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Pasteurella multocida toxin (PMT) is an exotoxin produced by several members of the zoonotic respiratory pathogen P. multocida . The role of PMT in disrupting the mammalian respiratory barrier remains to be elucidated. In this study, we discovered that inoculation of recombinantly expressed PMT increased the permeability of the respiratory epithelial barrier in mouse and respiratory cell models. This was evidenced by a decreased expression of tight junctions (ZO-1, occludin) and adherens junctions (β-catenin, E-cadherin), as well as enhanced cytoskeletal rearrangement. In mechanism, we demonstrated that PMT inoculation induced cytoplasmic Ca ²⁺ inflow, leading to an imbalance of cellular Ca ²⁺ homeostasis and endoplasmic reticulum stress. This process further stimulated the RhoA/ROCK signaling, promoting cytoskeletal rearrangement and reducing the expression of tight junctions and adherens junctions. Notably, the T-type voltage-gated Ca ²⁺ channel Ca _V 3.1 was found to participate in PMT-induced cytoplasmic Ca ²⁺ inflow. Knocking out Ca _V 3.1 significantly reduced the cytotoxicity induced by PMT on swine respiratory epithelial cells and mitigated cytoplasmic Ca ²⁺ inflow stimulated by PMT. Further analysis identified Ser (aa92), Glu (aa155), Tyr (aa167), and Leu (aa448) as crucial sites utilized by PMT to interact with Ca _V 3.1. These findings suggest Ca _V 3.1 serves as an important host receptor of PMT and contributes to PMT-induced respiratory epithelial barrier disruption.

Importance

PMT is a significant toxin produced by the zoonotic respiratory pathogen P. multocida , yet little is known about its pathogenesis beyond causing progressive atrophic rhinitis in pigs. In our study, we have discovered that PMT has the capacity to disrupt the integrity of the mammalian respiratory epithelial barrier. This disruption involves an imbalance in cellular Ca ²⁺ homeostasis, endoplasmic reticulum stress, and activation of the RhoA/ROCK signaling pathway induced by PMT. Importantly, we have identified Ca _V 3.1 as a pivotal receptor that plays a crucial role in the pathogenic effects of PMT. Our findings highlight the potential of Ca _V 3.1 as a target for intervention strategies aimed at combating the detrimental effects of PMT.