Th17 cells/IL-17A shape Pasteurella multocida serotype A infection in murine and rabbit models.

Pasteurella multocida (Pm) is an important zoonotic respiratory pathogen, especially serotype A, which can cause death in various hosts, including humans, farm animals, and wildlife. However, the exact mechanisms by which hosts mobilize the immune system against Pasteurella multocida serotype A (PmA) in mammals remain largely unexplored. In the present study, we found that the control of lung infection is critical for PmA infection. Furthermore, unbiased RNA sequencing analysis and histopathological studies revealed that T-cell associated immunity was not fully activated during PmA infection, although the host tended to stimulate Th17 cell and interleukin (IL)-17A-related pathways. To investigate the role of Th17 cells/IL-17A, we employed gain- and loss-of-function Th17 cells and IL-17A at the animal level via inhibitors, through in vitro induction of Th17 cells followed by reperfusion and recombinant IL-17A, respectively. We demonstrated that the host failed to fully activate Th17 cells/IL-17A, which is a key immune mechanism against P. multocida infection. Mechanistic studies revealed that the IL-6-JAK2-STAT3 axis contributed to Th17 cell/IL-17A activation in PmA infection. Therefore, using the Stat3 inhibitor Stattic or IL-6KO mouse models significantly limited Th17 cell/IL-17A activation and accelerated host death. Importantly, recombinant IL-17A had strong potential for clinical application, as recombinant IL-17A effectively protected rabbits infected with PmA. Thus, our study revealed that PmA induced T-cell immunodeficiency, and that the activation of Th17 cells/IL-17A via the IL-6-JAK2-STAT3 axis was a key mechanism against PmA. Therefore, targeting Th17 cells/IL-17A could be a potential strategy for the treatment of pasteurellosis and other respiratory bacterial diseases.