Cutaneous leishmaniasis manifestations range from self-healing localized skin ulcers/nodules to diffusely spread chronic lesions. Knowledge on the host-parasite interactions underpinning the different clinical presentations is scarce, in particular for L. aethiopica infections where disease can be extremely severe. Our aim is to define differences in skin immune responses and parasite virulence in CL patients at single cell/parasite level and how it underpins the different clinical presentations (localised, mucocutaneous and diffuse), by producing the first spatially-resolved 'ecological' map of the lesions.
Specific objectives: 1. To profile the full heterogeneity in skin and lesion immunity (single cell RNAseq), and the cellular microenvironment surrounding infected and non-infected macrophages (digital spatial profiling). 2. To study the genomic diversity of L. aethiopica and identify features associated with the different clinical presentations (whole genome sequencing). 3. To understand how parasites respond to the microenvironmental conditions and define parasite survival niches (digital spatial profiling). 4. Study metabolic determinants of skin immunity (e.g. lipid metabolism, bioenergetics, short-chain fatty acids) in the context of key structural features of the skin landscape known to influence local metabolism and immune response (e.g. adipose tissue, follicles, microvasculature) (SpatialOMx). 5. To investigate the association between patient outcomes and the above host/parasite factors at baseline.
Study Type
OBSERVATIONAL
Enrollment
92
4mm skin biopsy
venous blood sample to acquire plasma, PBMCs and whole blood
venous blood sample used for HLA typing
genome sequencing of parasite DNA that is extracted from the skin slit
University of Gondar
Gonder, Amhara, Ethiopia
Spatially resolved immunological characterization of the CL lesion using single cell RNA sequencing and digital spatial profiling
Using single cell RNA sequencing and digital spatial profiling methods, we will profile the full heterogeneity in healthy skin/lesion immunity and the cellular microenvironment surrounding infected and non-infected macrophages, respectively.
Time frame: Day 0
Genomic characterization of L. aethiopica using whole genome sequencing
Whole genome sequencing will allow us to study the genomic diversity of L. aethiopica and identify features associated with the different clinical presentations.
Time frame: Day 0
Defining microenvironment and parasite niches in CL lesions using digital spatial profiling
The digital spatial profiling will indicate the different microenvironmental conditions and parasite survival niches.
Time frame: Day 0
Spatially resolved determination of the metabolic profile of the CL lesion using spatial OMx
The metabolic determinants of skin immunity (e.g. lipid metabolism, bioenergetics, short-chain fatty acids) in the context of key structural features of the skin landscape known to influence local metabolism and immune response (e.g. adipose tissue, follicles, microvasculature) will be studied by SpatialOMx.
Time frame: Day 0
The association between host/parasite factors and patients after treatment using clinical parameters
Patients are clinically assessed at day 0 (baseline visit), day 28 and month 6. These clinical assessments include a medical questionnaire and lesion assessment, and are compared with the single cell RNA sequencing and spatial resolution data to define potential causal relations between patient outcomes and immunometabolic factors.
Time frame: Month 6
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