Editorial: Proinflammatory cytokines in pneumonic tularemia: too much too late?

Innate immunity is the first line of defense against a pathogen, responsible for detecting the presence of a foreign invader and then orchestrating a series of responses designed to limit pathogen replication and minimize tissue damage. However, some intracellular pathogens, such as Yersinia pestis and Francisella tularensis, replicate virtually unrestricted in their hosts, apparently unaffected by the immune system, quickly causing host death. Both of these organisms have been classified by the Centers for Disease Control and Prevention as Category A biological agents. In the case of F. tularensis, as few as 10 virulent organisms, when acquired via the airborne route, can cause a debilitating and potentially fatal infection. Indeed, untreated pneumonic tularemia is estimated to have a mortality rate of as much as 30– 60% in humans. In the murine model, mice succumb to respiratory tularemia in as little as 5 days. The mechanisms by which Francisella overwhelms the lungs and so rapidly causes death of the host remain important unanswered questions. Although antibiotic treatment can resolve respiratory tularemia, it must be initiated early in the disease progression to be effective, and often diagnosis is delayed as a result of the nonspecific clinical symptoms of tularemia. In light of this, vaccination is likely to be the best method for prevention of severe pneumonic tularemia. There is currently no licensed vaccine available for tularemia in the United States, prompting a renewed push to develop new vaccines and therapeutics. However, progress in vaccine development would be greatly facilitated by an improved understanding of the virulence mechanisms used by Francisella, as well as the nature of the immune response to the organism. Recent important murine studies have begun to unravel the immune response to Francisella in the unique environment of the host lung—and they have found that it is woefully lacking. Shortly after inhalation, Francisellae are found inside cells that typically act as cytokine-producing sentinels of infection, including airway macrophages, DC, and type II alveolar epithelial cells [1–3]. In spite of this diversity of infected cell types, there is an absence of crucial proinflammatory cytokines in infected mice, including IL-12p40, TNF, IL-6, and IL-1 . Revealing studies conducted by Bosio et al. [1] demonstrated that the virulent F. tularensis strain Schu S4 suppressed activation of resident mouse lung DC. Interestingly, Schu S4-infected mice also nonspecifically suppressed in vivo responses to intranasal administration of Escherichia coli LPS. The mediators responsible for these immunosuppressive phenomena remain to be fully defined, but immunomodulatory factors such as TGFand PGE-2 are produced in Francisella-infected lungs and may be key contributors [1, 2, 4]. In light of this in vivo immunosuppression, it is interesting to note that in vitro infection of murine macrophages with F. tularensis subsp. novicida activated the Src homology 2 domain-containing inositol phosphatase, resulting in diminished production of proinflammatory cytokines [5]. Other studies have similarly shown that mouse macrophages and human monocytes infected with an attenuated F. tularensis strain down-regulated intracellular signaling and TNF production [6]. Taken together, these data indicate that following lung infection, Francisella proliferates logarithmically in an actively immunosuppressed environment within the first 48–72 h after inhalation. Although Francisella promotes the activities of immunomodulatory products during early pneumonic infection, it is also clear that sometime between 48 h and 72 h after infection, there is an abrupt change of events: Numerous key cytokines and chemokines are up-regulated and produced in abundance. During virulent F. tularensis respiratory infection of mice, mRNA levels of essential antimicrobial cytokines such as IFNand TNF rose in the lung between Days 2 and 4 [7], and serum/distal organ levels of proinflammatory mediators such as RANTES, IL-6, and IL-1 became detectable on Days 3–4 [8]. However, by this time, key organs such as the lungs and liver can harbor more than 10 CFU bacteria, and this late up-regulation of antimicrobial host immune mechanisms may simply be too late to prevent death. Indeed, a number of studies support the hypothesis that augmenting production of proinflammatory cytokines early during infection could be beneficial: Mice administered a synthetic TLR 4 agonist or rIL-12 shortly before inhalation of Francisella exhibited diminished organ bacterial burdens and enhanced survival [9–11]. The study presented here by Sharma et al. provides evidence that the late upregulation of proinflammatory cytokines