Quantification of the Relationship between Bacterial Kinetics and Host Response for Monkeys Exposed to AerosolizedFrancisella tularensis

Abstract

ABSTRACTFrancisella tularensiscan be disseminated via aerosols, and once inhaled, only a few microorganisms may result in tularemia pneumonia. Effective responses to this threat depend on a thorough understanding of the disease development and pathogenesis. In this study, a class of time-dose-response models was expanded to describe quantitatively the relationship between the temporal probability distribution of the host response and thein vivobacterial kinetics. An extensive literature search was conducted to locate both the dose-dependent survival data and thein vivobacterial count data of monkeys exposed to aerosolizedF. tularensis. One study reporting responses of monkeys to four different sizes of aerosol particles (2.1, 7.5, 12.5, and 24.0 μm) of the SCHU S4 strain and three studies involving fivein vivogrowth curves of various strains (SCHU S4, 425, and live vaccine strains) initially delivered to hosts in aerosol form (1 to 5 μm) were found. The candidate models exhibited statistically acceptable fits to the time- and dose-dependent host response and provided estimates for the bacterial growth distribution. The variation pattern of such estimates with aerosol size was found to be consistent with the reported pathophysiological and clinical observations. The predicted growth curve for 2.1-μm aerosolized bacteria was highly consistent with the available bacterial count data. This is the first instance in which the relationship between thein vivogrowth ofF.tularensisand the host response can be quantified by mechanistic mathematical models.