Initial Delay in the Immune Response to Francisella tularensis Is Followed by Hypercytokinemia Characteristic of Severe Sepsis and Correlating with Upregulation and Release of Damage-Associated Molecular Patterns

Abstract

"Francisella tularensis subsp. novicida" intranasal infection causes a rapid pneumonia in mice with mortality at 4 to 6 days with a low dose of bacteria (10 2 bacteria). The short time to death suggests that there is a failure of the innate immune response. As the neutrophil is often the first cell type to infiltrate sites of infection, we focused on the emigration of neutrophils in this infection, as well as cytokines involved in their recruitment. The results indicated that there was a significant delay in the influx of neutrophils into the bronchoalveolar lavage fluid of F. tularensis subsp. novicida-infected mice. The delay in neutrophil recruitment in F. tularensis subsp. novicida-infected mice correlated with a delay in the upregulation of multiple proinflammatory cytokines and chemokines, as well as a delay in caspase-1 activation. Strikingly, the initial delay in the upregulation of cytokines through 1 day postinfection was followed by profound upregulation of multiple cytokines and chemokines to levels consistent with hypercytokinemia described for severe sepsis. This finding was further supported by a bacteremia and the cellular relocalization and release of high-mobility group box-1 and S100A9, both of which are damage-associated molecular pattern molecules and are known to be mediators of severe sepsis.

Phosphatidylinositol 3-Kinase Activation Attenuates the TLR2-Mediated Macrophage Proinflammatory Cytokine Response toFrancisella tularensisLive Vaccine Strain

“…For example, proinflammatory cytokine responses are significantly delayed in the lungs of mice infected intranasally with F. tularensis (7,8) and F. tularensis infection of macrophages and dendritic cells in vitro has been shown to suppress secretion of TNF and IL-12, respectively (10,77,78). Little is known, however, of the mechanisms by which F. tularensis infection can suppress host responses.…”

“…Indeed, macrophages and dendritic cells from TLR2 2/2 mice make poor proinflammatory cytokine responses to F. tularensis, and mice deficient in TLR2, but not TLR4, are much more susceptible to infection and death than wild-type (WT) controls (13,16,25). Interestingly, TLR2-dependent proinflammatory cytokine responses in the lung are significantly delayed (7,8), and several in vitro studies have suggested that F. tularensis can directly inhibit proinflammatory signaling in infected macrophages and dendritic cells (7,9,10,26). Although progress has been made in understanding the roles of TLRs and other PRRs (27)(28)(29) in recognizing F. tularensis, little is known about how F. tularensis modulates PRR signaling to its advantage during infection.…”

“…Recent studies suggest that an inadequate innate immune response to infection with F. tularensis likely contributes to its extreme virulence in humans and mice. Indeed, proinflammatory cytokines such as TNF, IL-12, and IFN-g appear crucial for effective immunity to and survival of F. tularensis infection (3)(4)(5)(6), yet infection itself appears to attenuate or delay the expression of these critical cytokines (7)(8)(9)(10). The mechanism(s) by which F. tularensis infection delays or impairs the proinflammatory response remain unknown.…”

Members of the Francisella tularensis Phagosomal Transporter Subfamily of Major Facilitator Superfamily Transporters Are Critical for Pathogenesis

“…Since the pathology induced by LVS has been attributed to the ability of this organism to produce an early cytokine storm (5,21,22), we hypothesized that the attenuated Fpt mutants would also exhibit a diminished early proinflammatory response. Livers from LVS-infected mice showed significantly increased levels of cytokine and iNOS mRNAs over a 24-to 72-h period, as previously reported (5,6).…”

Chronic Inflammation in the Epidermis: A Mathematical Model

“…These numerical computation results indicate the possibility that the time delay in immune cell recruitment can affect the outcome when two species are competitively bistable. A case study on Francisella tularensis infection, which may causes hypercytokinemia, reported at least a one-day delay in neutrophil recruitment post infection [45]. The introduction of a time delay in the recruitment of activated innate immune cells to the infection site in the skin exhibits interesting behaviors.…”