Innate immune response during Yersinia infection: critical modulation of cell death mechanisms through phagocyte activation

Abstract

Yersinia pestis, the etiological agent of plague, is one of the most deadly pathogens on our planet. This organism shares important attributes with its ancestral progenitor, Yersinia pseudotuberculosis, including a 70-kb virulence plasmid, lymphotropism during growth in the mammalian host, and killing of host macrophages. Infections with both organisms are biphasic, where bacterial replication occurs initially with little inflammation, followed by phagocyte influx, inflammatory cytokine production, and tissue necrosis. During infection, plasmid-encoded attributes facilitate bacterial-induced macrophage death, which results from two distinct processes and corresponds to the inflammatory crescendo observed in vivo: Naïve cells die by apoptosis (noninflammatory), and later in infection, activated macrophages die by pyroptosis (inflammatory). The significance of this redirected cell death for the host is underscored by the importance of phagocyte activation for immunity to Yersinia and the protective role of pyroptosis during host responses to anthrax lethal toxin and infections with Francisella, Legionella, Pseudomonas, and Salmonella. The similarities of Y. pestis and Y. pseudotuberculosis, including conserved, plasmid-encoded functions inducing at least two distinct mechanisms of cell death, indicate that comparative studies are revealing about their critical pathogenic mechanism(s) and host innate immune responses during infection. Validation of this idea and evidence of similar interactions with the host immune system are provided by Y. pseudotuberculosis-priming, cross-protective immunity against Y. pestis. Despite these insights, additional studies indicate much remains to be understood concerning effective host responses against Yersinia, including chromosomally encoded attributes that also contribute to bacterial evasion and modulation of innate and adaptive immune responses.

Figure 1.

Threshold-dependent macrophage activation during Yersinia infection. Macrophages from Y. pseudotuberculosis (Yptb)-infected mice were assessed for activation by ICAM-1 expression and compared with macrophages from uninfected mice (A). Shown are representative histograms from infected mice, with (right panel) and without (left panel) activated macrophages. Bacterial colonization of infected mice was quantified by plating and plotted as cfu at Days 4–6 postinfection. The presence of activated macrophages is indicated in the accompanying legend (B). Representative results from one of several experiments; data from ref. [20]. MLN, mesenteric lymph nodes.

Figure 2.

Redirected cell death during host response to Yersinia infection. Initial interaction of Yersinia with naïve macrophages results in the activation of caspase-3 and induction of noninflammatory apoptosis (left). With additional bacterial replication, macrophage activation occurs as a result of TLR stimulation (or other yet-to-be-defined pathways), and interaction with Yersinia results in caspase-1 activation, maturation, and release of IL-1β and IL-18 and cell lysis with the release of inflammatory intracellular contents (right).

Figure 3.

Pyroptosis is a conserved effector pathway important in combating infection. The interaction of naïve macrophages with anthrax lethal toxin or Salmonella results in pyroptosis [51]; with Yersinia, noninflammatory apoptosis occurs but can be redirected to pyroptosis (see text for more details [20]); with Legionella [66] or Francisella [67] infection, noninflammatory autophagy occurs and transitions to pyroptosis. Physiological outcome is dictated by cell death mechanism; control is subject to influence by pathogen (ligands and virulence determinants translocated into host cell) and host (macrophage activation and redirected use of cell death pathway) [50].