Pathology of Inhalational Francisella tularensis spp. tularensis SCHU S4 Infection in African Green Monkeys (Chlorocebus aethiops)

Abstract

Abstract. Tularemia, caused by Francisella tularensis, is a sporadic zoonotic disease with the potential to be an agent of biowarfare or bioterrorism. We describe here the gross, histologic, immunohistochemical, and ultrastructural findings in a group of 5 African green monkeys (AGMs) that received an average inhaled dose of 729 colony-forming units of F. tularensis and died or were euthanatized between days 7 and 11 post infection. Clinical changes were evident by 48 hours post infection, and key physiologic abnormalities included increases in body temperature, heart rate, peak cardiac pressure, and mean blood pressure. Prominent gross changes in all cases included numerous pinpoint to 1-cm, well-demarcated, necrotic foci present consistently in the lungs, mediastinal lymph nodes, and spleen but also seen in the heart, mediastinum, diaphragm, liver, urinary bladder, urethra, and mesentery. The lungs, mediastinal lymph nodes, and spleen were most severely affected, with as much as 50% of the tissue replaced by necrotic foci. Histologic changes in all tissues consisted of welldelineated foci of necrosis and neutrophilic and histiocytic inflammation, with varying amounts of hemorrhage, edema, fibrin, and vasculitis. Some lesions were immature pyogranulomas. Strong immunoreactivity was identified primarily within macrophages. Ultrastructurally, bacteria were present within cytoplasmic vacuoles of alveolar macrophages, many of which were degenerate. In summary, AGMs infected with F. tularensis by aerosol develop lethal multisystemic disease that particularly targets the lungs and lymphoid tissues. Thus, AGMs should serve as a suitable and reliable animal model for further studies of tularemia.

A spontaneous mutation in kdsD, a biosynthesis gene for 3 Deoxy-D-manno-Octulosonic Acid, occurred in a ciprofloxacin resistant strain of Francisella tularensis and caused a high level of attenuation in murine models of tularemia

“…tularensis subsp. tularensis strains used included the fully virulent Schu S4 [23] and the CipR mutant Schu S4 derivative [26] which had been previously selected with approval by the Centers for Disease Control. Previous characterization of the CipR mutant strain determined that the gyrA gene contained two base pair (bp) substitutions: C248→T and G259→T.…”

“…Human illness can range from the ulceroglandular form to more serious pneumonic or typhoidal tularemia [15]. In pneumonic tularemia, infection progresses from the lungs to other organs, primarily the liver and spleen [18–23]. The risk of infection is associated mainly with two subspecies, the more virulent F .…”

Antibodies Contribute to Effective Vaccination against Respiratory Infection by Type A Francisella tularensis Strains

“…Rather, the effects of IRS on bacterial growth were most clearly observed in the infected liver and spleen. The liver is a major site of F. tularensis colonization and replication (9), and pneumonic tularemia is associated with hepatocellular damage in multiple experimental animal models, including the F344 rat (8,32,42,45). Although the level of damage falls short of liver failure and may be reversible, such damage may nevertheless compromise the liver's ability to perform essential metabolic functions and to utilize its many innate immune mechanisms to control systemic bacterial growth (22,25).…”

Francisella DnaK Inhibits Tissue-nonspecific Alkaline Phosphatase

“…tion as a proinflammatory mediator by activating the plasma contact activation, or so-called "intrinsic" coagulations system (42). The pathology of the pulmonary tularemia sepsis syndrome is characterized by wide dissemination of necrotic foci with histolytic inflammation and pyogranulomas, accompanied by fibrin deposition, hemorrhage, and vascular inflammation (43). These pathologic changes are consistent with coagulation system activation.…”