Effect of inhibition of Toll-like receptor 3 signaling on pathogenesis of rabies virus in mouse model.

Abstract

Rabies is a zoonotic viral disease with inevitably fatal outcome. Toll-like receptor 3 (TLR3) could sense dsRNA viral infections, and implicated in pathogenesis of rabies and Negri bodies (NBs) formation. Present study was undertaken to elucidate the role of TLR3 in pathogenesis, NBs formation, and therapeutic potential of blocking TLR3/dsRNA interaction in rabies infection. Young Swiss albino mice were infected with 100 LD50 of street rabies virus (SRABV) intracerebrally (i/c) on day 0 and treated with 30 μg of CU CPT 4a (selective TLR3 inhibitor) i/c on 0, 3 and 5 days post-infection (DPI). Three mice each were sacrificed at 1, 3, 5, 7, 9, 11, and 13 DPI to study sequential pathological consequences through histopathology, Seller's staining, immunofluorescence, immunohistochemistry, TUNEL assay, flow cytometry, and viral and cytokine genes quantification by real-time PCR. CU CPT 4a inhibited TLR3 expression resulted in delayed development and decreased intensity of clinical signs and pathological lesions, low viral load, significantly reduced NBs formation, and increased survival time in SRABV-infected mice. These parameters suggested that TLR3 did influence the SRABV replication and NBs formation. Inhibition of TLR3 led to decreased expression of pro-inflammatory cytokines and interferons indicated an anti-inflammatory effect of CU CPT 4a during SRABV infection. Further, TLR3-inhibited group revealed normal CD4+/CD8+ T-cells ratio with less TUNEL-positive apoptotic cells indicated that immune cell kinetics are not affected during TLR3-inhibition. SRABV-infected and mock-treated mice were developed severe clinical signs and histopathological lesions, more NBs formation, high viral load, increased pro-inflammatory cytokines expression in brain, which were correlated with higher expression levels of TLR3. In conclusion, these data suggested that TLR3/dsRNA signaling pathway could play critical role in pathogenesis of SRABV infection in vivo and opens up new avenues of therapeutics.

• Authors: Sumit Sardana, Karam Pal Singh, Mani Saminathan, Sobharani Vineetha, Shibani Panda, Murali Dinesh, Madhulina Maity, Rajat Varshney, Sourabh Sulabh, Monalisa Sahoo, Triveni Dutt
• Journal: Acta tropica (Acta Trop) Vol. 234 Pg. 106589 (Oct 2022) ISSN: 1873-6254 [Electronic] Netherlands
• PMID: 35809612 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Elsevier B.V. All rights reserved.

Chemical References

• Cytokines
• TLR3 protein, mouse
• Toll-Like Receptor 3

Topics

• Animals
• Mice
• CD8-Positive T-Lymphocytes (metabolism)
• Cytokines (metabolism)
• Disease Models, Animal
• Rabies
• Rabies virus (genetics)
• Signal Transduction
• Toll-Like Receptor 3 (genetics, metabolism)