Unravelling the role of TLR4 in mediating the human dendritic cell activation by filaria

Identification of Toll-like receptor 4 (TLR4) as the crucial regulator of inflammation in human lymphatic filariasis has provoked the conception of TLR-directed therapy against filariasis.

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Molecular docking showing the interaction of microfilarial sheath antigen with phosphorylcholine (Mukherjee et al. Commun Biol. 2019 May 7;2:169. doi: 10.1038/s42003-019-0392-8.

Suprabhat Mukherjee (Assistant Professor at Kazi Nazrul University, India) and Jagadeesh Bayry (Director of Research at Institut National de la Santé et de la Recherche Médicale (INSERM),  Sorbonne Université, Centre de Recherche des Cordeliers, Paris, France)

Our report entitled “Wuchereria bancrofti filaria activates human dendritic cells and polarizes T helper 1 and regulatory T cells via Toll-like receptor  4 ” published in Communications Biology has completed its first anniversary (Mukherjee et al. 2019 Communications Biology1; https://www.nature.com/articles/s42003-019-0392-8). Herein we present overall scenario "After the Paper" on the background of "Behind the Paper" (https://naturemicrobiologycommunity.nature.com/posts/48673-tlr4-fuels-activation-of-human-dendritic-cells-and-cd4-t-cell-responses-to-human-filarial-parasite) that we wrote last year.

Lack of complete knowledge on the molecular immunopathogenesis has been the major obstacle in implementing the global filariasis elimination program. Dysregulation of immune-homeostasis characterized by chronic inflammation is considered as the pathogenic hallmark of human lymphatic filariasis. In 2017, a study by Mukherjee et al.2 demonstrated that a 70 kDa phosphorylcholine-binding novel sheath antigen of the filarid Wuchereria bancrofti (the major causative parasite of filariasis in human) induces inflammatory responses in macrophages by driving M2 to M1 polarization. However, activation of macrophages cannot rightfully represent a complete picture of filarial immunopathogenesis. An Indo-French joint research venture initiated at my lab revealed that the filarial sheath antigen induces human dendritic cell (DC) maturation as well as secretion of pro-inflammatory cytokines by signalling via TLR41. Furthermore, filarial sheath antigen-educated DCs polarized naïve CD4+ T cells toward Th1 and regulatory T cells (Tregs). Intriguingly, all these phenomena were primarily mediated via TLR4 signaling in DCs as pharmacological inhibition TLR4 signaling in DCs diminished both DC activation and CD4+ T cell polarization1. Therefore, the filarial antigen or TLR4 represent potential targets to adopt immunotherapeutic strategies against lymphatic filariasis.

The incredible influence of phosphorylcholine-binding filarial antigen in filarial immunopathogenesis prompted us to transform our research more application-oriented. While one year seems too short time to translate the fundamental knowledge to application, we have been able to set plan of work for the coming years. Design of vaccine candidate by using epitopes present in the filarial antigen and targeting the pro-inflammatory milieu by immunotherapeutic agents (e.g. intravenous immunoglobulin or IVIG, a therapeutic normal IgG obtained from the pooled plasma of several thousand healthy donors, and one of the widely used immunotherapeutic molecules for autoimmune and inflammatory diseases3,4) are the two major objectives we set for the immediate investigations. Currently we are in the stage of submitting a joint research proposal for the financial grant.

Since our publication back in 2019, many things have happened at professional level as well as in the research field pertaining to the paper. The article has got online attention in terms of reading and appreciation in several scientific platforms including ResearchGate, Google Scholar and Mendeley. Dr. Suprabhat Mukherjee, one of the primary authors of this work and also visiting researcher at my laboratory thanks to EMBO fellowship, has succeeded to obtain a tenured Assistant Professor position at Kazi Nazrul University, India. The work discussed here was instrumental for obtaining this position and to establish his research group. The work also played a big role in enriching the interests and knowledge of Dr. Mukherjee in human immunology. Notably, for counteracting the inflammatory consequences of lymphatic filariasis, he has recently designed a multi-epitope-based peptide vaccine using the secretary protease of filarial parasite to target human TLR4 (Das et al. 2020)5. Recently, a homolog of the W. bancrofti phosphoryl choline-binding protein has also been identified in a bovine filarial parasite (Setaria cervi) by Mukherjee et al. (2018)6.

COVID-19 pandemic has posed significant challenge on the control of a number of infectious diseases enlisted as ‘Neglected Tropical Diseases’ including lymphatic filariasis7. In particular, diagnosis of new cases of filarial infections as well as the treatment of existing patients have been interrupted during this pandemic. A new road map for 2021-2030 has been proposed by the World Health Orgnization7. In this context, TLR-directed immunotherapy is expected to provide us a direction on how to alleviate the inflammatory pathology in order to restrict the transformation of lymphatic filariasis to elephantiasis.

References

  1. Mukherjee, S., Karnam, A., Das, M., Sinha Babu, S.P. & Bayry, J. (2019). Wuchereria bancrofti filaria activates human dendritic cells and polarizes regulatory T cells via Toll-like receptor 4. Communications Biology. 2:169.
  2. Mukherjee, S., Mukherjee, Sa., Maiti, T.K., Bhattacharya, S. & Sinha Babu, S.P. (2017). A novel ligand of toll-like receptor 4 from the sheath of Wuchereria bancrofti microfilaria induces proinflammatory response in macrophages. The Journal of Infectious Diseases. 215: 954-965.
  3. Galeotti, C., Kaveri, S.V. & Bayry, J. (2017) IVIG-mediated effector functions in autoimmune and inflammatory diseases. International Immunology. 29:491-498.
  4. Galeotti, C., Kaveri, S.V. & Bayry, J. (2020).  Intravenous immunoglobulin immunotherapy for coronavirus disease-19 (COVID-19). Clinical & Translational Immunology. 9:e1198.
  5. Das, N.C., Patra, R., Sen Gupta, P.S., Ghosh, P., Bhattacharya, M., Rana, M.K. & Mukherjee, S. (2020). Designing of a novel multi-epitope peptide-based vaccine against Brugia malayi: an in silico Infection, Genetics and Evolution. doi: 10.1016/j.meegid.2020.104633 (Online ahead of print).
  6. Mukherjee, S., Joardar, N. & Sinha Babu, S.P. (2018). Exploring the homolog of a novel proinflammatory microfilarial sheath protein (MfP) of Wuchereria bancrofti in adult stage bovine filarial parasite Setaria cervi. Journal of Helminthology. 94:e15. (DOI: 10.1017/S0022149X18001050).
  7. World Health Organization (2020). Neglected tropical diseases: impact of COVID-19 and WHO’s response. Weekly epidemiological record. https://www.who.int/ Accessed on November 5, 2020.

Jagadeesh Bayry

Director of Research, INSERM

Prof. Bayry is a Director of Research at Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France. His research is aimed at understanding the cellular and molecular mechanisms of immune homeostasis, immunotherapy and deciphering the host-pathogen interaction. His h-index is 58 and he has authored more than 250 articles with over 12,000 citations. He serves as an Associate Editor and Editorial Board member of various journals and has edited four books. He is also a member of a commission at the European Research Council.

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