Clinical and pathologic features of cynomolgus macaques (Macaca fascicularis) infected with aerosolized Yersinia pestis

Abstract

Since the anthrax attacks of 2001, the emphasis on developing animal models of aerosolized select agent pathogens has increased. Many scientists believe that nonhuman primate models are the most appropriate to evaluate pulmonary response to, vaccines for, and treatments for select agents such as Yersinia pestis (Y. pestis), the causative agent of plague. A recent symposium concluded that the cynomolgus macaque (Macaca fascicularis) plague model should be characterized more fully. To date, a well-characterized cynomolgus macaque model of pneumonic plague using reproducible bioaerosols of viable Y. pestis has not been published. In the current study, methods for creating reproducible bioaerosols of viable Y. pestis strain CO92 (YpCO92) and pneumonic plague models were evaluated in 22 Indonesian-origin cynomolgus macaques. Five macaques exposed to doses lower than 250 CFU remained free of any indication of plague infection. Fifteen macaques developed fever, lethargy, and anorexia indicative of clinical plague. The 2 remaining macaques died without overt clinical signs but were plague-positive on culture and demonstrated pathology consistent with plague. The lethal dose of plague in humans is reputedly less than 100 organisms; in this study, 66 CFU was the dose at which half of the macaques developed fever and clinical signs (ED(50)), The Indonesian cynomolgus macaque reproduces many aspects of human pneumonic plague and likely will provide an excellent model for studies that require a macaque model.

Figure 1.

(A and C) Acute fibrinous interstitial pneumonia with bacteria in major pulmonary vessels and septal capillaries, consistent with hematogenous seeding of lung. (B and D) Acute suppurative bronchopneumonia consistent with primary pneumonia rather than hematogenous seeding of lung. Arrows point to bacteria, and arrowheads point to fibrin and neutrophils in a bronchiole; this animal also had slight alveolar hemorrhage. Magnification, ×40 (A and B), ×100 (C and D).

Figure 1.

(A and C) Acute fibrinous interstitial pneumonia with bacteria in major pulmonary vessels and septal capillaries, consistent with hematogenous seeding of lung. (B and D) Acute suppurative bronchopneumonia consistent with primary pneumonia rather than hematogenous seeding of lung. Arrows point to bacteria, and arrowheads point to fibrin and neutrophils in a bronchiole; this animal also had slight alveolar hemorrhage. Magnification, ×40 (A and B), ×100 (C and D).

Figure 1.

(A and C) Acute fibrinous interstitial pneumonia with bacteria in major pulmonary vessels and septal capillaries, consistent with hematogenous seeding of lung. (B and D) Acute suppurative bronchopneumonia consistent with primary pneumonia rather than hematogenous seeding of lung. Arrows point to bacteria, and arrowheads point to fibrin and neutrophils in a bronchiole; this animal also had slight alveolar hemorrhage. Magnification, ×40 (A and B), ×100 (C and D).

Figure 1.

(A and C) Acute fibrinous interstitial pneumonia with bacteria in major pulmonary vessels and septal capillaries, consistent with hematogenous seeding of lung. (B and D) Acute suppurative bronchopneumonia consistent with primary pneumonia rather than hematogenous seeding of lung. Arrows point to bacteria, and arrowheads point to fibrin and neutrophils in a bronchiole; this animal also had slight alveolar hemorrhage. Magnification, ×40 (A and B), ×100 (C and D).