Features of sepsis caused by pulmonary infection with Francisella tularensis Type A strain

Abstract

The virulence mechanisms of Francisella tularensis, the causative agent of severe pneumonia in humans and a CDC category A bioterrorism agent, are not fully defined. As sepsis is the leading cause of mortality associated with respiratory infections, we determined whether, in the absence of any known bacterial toxins, a deregulated host response resulting in sepsis syndrome is associated with lethality of respiratory infection with the virulent human Type A strain SchuS4 of F. tularensis. The C57BL/6 mice infected intranasally with a lethal dose of SchuS4 exhibited high bacterial burden in systemic organs and blood indicative of bacteremia. In correlation, infected mice displayed severe tissue pathology and associated cell death in lungs, liver and spleen. Consistent with our studies with murine model strain F. novicida, infection with SchuS4 caused an initial delay in upregulation of inflammatory mediators followed by development of severe sepsis characterized by exaggerated cytokine release, upregulation of cardiovascular injury markers and sepsis mediator alarmins S100A9 and HMGB-1. This study shows that pulmonary tularemia caused by the Type A strain of F. tularensis results in a deregulated host response leading to severe sepsis and likely represents the major cause of mortality associated with this virulent pathogen.

The Natural History of Pneumonic Tularemia in Female Fischer 344 Rats after Inhalational Exposure to Aerosolized Francisella tularensis Subspecies tularensis Strain SCHU S4

“…A more recent study using a higher aerosol exposure dose demonstrated many similarities in the natural history of pneumonic tularemia in mice and F344 rats infected with aerosolized F. tularensis subspecies tularensis, including the development of inflammation in the lungs, liver, and spleen with severe sepsis and coagulopathy, and high terminal bacterial burdens in these organs and blood at the time of death, 4 to 5 days after infection. 52 The most prominent difference between F344 rats and mice is the susceptibility of the latter to all F. tularensis subspecies, including subspecies novicida and LVS. 24 In this regard, F344 rats more …”

Protective Role for Macrophages in Respiratory Francisella tularensis Infection

“…It has been suggested that alveolar phagocytes are therefore detrimental to the host during respiratory infection, and a 2005 study reported that depletion of alveolar phagocytes following high challenge doses of LVS resulted in a modestly delayed time to death (7). The course of disease is characterized by a delayed immune response, followed by systemic dissemination and sepsis (8)(9)(10). Consequently, the prevailing opinion is that F. tularensis evades destruction by innate immunity and subverts myeloid cells, particularly macrophages, for its own benefit.…”

Interleukin-6 Is Essential for Primary Resistance to Francisella tularensis Live Vaccine Strain Infection

“…The role of IL-6 in immunity to F. tularensis, however, is not yet well defined. Several reports have shown that IL-6 is induced during primary infection of mice with either the virulent strain of F. tularensis SchuS4 or the attenuated LVS (22)(23)(24)(25)(26). In contrast to a potential role for prediction of vaccine-induced protection, IL-6 has also been suggested as a predictor of mortality in BALB/c mice infected intranasally with a dose of LVS that approximated the expected LD 50 (27).…”