Spatial Analysis of Host-parasite Interactions in Cutaneous Leishmaniasis in Ethiopia

Spatial Analysis of Host-parasite Interactions in the Skin Across the Clinical Spectrum of Cutaneous Leishmaniasis in Ethiopia

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.

Inclusion Criteria:

• Willing and able to provide informed consent
• Clinically confirmed CL diagnosis
• Between 12 and 50 years of age

Exclusion Criteria:

• Difficult or too painful sampling zone (see skin biopsy procedure below)
• (Primary) lesion size < 1 cm
• Already receiving CL treatment or received CL treatment in the last 3 months (excluding traditional medicine)
• Known major comorbidity at time of diagnosis (e.g. VL, HIV, TB, malaria, severe intestinal helminth infection)
• Medical history of VL
• Severely underweight (BMI<16)
• Known pregnancy
• Use of immunosuppressive medication in the last month
• Known excessive alcohol use (between >10 intakes/day and >10 intakes/week)
• History of hypersensitivity to local anaesthetics
• Presence of keloids/hypertrophic scars