B cells in L. ( V. ) braziliensis infected patient lymph nodes during the progression from early pre-lesional to lesional phases of diseases [ 81 ].…”

Section: Localized Cutaneous Leishmaniasismentioning

confidence: 99%

Cutaneous Manifestations of Human and Murine Leishmaniasis

Scorza

Carvalho

Wilson

2017

IJMS

164

136

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The leishmaniases are diseases caused by pathogenic protozoan parasites of the genus Leishmania. Infections are initiated when a sand fly vector inoculates Leishmania parasites into the skin of a mammalian host. Leishmania causes a spectrum of inflammatory cutaneous disease manifestations. The type of cutaneous pathology is determined in part by the infecting Leishmania species, but also by a combination of inflammatory and anti-inflammatory host immune response factors resulting in different clinical outcomes. This review discusses the distinct cutaneous syndromes described in humans, and current knowledge of the inflammatory responses associated with divergent cutaneous pathologic responses to different Leishmania species. The contribution of key hematopoietic cells in experimental cutaneous leishmaniasis in mouse models are also reviewed and compared with those observed during human infection. We hypothesize that local skin events influence the ensuing adaptive immune response to Leishmania spp. infections, and that the balance between inflammatory and regulatory factors induced by infection are critical for determining cutaneous pathology and outcome of infection.

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“…Another lipid phosphatase (encoded by LbrM. 25.21.80) may contribute to the parasite virulence, as it was shown to be among the 100 most abundantly expressed genes in Leishmania braziliensis skin lesions of humans with cutaneous leishmaniasis [20].…”

Section: Introductionmentioning

confidence: 99%

LmxM.22.0250-Encoded Dual Specificity Protein/Lipid Phosphatase Impairs Leishmania mexicana Virulence In Vitro

et al. 2019

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Protein phosphorylation/dephosphorylation is an important regulatory mechanism that controls many key physiological processes. Numerous pathogens successfully use kinases and phosphatases to internalize, replicate, and survive, modifying the host′s phosphorylation profile or signal transduction pathways. Multiple phosphatases and kinases from diverse bacterial pathogens have been implicated in human infections before. In this work, we have identified and characterized the dual specificity protein/lipid phosphatase LmDUSP1 as a novel virulence factor governing Leishmania mexicana infection. The LmDUSP1-encoding gene (LmxM.22.0250 in L. mexicana) has been acquired from bacteria via horizontal gene transfer. Importantly, its orthologues have been associated with virulence in several bacterial species, such as Mycobacterium tuberculosis and Listeria monocytogenes. Leishmania mexicana with ablated LmxM.22.0250 demonstrated severely attenuated virulence in the experimental infection of primary mouse macrophages, suggesting that this gene facilitates Leishmania pathogenicity in vertebrates. Despite significant upregulation of LmxM.22.0250 expression in metacyclic promastigotes, its ablation did not affect the ability of mutant cells to differentiate into virulent stages in insects. It remains to be further investigated which specific biochemical pathways involve LmDUSP1 and how this facilitates the parasite′s survival in the host. One of the interesting possibilities is that LmDUSP1 may target host′s substrate(s), thereby affecting its signal transduction pathways.

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Meta-transcriptome Profiling of the Human-Leishmania braziliensis Cutaneous Lesion

Cited by 57 publications

References 31 publications

Tissue and host species-specific transcriptional changes in models of experimental visceral leishmaniasis

Tissue and host species-specific transcriptional changes in models of experimental visceral leishmaniasis

Cutaneous Manifestations of Human and Murine Leishmaniasis

LmxM.22.0250-Encoded Dual Specificity Protein/Lipid Phosphatase Impairs Leishmania mexicana Virulence In Vitro

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