Pasteurella multocida activates apoptosis via the FAK-AKT-FOXO1 axis to cause pulmonary integrity loss, bacteremia, and eventually a cytokine storm

© 2024. The Author(s)..

Pasteurella multocida is an important zoonotic respiratory pathogen capable of infecting a diverse range of hosts, including humans, farm animals, and wild animals. However, the precise mechanisms by which P. multocida compromises the pulmonary integrity of mammals and subsequently induces systemic infection remain largely unexplored. In this study, based on mouse and rabbit models, we found that P. multocida causes not only lung damage but also bacteremia due to the loss of lung integrity. Furthermore, we demonstrated that bacteremia is an important aspect of P. multocida pathogenesis, as evidenced by the observed multiorgan damage and systemic inflammation, and ultimately found that this systemic infection leads to a cytokine storm that can be mitigated by IL-6-neutralizing antibodies. As a result, we divided the pathogenesis of P. multocida into two phases: the pulmonary infection phase and the systemic infection phase. Based on unbiased RNA-seq data, we discovered that P. multocida-induced apoptosis leads to the loss of pulmonary epithelial integrity. These findings have been validated in both TC-1 murine lung epithelial cells and the lungs of model mice. Conversely, the administration of Ac-DEVD-CHO, an apoptosis inhibitor, effectively restored pulmonary epithelial integrity, significantly mitigated lung damage, inhibited bacteremia, attenuated the cytokine storm, and reduced mortality in mouse models. At the molecular level, we demonstrated that the FAK-AKT-FOXO1 axis is involved in P. multocida-induced lung epithelial cell apoptosis in both cells and animals. Thus, our research provides crucial information with regard to the pathogenesis of P. multocida as well as potential treatment options for this and other respiratory bacterial diseases.

Medienart:

E-Artikel

Erscheinungsjahr:

2024

Erschienen:

2024

Enthalten in:

Zur Gesamtaufnahme - volume:55

Enthalten in:

Veterinary research - 55(2024), 1 vom: 08. Apr., Seite 46

Sprache:

Englisch

Beteiligte Personen:

Zhao, Guangfu [VerfasserIn]
Tang, Yunhan [VerfasserIn]
Dan, Ruitong [VerfasserIn]
Xie, Muhan [VerfasserIn]
Zhang, Tianci [VerfasserIn]
Li, Pan [VerfasserIn]
He, Fang [VerfasserIn]
Li, Nengzhang [VerfasserIn]
Peng, Yuanyi [VerfasserIn]

Links:

Volltext

Themen:

Apoptosis
Cytokine storm
EC 2.7.11.1
FAK-AKT-FOXO1 axis
FOXO1 protein, human
Forkhead Box Protein O1
Journal Article
Pasteurella multocida
Pathogenesis
Pneumonia
Proto-Oncogene Proteins c-akt
Pulmonary integrity

Anmerkungen:

Date Completed 10.04.2024

Date Revised 11.04.2024

published: Electronic

Citation Status MEDLINE

doi:

10.1186/s13567-024-01298-7

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM370793234