LeishMANIAdb: a comparative resource for Leishmania proteins

Abstract

Leishmaniasis is a detrimental disease causing serious changes in quality of life and some forms can lead to death. The disease is spread by the parasite Leishmania transmitted by sandfly vectors and their primary hosts are vertebrates including humans. The pathogen penetrates host cells and secretes proteins (the secretome) to repurpose cells for pathogen growth and to alter cell signaling via host-pathogen protein-protein interactions). Here, we present LeishMANIAdb, a database specifically designed to investigate how Leishmania virulence factors may interfere with host proteins. Since the secretomes of different Leishmania species are only partially characterized, we collated various experimental evidence and used computational predictions to identify Leishmania secreted proteins to generate a user-friendly unified web resource allowing users to access all information available on experimental and predicted secretomes. In addition, we manually annotated host-pathogen interactions of 211 proteins and the localization/function of 3764 transmembrane (TM) proteins of different Leishmania species. We also enriched all proteins with automatic structural and functional predictions that can provide new insights in the molecular mechanisms of infection. Our database may provide novel insights into Leishmania host-pathogen interactions and help to identify new therapeutic targets for this neglected disease. Database URL https://leishmaniadb.ttk.hu/.

Figure 1.

LeishMANIAdb content. All data were calculated on Leishmania infantum. A: Number of proteins in different proteomic datasets (purple: promastigote secretome, red: amastigote secretome, orange: exosome, green: housekeeping genes, blue: higher protein abundance level upon infection). B: Number of kinetoplastid and Leishmania close homologs. Each dot represents a protein (red: at least 80% of close homologs are in Leishmania, blue: other proteins). Green circles represent distinctive groups. C: Overlap between abundant, secreted and ‘Leishmania novelty’ proteins (for more detail see text). D: Distribution of all predicted SLiMs with different scores. Red marks candidate motifs above 0.85 cutoff (for more details see text).

Figure 2.

Layout of LeishMANIAdb. A: The search/browse result menu. B: Expression section of the entry page. C: Expansion section. D: Sequence features section. E: Putative motif mimicry section. F: Function section.

Figure 3.

A: Distribution of membrane protein quality levels of AlphaFold structure in Homo sapiens and Leishmania infantum. B: Upset diagram of proteins that are (1) secreted, (2) novel kinetoplastid, (3) expanded (or new) in Leishmania, (4) disordered, (5) contain candidate SLiMs. C: left: Multiple Sequence Alignment of 3ʹA2 related proteins (alignment is available under UniProt AC: E9AGZ3). Amyloidogenic regions, conserved cysteine and integrin-binding motifs are highlighted; right: proposed topology of 3ʹA2 related proteins. D: Frequent SLiMs in the cytoplasmic tail regions of amastins (the numbers denote the unique/total occurrences).