The Interactions between<i>Bacillus anthracis</i>and Macrophages

Welkos, Susan L.; Bozue, Joel A.; Cote, Christopher K.

doi:10.1002/9780470891193.ch10

Cited by 4 publications

(6 citation statements)

References 184 publications

(244 reference statements)

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“…Therefore, in view of the results reported above, the ability of the htrA mutated strain to propagate in phagocytic cells was addressed in the J774.1 murine‐macrophage infection assay. This assay monitors the expansion of the bacteria (by viable counting) and lysis of the macrophages [which may be quantified by release into the medium of the intracellular enzyme lactate dehydrogenase (LDH)] following internalization of spores (Welkos et al ., 2011). Typically, B. anthracis bacilli can be detected in the supernatant of infected J774.1 cells 4 h post infection (multiplicity of infection 1:5), concomitant with the onset of macrophage lysis.…”

Section: Resultsmentioning

confidence: 99%

“…The interaction of B. anthracis spores with phagocytic cells is critical in anthrax pathogenesis representing the initial step of infection, required for germination of the spores into toxin producing bacilli and systemic dissemination of the bacteria (for a recent review, see Welkos et al ., 2011). Furthermore, the intra‐macrophage milieu exerts severe environmental insults, in particular oxidative stress, upon invading micro‐organisms, representing a primary antibacterial sentinel mechanism.…”

Section: Resultsmentioning

confidence: 99%

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HtrA is a major virulence determinant of Bacillus anthracis

Chitlaru

Zaide

Ehrlich

et al. 2011

Molecular Microbiology

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

HtrA is a major virulence determinant of Bacillus anthracis

Chitlaru

Zaide

Ehrlich

et al. 2011

Molecular Microbiology

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“…It is generally recognized that in vitro assays of pathogen growth and survival in macrophages are in all likelihood suboptimal models of host infection and not necessarily predictive of in vivo differences in strain virulence [ 32 , 80 , 92 , 93 ]. It is certainly true that no relatively simple in vitro system can model the complex processes involved in pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…This work employed one strain, K96243, and derivatives of it; although the findings do not inform those of the present study, they exemplify the application of specific macrophage phenotype as a potential in vitro biomarker for infection. Macrophage modeling has been used in studies with Burkholderia , as well as other pathogens (e.g., Yersinia pestis , Yersinia pseudotuberculosis , Francisella tularensis , and Bacillus anthracis ); to probe potential mechanisms of pathogenesis and host responses, such as putative roles in infection of specific bacterial-associated mechanisms and virulence factors [ 29 – 32 , 79 – 87 , 89 , 92 – 96 ]. Macrophage models have been essential in efforts to better understand the roles of the type III and type VI secretion systems (T3SS and T6SS) in the pathogenesis of disease, the mechanisms associated with specific factors encoded by these systems (facilitating intracellular survival, replication, movement, and spread to other cells), and the cellular responses employed by the host to contain these pathogens.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Burkholderia pseudomallei Strains Using a Murine Intraperitoneal Infection Model and In Vitro Macrophage Assays

et al. 2015

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Burkholderia pseudomallei, the etiologic agent of melioidosis, is a gram-negative facultative intracellular bacterium. This bacterium is endemic in Southeast Asia and Northern Australia and can infect humans and animals by several routes. It has also been estimated to present a considerable risk as a potential biothreat agent. There are currently no effective vaccines for B. pseudomallei, and antibiotic treatment can be hampered by nonspecific symptomology, the high incidence of naturally occurring antibiotic resistant strains, and disease chronicity. Accordingly, there is a concerted effort to better characterize B. pseudomallei and its associated disease. Before novel vaccines and therapeutics can be tested in vivo, a well characterized animal model is essential. Previous work has indicated that mice may be a useful animal model. In order to develop standardized animal models of melioidosis, different strains of bacteria must be isolated, propagated, and characterized. Using a murine intraperitoneal (IP) infection model, we tested the virulence of 11 B. pseudomallei strains. The IP route offers a reproducible way to rank virulence that can be readily reproduced by other laboratories. This infection route is also useful in distinguishing significant differences in strain virulence that may be masked by the exquisite susceptibility associated with other routes of infection (e.g., inhalational). Additionally, there were several pathologic lesions observed in mice following IP infection. These included varisized abscesses in the spleen, liver, and haired skin. This model indicated that commonly used laboratory strains of B. pseudomallei (i.e., K96243 and 1026b) were significantly less virulent as compared to more recently acquired clinical isolates. Additionally, we characterized in vitro strain-associated differences in virulence for macrophages and described a potential inverse relationship between virulence in the IP mouse model of some strains and in the macrophage phagocytosis assay. Strains which were more virulent for mice (e.g., HBPU10304a) were often less virulent in the macrophage assays, as determined by several parameters such as intracellular bacterial replication and host cell cytotoxicity.

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“…The role of HtrA BA in promoting tolerance to various stress stimuli, similar to that observed in a variety of Gram-positive and negative bacteria (Skórko-Glonek et al, 2013; Backert et al, 2018) may represent the basis for the dramatic virulence-attenuation of the htrA disrupted bacteria, reflecting the inability of the mutated cells to cope with stress conditions encountered in the host. Of note, resilience to oxidative stress in the course of infection is considered to represent an important feature of pathogenic bacteria in general, and B. anthracis in particular (Welkos et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Distinct Contribution of the HtrA Protease and PDZ Domains to Its Function in Stress Resilience and Virulence of Bacillus anthracis

et al. 2019

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Anthrax is a lethal disease caused by the Gram-positive spore-producing bacterium Bacillus anthracis . We previously demonstrated that disruption of htrA gene, encoding the chaperone/protease HtrA BA (High Temperature Requirement A of B. anthracis ) results in significant virulence attenuation, despite unaffected ability of Δ htrA strains (in which the htrA gene was deleted) to synthesize the key anthrax virulence factors: the exotoxins and capsule. B. anthracis Δ htrA strains exhibited increased sensitivity to stress regimens as well as silencing of the secreted starvation-associated Neutral Protease A (NprA) and down-modulation of the bacterial S-layer. The virulence attenuation associated with disruption of the htrA gene was suggested to reflect the susceptibility of Δ htrA mutated strains to stress insults encountered in the host indicating that HtrA BA represents an important B. anthracis pathogenesis determinant. As all HtrA serine proteases, HtrA BA exhibits a protease catalytic domain and a PDZ domain. In the present study we interrogated the relative impact of the proteolytic activity (mediated by the protease domain) and the PDZ domain (presumably necessary for the chaperone activity and/or interaction with substrates) on manifestation of phenotypic characteristics mediated by HtrA BA . By inspecting the phenotype exhibited by Δ htrA strains trans -complemented with either a wild-type, truncated (ΔPDZ), or non-proteolytic form (mutated in the catalytic serine residue) of HtrA BA , as well as strains exhibiting modified chromosomal alleles, it is shown that (i) the proteolytic activity of HtrA BA is essential for its N-terminal autolysis and subsequent release into the extracellular milieu , while the PDZ domain was dispensable for this process, (ii) the PDZ domain appeared to be dispensable for most of the functions related to stress resilience as well as involvement of HtrA BA in assembly of the bacterial S-layer, (iii) conversely, the proteolytic activity but not the PDZ domain, appeared to be dispensable for the role of HtrA BA in mediating up-regulation of the extracellular protease NprA under starvation stress, and finally (iv) in a murine model of anthrax, the HtrA BA PDZ domain, was dispensable for manifestation of B. anthracis virulence. The unexpected dispensability of the PDZ domain may represent a unique characteristic of HtrA BA amongst bacterial serine proteases of the HtrA family.

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The Interactions betweenBacillus anthracisand Macrophages

Cited by 4 publications

References 184 publications

HtrA is a major virulence determinant of Bacillus anthracis

HtrA is a major virulence determinant of Bacillus anthracis

Characterization of Burkholderia pseudomallei Strains Using a Murine Intraperitoneal Infection Model and In Vitro Macrophage Assays

Distinct Contribution of the HtrA Protease and PDZ Domains to Its Function in Stress Resilience and Virulence of Bacillus anthracis

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