Salmonella Rapidly Kill Dendritic Cells via a Caspase-1- Dependent Mechanism

Abstract

Dendritic cells provide a critical link between innate and acquired immunity. In this study, we demonstrate that the bacterial pathogen Salmonella enterica serovar Typhimurium can efficiently kill these professional phagocytes via a mechanism that is dependent on sipB and the Salmonella pathogenicity island 1-encoded type III protein secretion system. Rapid phosphatidylserine redistribution, caspase activation, and loss of plasma membrane integrity were characteristic of dendritic cells infected with wild-type Salmonella, but not sipB mutant bacteria. Caspase-1 was particularly important in this process because Salmonella-induced dendritic cell death was dramatically reduced in the presence of a caspase-1-specific inhibitor. Furthermore, dendritic cells obtained from caspase-1-deficient mice, but not heterozygous littermate control mice, were resistant to Salmonella-induced cytotoxicity. We hypothesize that Salmonella have evolved the ability to selectively kill professional APCs to combat, exploit, or evade immune defense mechanisms.

Salmonella inhibit T cell proliferation by a direct, contact-dependent immunosuppressive effect

“…We published evidence demonstrating that Salmonella are capable of killing DC via a caspase-1-dependent mechanism and that sipB-deficient Salmonella, which are unable to express a fully functional SPI1-encoded TTSS, are not cytotoxic (6). On the basis of these findings, we hypothesized that Salmonella-induced death of the antigen-presenting cell may be the reason why T cells, when cocultured with Salmonella-infected DC, fail to proliferate.…”

“…Bacteria were grown as described in ref. 6. Heat-killed bacteria were obtained by incubating bacterial suspensions at 65°C for 20 min.…”

Cell death in the host response to infection

“…Also, Salmonella-induced caspase-1 dependent cell death does not lead to activation of caspases-3, -6 or -7, 45,48 again indicating a form of death independent of apoptotic pathways. Interestingly, caspase-1 dependent cell death during Salmonella infection has also been described in dendritic cells, 49 suggesting that this form of cytotoxicity is not restricted to macrophages, but may occur in several immune cell types. Since these initial reports, caspase-1-dependent cell death has been described in macrophages infected with Listeria Figure 1 Pathogen-induced host cell death.…”

“…82,83 In contrast, the inhibitor of actin rearrangement, cytochalasin D, interferes with bacterial entry into the cytosol and caspase-1 activation. 41,49,52,56,66 In some cases, the effector molecule responsible for caspase-1 activation has been identified. For the flagellated bacteria Salmonella typhimurium, 82,83 Legionella pneumophila, 54 and Pseudomonas aeruginosa, 86,91 proper expression of flagellin is required for caspase-1 activation.…”

Salmonella enterica serovar Choleraesuis infection of the porcine jejunal Peyer's patch rapidly induces IL-1β and IL-8 expression

“…Binding of flagellin toTLR5 activates NF-κB and MAPK signaling pathways and induces expression of inflammation-associated genes, including IL-8 and other chemokines (CXCL8) (Elewaut et al, 1999;Gewirtz et al, 2001a;Medzhitov, 2001). Injection of SipB protein by Salmonella serovar Typhimurium or Dublin induces caspase-1-mediated cell death of macrophages and dendritic cells (Hersh et al, 1999;van der Velden et al, 2003;Watson et al, 2000). Caspase-1 enzymatically cleaves IL-1β and IL-18 to their bioactive forms, and IL-1β additionally activates NF-κB-mediated transcription of chemokines (Lee et al, 2004;Monack et al, 2000).…”