Reversal of filarial serpin Wb123-urokinase plasminogen activator receptor mediated alternative macrophage activation by monoclonal antibody

Sep 29, 2026

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Macrophage polarization governs parasite survival or clearance in lymphatic filariasis, with evidence that filarial parasites favor alternative polarization to drive immune evasion and persistent infection. The molecular basis for filaria-induced alternative macrophage activation remains incompletely defined. This work uses in-silico screening to identify highly expressed filarial serpins in infective L3 larvae, then clones and purifies Wb123 from Wuchereria bancrofti. rWb123 enhances alternative activation markers (CD163, arginase-1, IL-6, pSTAT3), promotes uPAR-dependent signaling, suppresses LPS/IFN-γ–driven classical activation, and is blocked by monoclonal antibody or uPAR inhibition, rescuing proinflammatory responses.

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CategoryHealthcare

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Abstract

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OPEN ACCESS Citation: Upadhyay P, Munjal A, Mondal A, Singh G, Mukherjee S, Siwach S, et al. (2025) Reversal of filarial serpin Wb123-urokinase plasminogen activator receptor mediated alternative macrophage activation by monoclonal antibody. PLoS Negl Trop Dis 19(12): e0013726. [https://doi.org/10.1371/](https://doi.org/10.1371/)[ ](https://doi.org/10.1371/)[journal.pntd.0013726](journal.pntd.0013726) Editor: Francesca Tamarozzi, IRCCS Sacro Cuore Don Calabria Hospital, ITALY Received: May 9, 2025 Accepted: November 6, 2025 Published: December 22, 2025 Copyright: © 2025 Upadhyay et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data availability statement: All relevant data are within the manuscript and its Supporting information files. Funding: SP is thankful to Council of Science and Technology, Uttar Pradesh (CST-UP, RESEARCH ARTICLE Reversal of filarial serpin Wb123-urokinase plasminogen activator receptor mediated alternative macrophage activation by monoclonal antibody Prince Upadhyay1, Akshay Munjal2, Abir Mondal1, Gagandeep Singh3, Soumyadeep Mukherjee1, Shagun Siwach2, Millee Chandoulla2, Mahesh C. Kaushik4, Puneet K. Gupta5, Soumya Pati1,6*, Shailja Singh2* 1 Department of Life Sciences, School of Natural Sciences, Shiv Nadar Institution of Eminence, DelhiNCR, India, 2 Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, India, 3 Section of Microbiology, Central Ayurveda Research Institute Jhansi, Jhansi, Uttar Pradesh, India, 4 TCI Foundation, Gurugram, Haryana, India, 5 Tropical Animal Genetics Pvt Ltd. , SPIC Bioprocess Laboratory, Anna University, Chennai, Tamil Nadu, India, 6 Amity Institute of Neuropsychology & Neurosciences, Amity University, Noida, Uttar Pradesh, India * [shailja.jnu@gmail.com](shailja.jnu@gmail.com) (SS); [spati@amity.edu](spati@amity.edu) (SP) Abstract Potent inflammatory responses from host-parasite interactions in lymphatic filariasis are driven by macrophage polarization, which critically determines parasite survival or clearance. Evidence suggests that filarial parasite promote alternative macrophage polarization, facilitating immune evasion and persistent infection. However, the precise molecular mechanisms underlying filaria-induced alternative macrophage activation remain to be fully elucidated. Recently, serine protease inhibitors (serpins) have been implicated in alternative immune activation. Building on this insight, we explored and identified putative filarial serpins to be highly expressed in the infective L3 larval stage using in-silico analysis approach. Among all, Wb123, a serpin of Wuchereria bancrofti, the most predominantly found filarial worm, was cloned and purified to establish its role in alternative activation. We observed elevated markers of alternative activation; namely CD163, arginase-1, IL-6 and pSTAT3 expression, following rWb123 treatment. Furthermore, our results also indicated that rWb123 interacts with urokinase plasminogen activator receptor (uPAR) to activate the alternative activation pathway. Interestingly, rWb123 treatment attenuated the classical macrophage activation induced by lipopolysaccharide (LPS) and interferon-gamma (IFN-γ) as evident from muted CD86, nitric oxide (NO) and reactive oxygen species (ROS) expression. Notably, use of monoclonal antibody (MAbG8) to rWb123 or blocking uPAR impedes the rWb123-induced alternative activation and rescues the proinflammatory response to LPS-IFN-γ . These data confirmed that, uPAR dependent alternative activation by Wb123 enables filarial parasites to evade a strong pro-inflammatory immune PLOS Neglected Tropical Diseases | [https://doi.org/10.1371/journal.pntd.0013726](https://doi.org/10.1371/journal.pntd.0013726) December 22, 2025 1 / 22 Project ID-3

FAQs

What immune process does the study focus on in lymphatic filariasis?

The study focuses on macrophage polarization, particularly how alternative macrophage activation supports parasite survival and immune evasion in lymphatic filariasis.

How was Wb123 identified and tested?

Putative filarial serpins highly expressed in infective L3 larvae were identified using an in-silico approach; Wb123 was then cloned, purified, and tested using recombinant protein to assess macrophage activation.

What signaling target links Wb123 to alternative activation?

The results show that rWb123 interacts with the urokinase plasminogen activator receptor (uPAR) to activate the alternative macrophage activation pathway.

How do monoclonal antibody or uPAR blocking affect the outcomes?

Neutralizing rWb123 with monoclonal antibody or blocking uPAR impedes the rWb123-induced alternative activation and rescues the proinflammatory response to LPS/IFN-γ.

Sep 29, 2026

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