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

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.

The role of turmeric and black pepper oil nanoemulsion in attenuating cytokine storm triggered by duck hepatitis A virus type I (DHAV-I)-induced infection in ducklings.

The cytokine storm induced by duck hepatitis A virus type 1 (DHAV-1) infection significantly contributes to severe, rapid deaths and economic losses in the duck industry in Egypt. This study aimed to investigate the potential inhibitory effect of a nanoemulsion containing turmeric and black pepper oil on the immune response and pathogenesis of DHAV-1 in ducklings. A total of 105 ducklings from nonvaccinated breeders were divided into 5 experimental groups, each comprising 21 birds. The negative control group (G1) remained noninfected with DHAV-1 and nontreated with nanoemulsion, while the positive control group (G2) was infected with DHAV-1 but not treated with nanoemulsion. The other 2 groups (G3, the supplemented group which was noninfected with DHAV-1), and group 4 (the prophylactic group G4) which was infected with DHAV-1, both received nanoemulsion throughout the experiment. Group 5 (G5, the therapeutic group), on the other hand, which was infected with DHAV-1 received nanoemulsion only from the onset of clinical signs. At 5 days old, the ducklings in the positive control (G2), the prophylactic (G4), and the therapeutic group (G5) were infected with DHAV-1. All the ducklings in the infected groups exhibited depression, anorexia, and opisthotonos, and their livers displayed various degrees of ecchymotic hemorrhage, liver enlargement, and microscopic pathological lesions. Notably, the positive control group (G2) experienced the most severe and pronounced effects compared to the other infected groups treated with the nanoemulsion. Meanwhile, the viral RNA loads were lower in the liver tissues of the infected ducklings treated with the nanoemulsion (G4, and G5) compared to the positive control group G2. Additionally, the nanoemulsion effectively modulated proinflammatory cytokine expression, antioxidant enzymes, liver enzymes, and lipid profile of treated ducklings. In conclusion, the turmeric and black pepper oil nanoemulsion has the potential to be a therapeutic agent for regulating and modulating the immune response, decreasing DHAV-1-induced cytokine storms, and minimizing mortality and economic losses in the duck business. More research is needed to understand how turmeric and black pepper oil nanoemulsion alleviates DHVA-1-induced cytokine storms and lowers duckling mortality.