Abstract
Lethal factor (LF) is a component of the B. anthracis exotoxin and critical for pathogenesis. The roles of LF in early anthrax pathogenesis, such as colonization and dissemination from the initial site of infection, are poorly understood. In mice models of infection, LF-deficient strains either have altered dissemination patterns or do not colonize, precluding analysis of the role of LF in colonization and dissemination from the portal of entry. Previous reports indicate rabbit and guinea pig models infected with LF-deficient strains have decreased virulence, yet the inability to use bioluminescent imaging techniques to track B. anthracis growth and dissemination in these hosts makes analysis of early pathogenesis challenging. In this study, the roles of LF early in infection were analyzed using bioluminescent signature tagged libraries of B. anthracis with varying ratios of LF-producing and LF-deficient clones. Populations where all clones produced LF and populations where only 40% of clones produce LF were equally virulent. The 40% LF-producing clones trans complimented the LF mutants and permitted them to colonize and disseminate. Decreases of the LF producing strains to 10% or 0.3% of the population led to increased host survival and decreased trans complementation of the LF mutants. A library with 10% LF producing clones could replicate and disseminate, but fewer clones disseminated and the mutant clones were less competitive than wild type. The inoculum with 0.3% LF producing clones could not colonize the host. This strongly suggests that between 10% and 0.3% of the population must produce LF in order to colonize. In total, these findings suggest that a threshold of LF must be produced in order for colonization and dissemination to occur in vivo. These observations suggest that LF has a major role in the early stages of colonization and dissemination.
Highlights
Bacillus anthracis is a Gram-positive organism that is the etiological agent of anthrax [1]
While techniques exist that can quantify the amount of Lethal factor (LF) within a host, difficulties still exist for quantifying the amount of LF that has been delivered to the cells and are inducing a biological effect [27,36,40]
By adjusting the amount of LF produced by a population, one can determine the effect of this amount on dissemination without making assumptions based on exotoxin internalization rates or clearance from the host
Summary
Bacillus anthracis is a Gram-positive organism that is the etiological agent of anthrax [1]. Anthrax can occur via cutaneous, inhalational, and gastrointestinal routes; the latter two forms are highly lethal in livestock and humans [2]. The infectious particle for B. anthracis is the spore, which is characterized as metabolically inert and highly resistant to many forms of bactericidal killing [3]. The spore senses the host environment and germinates to form the vegetative bacillus [4]. The bacilli are able to multiply to high numbers in the host due to their potent exotoxin and anti-phagocytic capsules [1]. The bacteria cause the death of the host, inducing the bacilli to undergo sporulation and subsequently releasing spores into the soil as the tissue decays
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