Vaishalli, PM and Das, R and Cheema, HS and Ghosh, S and Chandana, M and Anand, A and Murmu, KC and Padmanaban, G and Ravindran, B and Nagaraj, VA (2024) Plasmodium berghei HMGB1 controls the host immune responses and splenic clearance by regulating the expression of pir genes. In: Journal of Biological Chemistry, 300 (11).
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Abstract
High mobility group box (HMGB) proteins belong to the high mobility group (HMG) superfamily of non-histone nuclear proteins that are involved in chromatin remodeling, regulation of gene expression, and DNA repair. When extracellular, HMGBs serve as alarmins inducing inflammation, and this is attributed to the proinflammatory activity of box B. Here, we show that Plasmodium HMGB1 has key amino acid changes in box B resulting in the loss of TNF-α stimulatory activity. Site-directed mutagenesis of the critical amino acids in box B with respect to mouse HMGB1 renders recombinant Plasmodium berghei (Pb) HMGB1 capable of inducing TNF-α release. Targeted deletion of PbHMGB1 and a detailed in vivo phenotyping show that PbHMGB1 knockout (KO) parasites can undergo asexual stage development. Interestingly, Balb/c mice-infected with PbHMGB1KO parasites display a protective phenotype with subsequent clearance of blood parasitemia and develop long-lasting protective immunity against the challenges performed with Pb wildtype parasites. The characterization of splenic responses shows prominent germinal centers leading to effective humoral responses and enhanced T follicular helper cells. There is also complete protection from experimental cerebral malaria in CBA/CaJ mice susceptible to cerebral pathogenesis with subsequent parasite clearance. Transcriptomic studies suggest the involvement of PbHMGB1 in pir expression. Our findings highlight the gene regulatory function of parasite HMGB1 and its in vivo significance in modulating the host immune responses. Further, clearance of asexual stages in PbHMGB1KO-infected mice underscores the important role of parasite HMGB1 in host immune evasion. These findings have implications in developing attenuated blood-stage vaccines for malaria. © 2024 The Authors
| Item Type: | Journal Article |
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| Publication: | Journal of Biological Chemistry |
| Publisher: | American Society for Biochemistry and Molecular Biology Inc. |
| Additional Information: | The copyright for this article belongs to the authors. |
| Keywords: | Diseases; Gene expression; Gene expression regulation; Immune system; Malaria control; Pathology, Gene knockout; HMGB1; Host immune evasion; Inflammation; Malaria; Parasite clearance; Parasite-; Pathogenesis; Recombinant protein expression; Site directed mutagenesis, Mammals |
| Department/Centre: | Division of Biological Sciences > Biochemistry |
| Date Deposited: | 19 Nov 2024 19:17 |
| Last Modified: | 19 Nov 2024 19:17 |
| URI: | http://eprints.iisc.ac.in/id/eprint/86748 |
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