Cross talk between Leishmania donovani CpG DNA and Toll-like receptor 9: an immunoinformatics approach.
The precise and potential contribution of Toll-like receptors (TLRs) signaling pathways in fighting parasitic infections of Leishmania spp., an intracellular protozoan parasite, has gained significant attention during the last decades. Although it is well established that TLR9 recognizes CpG motifs in microbial genomes, the specificity of the CpG DNA pattern of Leishmania parasite interacting with endosomal TLR9 is still unknown. Hence in our study to identify the CpG DNA pattern of Leishmania donovani acting as ligand for TLR9, consecutive homology searches were performed using known CpG ODN 2216 as initial template until a consistent CpG pattern in L. donovani was found. A reliable model of TLR9 ectodomains (ECDs) as well as CpG DNA patterns was predicted to develop the 3D structural complexes of TLR9 ECD-CpG DNA utilizing molecular modeling and docking approaches. The results revealed the preferential specificity of L. donovani CpG DNA to TLR9 compared to control ODN and other CpG patterns. The interface between TLR9 and L. donovani CpG DNA was also found to be geometrically complementary with the LRR11 region of TLR9, acting as the critical region for ligand recognition. The L. donovani CpG pattern identified can be employed to derive a platform for development of an innate immunomodulatory agent for deadly disease.
Department of Biosciences, Integral University, Lucknow, 226026, UP, India.
Chhedi Lal
CL
Gupta
Department of Bioengineering, Integral University, Lucknow, 226026, UP, India.
Salman
S
Akhtar
Department of Biology, University of Ottawa, 30 Marie-Curie, Ottawa, ON, K1N 6N5, Canada; Medipure Pharmaceuticals Inc., Maple Ridge, BC, V2X 2Z3, Canada.
Andrew
A
Waye
Center for Stroke Recovery, Ottawa Hospital Research Institute and Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Medipure Pharmaceuticals Inc., Maple Ridge, BC, V2X 2Z3, Canada.
Nihar R
NR
Pandey
Department of Biosciences, Integral University, Lucknow, 226026, UP, India.
Neelam
N
Pathak
Department of Biosciences, Integral University, Lucknow, 226026, UP, India. Electronic address: preeti2874@gmail.com.
Preeti
P
Bajpai
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D019295:Computational Biology; D018899:CpG Islands; D016054:DNA, Protozoan / Q000737:chemistry / Q000235:genetics*; D054884:Host-Pathogen Interactions / Q000235:genetics / Q000276:immunology; D006801:Humans; D007893:Leishmania donovani / Q000235:genetics* / Q000276:immunology* / Q000472:pathogenicity; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000235:genetics*; D011487:Protein Conformation; D020239:Receptor Cross-Talk; D015398:Signal Transduction; D051217:Toll-Like Receptor 9 / Q000737:chemistry / Q000378:metabolism* / Q000819:agonists
C526902:CpG ODN 2216; D016054:DNA, Protozoan; D008024:Ligands; D009838:Oligodeoxyribonucleotides; C495371:TLR9 protein, human; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9
Homology modeling; Immune response; PAMPs; Parasitic infection; Toll-like receptor