Experimental Tularemia in Macaca mulatta: Relationship of Aerosol Particle Size to the Infectivity of Airborne Pasteurella tularensis

Abstract

Ninety-six Macaca mulatta were exposed to aerosol particles containing Pasteurella tularensis. Four different aerosols were employed that contained particle size distributions with median diameters of 2.1, 7.5, 12.5, or 24.0 Am. Size distributions were calculated only for those particles observed by phase microscope to contain organisms. Animals exposed to particles whose median diameters were either 2.1 or 7.5 ,4m were all infected and showed extensive infection of the lower respiratory tract, evidenced by large patches of consolidation with many necrotic foci on the surface. Death occurred in these animals 4 to 8 days after exposure. Monkeys exposed to 12.5or 24.0-,um median diameter particles presented involvement of the cervical and mandibular lymph nodes, evidenced by swelling and abscess formation. Thirty-eight of the 45 animals in this group were infected. Those animals succumbing to the disease died from 8 to 21 days after exposure. The respiratory LDM values increased from 14 to 4,447 cells as the median diameter was raised from 2.1 to 24.0 ,um.

Establishment of lethal inhalational infection with Francisella tularensis (tularaemia) in the common marmoset (Callithrix jacchus)

“…Low LD 50 values for F. tularensis in systemic and airborne murine models of infection, of approximately 10-20 CFU have been reported . Our results are also consistent with the low LD 50 values reported previously in rhesus macaques (approximately 14 CFU) (Day & Berendt 1972) and low infectivity in humans (Saslaw et al 1961), although the LD 50 for humans is not known. The low LD 50 reported in this study has provided supporting evidence that the marmoset is highly susceptible to F. tularensis by the airborne route and may be a relevant and comparable model of tularaemia.…”

“…A log increase or decrease in colony-forming units (CFU) was to be used for each step-up or step-down stage, starting from a target estimated susceptible dose of approximately 100 CFU. This was based on a reported LD 50 of 14 CFU in macaques (Day & Berendt 1972). Steps 1 and 2 of the study progressed as planned, however, because of the low infectivity of the bacteria, step 3 consisted of three experiments at a target dose of 100 CFU.…”

“…In order to undertake the pivotal studies, however, that would be required for licensure of any therapy, non-human primate (NHP) models of infection are likely to be required. Early work, undertaken during 1960s and 1970s, used the rhesus macaque (Macaca mulatta) to model tularaemia pathogenesis (Tulis et al 1970;Day & Berendt 1972;Schricker et al 1972;Hall et al 1973). Studies evaluating medical countermeasures such as antibiotics (Sawyer et al 1966), and the efficacy of the live vaccine strain (LVS) tularaemia vaccine (Eigelsbach et al 1962;Tulis et al 1969) were also undertaken in the rhesus macaque.…”

A dose and time response Markov model for the in-host dynamics of infection with intracellular bacteria following inhalation: with application toFrancisella tularensis

“…However, for the time from bacterial uptake to cell death and the associated release of bacteria (birth), a simple incell mechanistic model (based on a pure birth process with saturation of available nutrients) suggests that the variance is being overestimated by the exponential distribution. In other areas, however, the variability may well be underestimated, because the model fails to account for variability in other sources that can affect dispersion, such as bacterial age [42], diameter [7,51], agglutination, number retained and deposition site [23].…”

Review and comparison between the Wells–Riley and dose-response approaches to risk assessment of infectious respiratory diseases

“…For example, the ID 50 of influenza virus is about two orders higher when the virus was introduced to the nasal cavity by intranasal drop than introduced to lower respiratory tract via aerosol inhalation (Alford et al, 1966;Douglas, 1975). As the respiratory deposition of aerosols depends on their sizes, the variation of pathogen infectivity when carried by infectious particles of different sizes was also observed, as shown by many experimental infection studies (e.g., Day and Berendt, 1972;Wells, 1955).…”