Updating Perspectives on the Initiation of Bacillus anthracis Growth and Dissemination through Its Host

Weiner, Zachary P.; Glomski, Ian J.

doi:10.1128/iai.06061-11

Cited by 53 publications

(74 citation statements)

References 71 publications

(121 reference statements)

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“…This suggests that in a murine subcutaneous infection, the initial site of infection is a crucial point that determines whether the host will survive the infection. Similar studies have found that removing the infected portion of the ear or genetically deleting the CMG2 receptor from myeloid cells leads to increases in mouse survival [183,264]. Our findings, however, imply that LF is critical for this survival and dissemination from the initial site.…”

Section: Discussioncontrasting

confidence: 54%

“…A recent review from our laboratory examining these differences posed a Jailbreak model of dissemination that synthesized many of the features of phagocyte independent dissemination [264]. This model proposes that B. anthracis spores not only sense the host, but they sense favorable environments in the host for germination.…”

Section: Phagocyte Independent Dissemination In the Hostmentioning

confidence: 99%

“…Regardless of the route of infection, B. anthracis has a common method of dissemination ( Figure 3) [264,265]. Spores germinate in the initial site of the infection and the vegetative bacilli produce the exotoxin and capsule (Weiner et al, 2014).…”

Section: Dissemination Of Bacillus Anthracis In the Hostmentioning

confidence: 99%

“…The spores were then collected from plates and purified on an Omnipaq gradient (350 mg of iodine/mL, GE Healthcare, NJ) as described previously [81,264,289].…”

Section: Introductionmentioning

confidence: 99%

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Opening moves: early events in anthrax pathogenesis and their consequences for dissemination

Lowe

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Bacillus anthracis is a Gram positive sporulating bacterium that is the causative agent of anthrax. Early steps in dissemination are understudied due to the asymptomatic and asynchronous nature of B. anthracis infections. The goals of these studies are to establish a model of the early steps of B. anthracis infections and examine how the initial site of infection and exotoxin production affect bacterial dissemination. In these studies, a mouse model was used in combination with a bioluminescent signature tagged library to determine how B.anthracis disseminates through the host and the roles of an exotoxin component, lethal factor, in colonization and dissemination. This library allowed for real time observation of dissemination and analysis of bacterial population dynamics. In the first set of experiments, mice were infected via inhalational or subcutaneous routes with the tagged library to determine how the bacterial population changed during dissemination. In inhalational and subcutaneous infections, the disseminated population was comprised of a small subset of the original library.This indicated the presence of a population bottleneck, a random decrease in genetic diversity during the infection. Surprisingly, the diminishment and location of the bottleneck varied depending on the initial site of infection. This suggested B. anthracis exploits multiple host environments and some sites may be more permissive for dissemination than others. In the second set of experiments, mice were infected with a signature tagged library where a portion of clones lacked lethal factor. Lethal factor is known to be an important virulence factor as deletion results in attenuated or complete loss of virulence in most animal models. Host survival increased when < 10% of the library produced lethal factor, but few other differences were observed. Furthermore, decreases in the proportion of lethal factor producing clones led to fewer clones disseminating. These findings suggest that a threshold of lethal factor must be ii produced for colonization and dissemination to occur in vivo. In total, this work provides an understanding of how B. anthracis is able to rapidly disseminate from a several tissues and gives insights in where future therapeutics should be focused to reduce disease incidence.iii

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Section: Discussioncontrasting

confidence: 54%

Section: Phagocyte Independent Dissemination In the Hostmentioning

confidence: 99%

Section: Dissemination Of Bacillus Anthracis In the Hostmentioning

confidence: 99%

“…The spores were then collected from plates and purified on an Omnipaq gradient (350 mg of iodine/mL, GE Healthcare, NJ) as described previously [81,264,289].…”

Section: Introductionmentioning

confidence: 99%

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Opening moves: early events in anthrax pathogenesis and their consequences for dissemination

Lowe

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“…The sero-status with respect to anti-PA IgG and TNA titers of each individual animal in the groups was measured just prior to the spore challenge and are shown in Table 2, experiment B. One day after the spore challenge, as has been previously reported 18,19 robustly growing B. anthracis was evident in nasally associated lymphoid tissues (NALT) in all animals in the unvaccinated control group, whereas in animals in the three vaccinated groups only a marginal growth was detected that was reminiscent of an abortive growth pattern associated with an aerosolic infection of Sterne strain 7702 lacking the pag gene (Δpag) described previously. 18 Nonetheless, this limited growth that was strictly confined to NALT was completely cleared by day 2 post-challenge in all of the animals in all three vaccinated groups except one mouse likely to be an outlier in the LC16M8/IL-15/PA group (one death in two separate experiments involving 20 mice), which had sustained growth in NALT without further dissemination but died on day 5 post-challenge.…”

Section: Resultsmentioning

confidence: 99%