A microbiota-driven mechanism underlies severity of leishmaniasis infection

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In a recent study posed to the medRxiv* preprint server, researchers in Brazil and the United States investigated the probable impact of the skin microbiome microbiota on the outcomes of cutaneous leishmaniasis.

Study: Multi-omic profiling of cutaneous leishmaniasis infections reveals microbiota-driven mechanisms underlying disease severity. Image Credit: Kateryna Kon / ShutterstockStudy: Multi-omic profiling of cutaneous leishmaniasis infections reveals microbiota-driven mechanisms underlying disease severity. Image Credit: Kateryna Kon / Shutterstock

*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Background

Cutaneous leishmaniasis, caused by the Leishmania braziliensis parasite, results in inflammation and cutaneous damage, with unpredictable and highly variable outcomes. The infection may present clinically as solitary healing dermatological lesions or chronic cutaneous ulcers, with mucosal and disseminated lesions that are quite disfiguring.

The parasitic counts and immunological responses of the host could impact disease prognosis. The pentavalent antimony (Sbv) treatment has failed to resolve the lesions, and therapeutic vaccines are unavailable. Therefore, improving the understanding of the immunopathogenesis of the disease could aid in developing targeted and effective drugs against Leishmania braziliensis.

Studies have reported that the breach in the skin by Leishmania braziliensis results in microbiome dysbiosis, promoting pathological changes and elevated levels of inflammatory cytokines and chemokines such as interleukin-17 and interleukin-1β. However, the clinical relevance of the immunological findings is not clear.

About the study

In the present study, researchers investigated whether the skin's microbiome affects the immunological responses and outcomes of cutaneous leishmaniasis.

The team performed an integrated multi-transcriptomic analysis of the skin microbiome and host transcriptome for 62 individuals infected with L. braziliensis, among which 20 and 42 were men and women, respectively, with average participant age of 30.0 years. The lesional and contralateral unaffected skin swabs were subjected to 16S ribosomal ribonucleic acid (rRNA) amplicon sequencing (16S-seq) to assess the microbial profiles longitudinally.

The lesional biopsy tissues were subjected to ribonucleic acid sequencing analysis to determine the host transcriptomic profiles and quantitative polymerase chain reaction (PCR) was performed to quantify the lesional bacterial burden. Due to greater Staphylococcus aureus abundance in lesions, as determined by differential taxa abundance analysis between the lesional and contralateral unaffected skin swab specimens, a customized Staphylococcus aureus pan-genome was constructed with clinical S. aureus isolates.

To investigate the probable contribution of Staphylococcus aureus bacteria-induced interleukin-1β in disease pathogenesis, IL-1β signaling pathways were neutralized in B6 mice infected with L. braziliensis and colonized with S. aureus. In addition, continuous differential gene expression (DGE) and gene ontology (GO) analyses were performed.

The study dataset comprised (i) a ribonucleic acid sequencing analysis dataset from lesional biopsy specimens (n=51) obtained before Sbv therapy; (ii) a 16S ribosomal ribonucleic acid sequencing dataset of swab specimens obtained from the lesional surfaces before Sbv therapy and during follow-up (day 30 to day 240) for a few patients; (iii) an S. aureus library prepared from the lesional specimens and their genetic sequences; and (iv) clinical meta-analysis data including demographic variables. Clinical meta-analysis data included lesion site and size, lymphadenopathy, delayed type of hypersensitivity (DTH) measurements, healing duration, and disease outcomes.

Results

Bacterial burden was more significant in lesional swabs than the unaffected, contralateral skin swabs, and 84% of patients showed skin microbiome alterations in the leishmanial lesions. The lesional microbiome showed Staphylococcus aureus predominance, followed by Streptococcus and Corynebacterium. Staphylococcus aureus abundance was related to delays in healing, poorer clinical outcomes, and elevated expression of inflammatory IL-1 family cytokines, especially IL-1β, and C-X-C motif ligand (CXCL) chemokine family involved in neutrophil chemotaxis.

IL-1β was essential in modulating the outcomes of cutaneous leishmaniasis in mice colonized with S. aureus, and IL-1β neutralization lowered inflammation and improved pathology. The findings indicated that IL-1 drove disease severity in Staphylococcus aureus-dominated leishmanial lesions in mice, and therefore, IL-1 could be targeted to develop therapeutic agents for cutaneous leishmaniasis in humans. Individuals with elevated S.aureus counts showed delayed responses to treatment, with lesions persistent beyond 300.0 days.

The findings indicated that elevated parasite counts were related to treatment failures and that the longitudinal changes observed in the leishmanial lesional microbiome were not likely to be driven by Sbv treatment alone. Lesional microbial deviations away from skin-like profiles were related to elevated expression of pro-inflammatory genes. The findings showed a relationship between the lesional microbiome, clinical outcomes, and cytotoxic and pro-inflammatory host transcriptomes, but not with B lymphocyte-associated responses.

Lesions with elevated L. braziliensis counts expressed clinical outcome-associated pro-inflammatory genetic signatures, with elevated cytotoxic T lymphocyte and natural killer lymphocyte counts. S. aureus colonization promoted disease in B6 mice by promoting inflammation, indicating that S. aureus contributed to the leishmaniasis-associated inflammation and disease outcomes.  

Genes most strongly associated with leishmaniasis included genes coding for cytotoxicity-associated receptors and effector substances such as perforin-1, granulysin, granzyme B, and killer cell immunoglobulin-like receptor 2DL4 (KIR2DL4). Other associated genes coded for neutrophil chemotaxes and effector functions, such as CXCL-3, carcinoembryonic antigen-related cell adhesion molecule 3 (CEACAM3), and CXCL-1; and for inflammatory cytokines such as IL-1α, -1β,-24, secretory leukocyte peptidase inhibitor  (SLPI) and oncostatin M.

Overall, the study findings showed that the skin microbiome in leishmanial lesions influences the progression of the disease and may delay healing time due to increased levels of IL-1.

*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Pooja Toshniwal Paharia

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Pooja Toshniwal Paharia

Dr. based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.

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