In-silico evidences on filarial cystatin as a putative ligand of human TLR4

Abstract

Cystatin is a small molecular weight immunomodulatory protein of filarial parasite that plays a pivotal role in downregulating the host immune response to prolong the survival of the parasite inside the host body. Hitherto, this protein is familiar as an inhibitor of human proteases. However, growing evidences on the role of cystatin in regulating inflammatory homeostasis prompted us to investigate the molecular reasons behind the explicit anti-inflammatory trait of this protein. We have explored molecular docking and molecular dynamics simulation approaches to explore the interaction of cystatin of Wuchereria bancrofti (causative parasite of human filariasis) with human Toll-like receptors (TLRs). TLRs are the most crucial component of frontline host defence against pathogenic infections including filarial infection. Our in-silico data clearly revealed that cystatin strongly interacts with the extracellular domain of TLR4 (binding energy=-93.5 ± 10 kJ/mol) and this biophysical interaction is mediated by hydrogen bonding and hydrophobic interaction. Molecular dynamics simulation analysis revealed excellent stability of the cystatin-TLR4 complex. Taken together, our data indicated that cystatin appears to be a ligand of TLR4 and we hypothesize that cystatin-TLR4 interaction most likely to play a key role in activating the alternative activation pathways to establish an anti-inflammatory milieu. Thus, the study provokes the development of chemotherapeutics and/or vaccines for targeting the cystatin-TLR4 interaction to disrupt the pathological attributes of human lymphatic filariasis. Our findings are expected to provide a novel dimension to the existing knowledge on filarial immunopathogenesis and it will encourage the scientific communities for experimental validation of the present investigation.

Communicated by Ramaswamy H. Sarma

Keywords:

• Cystatin
• filarial parasite
• TLR4
• molecular docking
• molecular dynamics simulation
• ligand

Acknowledgements

PSSG acknowledges IISER Berhampur for providing him with Institute Postdoctoral Fellowship to carry out this work. RP acknowledges the Department of Higher Education, Govt. of West Bengal for awarding Swami Vivekananda Merit Cum Means Fellowship. The authors acknowledge IISER Berhampur for the computational infrastructural support.

Disclosure statement

The authors declare that there is no conflict of interest.

Author contribution

Designed and performed all the experiments: NCD, PSSG, SB & RP; Analyzed the data and wrote the manuscript: PSSG & SM; Edited the draft: NCD, RP, MKR, and SM; Finalized the manuscript: SM; Conceived, designed, and supervised the study: SM.