Rat survival to anthrax lethal toxin is likely controlled by a single gene

Abstract

We examined whether survival of different rat strains administered anthrax lethal toxin is genetically determined. A reproducible test population of first filial generation hybrid rats was bred based on the susceptibility of progenitors to anthrax lethal toxin and to maximize genetic diversity across the strains. These rats were then tested with varying doses of anthrax lethal toxin. We found that all 'sensitive' strains died within 2 h following systemic administration of 240 mg/kg lethal toxin, while one strain survived following a five times higher dose (1.4 mg/kg). The ability of lethal toxin to lyse macrophage cultures derived from the bone marrow of these strains corresponded with in vivo results. We conclude that a rat test population can detect strain differences in response to anthrax lethal toxin. Survival is influenced by the host genome background and is likely due to a single gene with a recessive mode of inheritance.

Proteasome Inhibitors Prevent Caspase-1-Mediated Disease in Rodents Challenged with Anthrax Lethal Toxin

“…Genetic backcrossing experiments in rats further suggested that a dominant gene not only controlled LT killing in vitro, but also LT-mediated disease progression. 19 This in vitro and in vivo correlation in rats is clearly distinct from the murine system, where in vitro and in vivo LT susceptibilities do not correlate. 30,31 Based on these studies, we hypothesized that a dominant gene controls macrophage killing as well as vascular collapse in rats challenged with LT. To test this hypothesis we initially determined whether the inflammatory proteincaspase-1 controlled macrophage killing of susceptible rat macrophages.…”

“…4,29 -31 Recent studies have indicated that LT susceptibility of rat macrophages is also strain-dependent and controlled by a single, dominant gene, potentially the rat homologue of murine Nalp1b. 19 Based on the similar LT susceptibility pattern of murine and rat macrophages, we predicted that LT killing of susceptible rat macrophages was also caspase-1-dependent. Genetic backcrossing experiments in rats further suggested that a dominant gene not only controlled LT killing in vitro, but also LT-mediated disease progression.…”

“…Rats are divided into susceptible strains that are rapidly killed after LT challenge, and strains that are resistant to rapid disease progression. 19 In contrast to mice, however, the in vivo LT susceptibility of rat strains closely mimics the in vitro susceptibility of their corresponding macrophages. 19 Backcrossing experiments using susceptible and resistant rat strains suggest that the (in vivo and in vitro) LT susceptibility in rats is controlled by a single dominant gene.…”

“…19 In contrast to mice, however, the in vivo LT susceptibility of rat strains closely mimics the in vitro susceptibility of their corresponding macrophages. 19 Backcrossing experiments using susceptible and resistant rat strains suggest that the (in vivo and in vitro) LT susceptibility in rats is controlled by a single dominant gene. 19 After LT administration, rats develop pulmonary edema, and die from a vascular collapse, a hallmark of human anthrax.…”

“…19 Backcrossing experiments using susceptible and resistant rat strains suggest that the (in vivo and in vitro) LT susceptibility in rats is controlled by a single dominant gene. 19 After LT administration, rats develop pulmonary edema, and die from a vascular collapse, a hallmark of human anthrax. 20 -22 Due to greater similarities with human anthrax, the rat model of LT-induced disease may be superior to the murine model.…”