Comparison of experimental respiratory tularemia in three nonhuman primate species

Abstract

Tularemia is a zoonotic disease caused by Francisella tularensis, which is transmitted to humans most commonly by contact with infected animals, tick bites, or inhalation of aerosolized bacteria. F. tularensis is highly infectious via the aerosol route; inhalation of as few as 10-50 organisms can cause pneumonic tularemia. Left untreated, the pneumonic form has more than > 30% case-fatality rate but with early antibiotic intervention can be reduced to 3%. This study compared tularemia disease progression across three species of nonhuman primates [African green monkey (AGM), cynomolgus macaque (CM), and rhesus macaque (RM)] following aerosolized F. tularensis Schu S4 exposure. Groups of the animals exposed to various challenge doses were observed for clinical signs of infection and blood samples were analyzed to characterize the disease pathogenesis. Whereas the AGMs and CMs succumbed to disease following challenge doses of 40 and 32 colony forming units (CFU), respectively, the RM lethal dose was 276,667 CFU. Following all challenge doses that caused disease, the NHPs experienced weight loss, bacteremia, fever as early as 4 days post exposure, and tissue burden. Necrotizing-to-pyogranulomatous lesions were observed most commonly in the lung, lymph nodes, spleen, and bone marrow. Overall, the CM model consistently manifested pathological responses similar to those resulting from inhalation of F. tularensis in humans and thereby most closely emulates human tularemia disease. The RM model displayed a higher tolerance to infection and survived exposures of up to 15,593 CFU of aerosolized F. tularensis.

Aerosol prime-boost vaccination provides strong protection in outbred rabbits against virulent type A Francisella tularensis

“…Once the organism has entered the host, it can disseminate throughout the body and infect a wide array of cell types including macrophages, dendritic cells, epithelial cells, hepatocytes and even erythrocytes. Lung, liver, spleen, and bone marrow are primary targets for bacterial replication and pathogenesis although all organs can be affected, including heart and brain [ 3 – 8 ]. The widespread infection is thought to induce septic shock, disseminated intravascular coagulation and/or acute respiratory distress syndrome resulting in multi-organ failure and death [ 1 , 6 ].…”

The Cynomolgus Macaque Natural History Model of Pneumonic Tularemia for Predicting Clinical Efficacy Under the Animal Rule

“…Among non-human primates (NHPs), rhesus and cynomolgus macaques, African Green monkeys, and marmosets have been used in tularemia studies (Lyons and Wu, 2007 ). Recent studies (Glynn et al, 2015 , and data described in this manuscript) demonstrated that the infectious dose and disease pathophysiology in cynomolgus macaques challenged with aerosolized F. tularensis strain Schu S4, closely resemble human pneumonic tularemia caused by F. tularensis subsp. tularensis (Type A) strains, the most severe and lethal form of the disease.…”

The Fluorocycline TP-271 Is Efficacious in Models of Aerosolized Francisella tularensis SCHU S4 Infection in BALB/c Mice and Cynomolgus Macaques

“…Therefore, well-defined animal models need to be utilized to evaluate the efficacy of new antibiotics against tularemia, and this is reflected in the 2015 FDA guidance implementing the Animal Rule for the approval of vaccines and therapeutics when human efficacy studies are not ethical or feasible (9). The natural history of infection due to aerosolized exposure to F. tularensis strain SCHU S4 has been well characterized in mice and nonhuman primates (10,11). In studies using mouse models of aerosolized exposure to F. tularensis, pathology similar to that of human infections has been observed (12,13).…”

“…In studies using mouse models of aerosolized exposure to F. tularensis, pathology similar to that of human infections has been observed (12,13). In a comparison of three nonhuman primate (NHP) species, Glynn et al concluded that the cynomolgus macaque respiratory tularemia model most closely simulated human tularemia clinical and pathological (gross and microscopic) manifestations and tissue bacterial burden (11).…”