Bacillus anthracis Spore Entry into Epithelial Cells Is an Actin-Dependent Process Requiring c-Src and PI3K

Xue, Qiong; Jenkins, Sarah A.; Gu, Cheng; Smeds, Emanuel; Liu, Qing; Vasan, Ranga; Russell, Brooke; Xu, Yi

doi:10.1371/journal.pone.0011665

Cited by 18 publications

(30 citation statements)

References 34 publications

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“…Specifically, Src kinase activity is required for the internalization of Neisseria spp. and Staphylococcus aureus and is needed for both Streptococcus pneumoniae and Bacillus anthracis dissemination (albeit via different mechanisms), given that translocation through lung epithelial cells is inhibited when SFK inhibitors are added in vitro to experiments with the last two pathogens (1,2,32,63,78,89). In a comparable manner, the addition of PP2 clearly inhibits B. burgdorferi invasion (Fig.…”

Section: Discussionmentioning

confidence: 88%

“…4A); however, it is still not known which of the SFK members are involved in this process. Since SU6656 has been shown to alter the dissemination of B. anthracis during infection (89), it is possible that B. burgdorferi dissemination and/or long-term survival may be adversely affected in existing SFK knockout mice or in mice that are treated over time with SU6656. Additional experimentation is required to address this possibility.…”

Section: Discussionmentioning

confidence: 99%

“…4A). Another Src family kinase inhibitor, SU6656, which inhibits a subset of Src kinases (10,75,89), significantly inhibited the internalization of B. burgdorferi but, in contrast to the PP2 treatment, did not abolish it (Fig. 4B).…”

Section: Nonprofessional Phagocytic Cells Differentially Internalizementioning

confidence: 99%

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Invasion of Eukaryotic Cells byBorrelia burgdorferiRequires β₁Integrins and Src Kinase Activity

Weening

Faske

et al. 2011

Infect Immun

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Lyme disease, caused by the bacterium Borrelia burgdorferi, is the most widespread tick-borne infection in the northern hemisphere that results in a multistage disorder with concomitant pathology, including arthritis. During late-stage experimental infection in mice, B. burgdorferi evades the adaptive immune response despite the presence of borrelia-specific bactericidal antibodies. In this study we asked whether B. burgdorferi could invade fibroblasts or endothelial cells as a mechanism to model the avoidance from humorally based clearance. A variation of the gentamicin protection assay, coupled with the detection of borrelial transcripts following gentamicin treatment, indicated that a portion of B. burgdorferi cells were protected in the short term from antibiotic killing due to their ability to invade cultured mammalian cells. Long-term coculture of B. burgdorferi with primary human fibroblasts provided additional support for intracellular protection. Furthermore, decreased invasion of B. burgdorferi in murine fibroblasts that do not synthesize the ␤ 1 integrin subunit was observed, indicating that ␤ 1 -containing integrins are required for optimal borrelial invasion. However, ␤ 1 -dependent invasion did not require either the ␣ 5 ␤ 1 integrin or the borrelial fibronectin-binding protein BBK32. The internalization of B. burgdorferi was inhibited by cytochalasin D and PP2, suggesting that B. burgdorferi invasion required the reorganization of actin filaments and Src family kinases (SFK), respectively. Taken together, these results suggest that B. burgdorferi can invade and retain viability in nonphagocytic cells in a process that may, in part, help to explain the phenotype observed in untreated experimental infection.Borrelia burgdorferi sensu lato is the causative agent of Lyme disease and the most widespread arthropod infection in North America, Europe, and Asia (3,60,80,81). The disease is transmitted via Ixodes ticks and presents as a multistage disorder that is initially characterized by a flu-like illness and a painless rash known as erythema migrans (60,(79)(80)(81). Subsequently the disease can involve cardiac, neurologic, and joint abnormalities if therapeutic approaches are not sought early in the infectious process (60,80,81). If treated early, patients generally respond well to antibiotic therapy (80,81).During experimental infection in mice, persistence is observed in the absence of antibiotic therapy. These experimentally infected animals have high-titered antibodies that kill B. burgdorferi in vitro; however, we know strikingly little as to how these spirochetes evade humoral clearance under these conditions. One contributing factor may be that B. burgdorferi invades nonphagocytic mammalian cells in vivo, thereby providing an immunoprotected niche. Along these lines, several groups have reported that B. burgdorferi is able to internalize into different eukaryotic cells, including endothelial cells, fibroblasts, neuronal, and neuroglial cells (24,46,52,53). However, the fate of internalized spir...

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

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Invasion of Eukaryotic Cells byBorrelia burgdorferiRequires β₁Integrins and Src Kinase Activity

Weening

Faske

et al. 2011

Infect Immun

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“…Spores of B. anthracis were significantly better at persisting in the lung than spores of a non-exosporium-possessing B. subtilis strain, and some of the persisting spores were found within epithelial cells (138). Treatment of mice with an Src family kinase inhibitor significantly reduced B. anthracis dissemination from the lung to distal organs and prolonged the median survival time for mice compared to those for the untreated control group (139). There appears to be a signaling pathway specifically required for spore entry into epithelial cells, and these studies provided evidence suggesting that this pathway is important for dissemination and virulence in vivo (139).…”

Section: Functions Of the Exosporium In An Infected Hostmentioning

confidence: 99%

The Exosporium Layer of Bacterial Spores: a Connection to the Environment and the Infected Host

Stewart

2015

Microbiol Mol Biol Rev

139

155

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SUMMARYMuch of what we know regarding bacterial spore structure and function has been learned from studies of the genetically well-characterized bacteriumBacillus subtilis. Molecular aspects of spore structure, assembly, and function are well defined. However, certain bacteria produce spores with an outer spore layer, the exosporium, which is not present onB. subtilisspores. Our understanding of the composition and biological functions of the exosporium layer is much more limited than that of other aspects of the spore. Because the bacterial spore surface is important for the spore's interactions with the environment, as well as being the site of interaction of the spore with the host's innate immune system in the case of spore-forming bacterial pathogens, the exosporium is worthy of continued investigation. Recent exosporium studies have focused largely on members of theBacillus cereusfamily, principallyBacillus anthracisandBacillus cereus. Our understanding of the composition of the exosporium, the pathway of its assembly, and its role in spore biology is now coming into sharper focus. This review expands on a 2007 review of spore surface layers which provided an excellent conceptual framework of exosporium structure and function (A. O. Henriques and C. P. Moran, Jr., Annu Rev Microbiol61:555–588, 2007,http://dx.doi.org/10.1146/annurev.micro.61.080706.093224). That review began a process of considering outer spore layers as an integrated, multilayered structure rather than simply regarding the outer spore components as independent parts.

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“…An alternative model for phagocyte independent dissemination is that the spores and vegetative bacilli can be internalized by epithelial cells directly [62,271,[278][279][280][281]. These studies are supported by in vitro and in vivo studies that demonstrate that the spores are able to adhere, invade, and transcytose through the epithelial layer [271,279,280].…”

Section: Investigations Of B Anthracis Infections With Bioluminescenmentioning

confidence: 96%

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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Bacillus anthracis Spore Entry into Epithelial Cells Is an Actin-Dependent Process Requiring c-Src and PI3K

Cited by 18 publications

References 34 publications

Invasion of Eukaryotic Cells byBorrelia burgdorferiRequires β₁Integrins and Src Kinase Activity

Invasion of Eukaryotic Cells byBorrelia burgdorferiRequires β₁Integrins and Src Kinase Activity

The Exosporium Layer of Bacterial Spores: a Connection to the Environment and the Infected Host

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

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Bacillus anthracis Spore Entry into Epithelial Cells Is an Actin-Dependent Process Requiring c-Src and PI3K

Cited by 18 publications

References 34 publications

Invasion of Eukaryotic Cells byBorrelia burgdorferiRequires β1Integrins and Src Kinase Activity

Invasion of Eukaryotic Cells byBorrelia burgdorferiRequires β1Integrins and Src Kinase Activity

The Exosporium Layer of Bacterial Spores: a Connection to the Environment and the Infected Host

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

Contact Info

Product

Resources

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Invasion of Eukaryotic Cells byBorrelia burgdorferiRequires β₁Integrins and Src Kinase Activity

Invasion of Eukaryotic Cells byBorrelia burgdorferiRequires β₁Integrins and Src Kinase Activity