No abstract

B cells are a target of Salmonella infection, allowing bacteria survival without inducing pyroptosis. This event is due to downregulation of Nlrc4 expression and lack of inflammasome complex activation, which impairs the secretion of IL-1β. YAP phosphorylation is required for downregulation of Nlrc4 in B cells during Salmonella infection; however, the microorganism’s mechanisms underlying the inhibition of the NLRC4 inflammasome in B cells are not fully understood. Our findings demonstrate that the Salmonella effector SopB triggers a signaling cascade involving PI3K, PDK1 and mTORC2 that activates Akt with consequent phosphorylation of YAP. When we deleted sopB in Salmonella, infected B cells that lack Rictor, or inhibited the signaling cascade using a pharmacological approach, we were able to restore the function of the NLRC4 inflammasome in B cells and the ability to control the infection. Furthermore, B cells from infected mice exhibited activation of Akt and YAP phosphorylation, suggesting that Salmonella also triggers this pathway in vivo. In summary, our data demonstrate that the Salmonella effector inositide phosphate phosphatase SopB triggers the PI3K-Akt-YAP pathway to inhibit the NLRC4 inflammasome in B cells. This study provides further evidence that Salmonella triggers cellular mechanisms in B lymphocytes to manipulate the host environment by turning it into a survival niche to establish a successful infection.

It is well established that B cells play an important role during infections beyond antibody production. B cells produce cytokines and are APCs for T cells. Recently, it has become clear that several pathogenic bacterial genera, such as Salmonella, Brucella, Mycobacterium, Listeria, Francisella, Moraxella, and Helicobacter, have evolved mechanisms such as micropinocytosis induction, inflammasome down‐regulation, inhibitory molecule expression, apoptosis induction, and anti‐inflammatory cytokine secretion to manipulate B cell functions influencing immune responses. In this review, we summarize our current understanding of B cells as targets of bacterial infection and the mechanisms by which B cells become a niche for bacterial survival and replication away from extracellular immune responses such as complement and antibodies.

Salmonella is a Gram-negative bacterium known to be the major cause of gastrointestinal diseases and systemic infections. During infection of murine B cells, Salmonella activates the PI3K/Akt pathway through its effector, SopB. This signaling pathway induces the downregulation of NLRC4 transcription, resulting in reduced secretion of IL-1β. Thus, Salmonella-infected B cells do not progress to pyroptosis; consequently, the bacteria can survive inside these cells. However, the mechanism by which Salmonella evades the control of B cells has not yet been elucidated. In this study, we found that SopB activates mTORC1, which is necessary for bacterial survival, since B cells cultured with the mTORC1 inhibitor rapamycin and B cells lacking raptor can control Salmonella infection. A similar result was observed in B cells when they were infected with the Salmonella SopB mutant (Δsopb). Salmonella also promoted the phosphorylation of the ULK1 complex at serine 757 (Ser757) by mTORC1, resulting in decreased levels of LC3-II in infected B cells. In this study, we did not observe these results when B cells were infected with Δsopb Salmonella. Our results demonstrated that Salmonella survival within B cells depends on the inhibition of autophagy by mTORC1 activation.