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Lymphotoxin-α Orchestrate Hypoxia and Immune factors to Induce Experimental Cerebral Malaria: Inhibition Mitigates Pathogenesis, Neurodegeneration, and Increase Survival

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Abstract

Knockdown studies have shown lymphotoxin-α (Lt-α) as a critical molecule for Experimental cerebral malaria (ECM) pathogenesis. We investigated the role of lymphotoxin-α in regulating active caspase-3 and calpain1. T cell infiltration into the brains, and subsequent neuronal cell death are the essential features of Plasmodium berghei ANKA(PbA)-induced ECM. Our results showed increased Lt-α levels during ECM. Treatment of naïve mice with serum from ECM mice and exogenous Lt-α was lethal. We inhibited Lt-α in vivo during PbA infection by injecting the mice with anti-Lt-α antibody. Inhibition of Lt-α mitigated neuronal cell death and increased mice’s survival until 30-day post-infection (p.i.) compared to only 15 days survival of PbA control mice.

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Acknowledgements

Funding sources: DST- SERB Core grant, File Nos. CRG/2020/005021, CRG/2019/002570, and financial support to the University of Hyderabad-IoE by the Ministry of Education, Government of India (F11/9/2019-U3 (A). DST-FIST and UGC-SAP to the Department of Biotechnology and Bioinformatics, BUILDER-DBT-BT/INF/22/SP41176/2020 to the School of Life Sciences are gratefully acknowledged.

Funding

This study is funded by DBT (DBT: BT/PR18168/MED/29/1064/2016; DBT: BT/PR13111/MED/29/149/2009, dt. 24 June 2010; DBT-JRF/06–07/184), UPE (UH/UPE-2/28/2015 Dated. 01.12.2015; UH/UGC/UPE-2/Interface studies/Research Projects/B1.4, 24.04.2014), and DST (DST: D.O. No. SR/CSRI/196/2016; DST: SB/EMEQ-257/2013, dt. 12.07.2013).

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  1. Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, India

    Prabhakar Eeka & Prakash Babu Phanithi

  2. Department of Biotechnology, GITAM Institute of Sciences, GITAM Deemed to Be University, Visakhapatnam, India

    Prabhakar Eeka

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  1. Prabhakar Eeka
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Eeka, P., Phanithi, P.B. Lymphotoxin-α Orchestrate Hypoxia and Immune factors to Induce Experimental Cerebral Malaria: Inhibition Mitigates Pathogenesis, Neurodegeneration, and Increase Survival. J Mol Neurosci 72, 2425–2439 (2022). https://doi.org/10.1007/s12031-022-02076-w

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