RTX Toxin Plays a Key Role in Kingella kingae Virulence in an Infant Rat Model

Chang, Dennis W.; Nudell, Yoav A.; Lau, Jenny; Zakharian, Eleonora; Balashova, Nataliya V.

doi:10.1128/iai.01636-14

Cited by 36 publications

(45 citation statements)

References 60 publications

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“…Animals inoculated with the wild PYKK081 strain developed a rapidly fatal illness characterized by weight loss, bacteremia, abdominal wall necrotic lesions, and damage to the pups' thymuses, spleens, liver, lungs, and bone marrow, whereas inoculation of the animals with the KKNB100 mutant did not result in clinical disease or demonstrable bacteremia, corroborating the importance of the RTX toxin as a virulence factor and its role in the pathogenesis of disease (79). Remarkably, intraperitoneal or intra-articular inoculation of 21-day-old rats with the wild-type strain did not result in observable disease, bacteremia, or septic arthritis, indicating that the age-dependent susceptibility to invasive infections observed in humans can be closely reproduced in the animal model (79).…”

Section: Rtx Toxinmentioning

confidence: 73%

“…The potential role of K. kingae RTX toxin has been further investigated using an animal model of infection in a recent study (79). Intraperitoneal inoculation of 7-day-old Sprague-Dawley rats with 8 ϫ 10 6 CFU of a virulent K. kingae strain isolated from a child with septic arthritis (strain PYKK081) resulted in a marked reduction in the circulating white blood cells (WBCs) compared with the leukocyte count in animals injected with a toxin-deficient mutant of the same wild-type strain (designated KKNB100), suggesting that the depressed acute immune response induced by the RTX toxin may represent a strategy aimed to guarantee K. kingae's subsistence in the host's bloodstream, skeletal tissues, and endocardium (79).…”

Section: Rtx Toxinmentioning

confidence: 99%

“…Intraperitoneal inoculation of 7-day-old Sprague-Dawley rats with 8 ϫ 10 6 CFU of a virulent K. kingae strain isolated from a child with septic arthritis (strain PYKK081) resulted in a marked reduction in the circulating white blood cells (WBCs) compared with the leukocyte count in animals injected with a toxin-deficient mutant of the same wild-type strain (designated KKNB100), suggesting that the depressed acute immune response induced by the RTX toxin may represent a strategy aimed to guarantee K. kingae's subsistence in the host's bloodstream, skeletal tissues, and endocardium (79). Animals inoculated with the wild PYKK081 strain developed a rapidly fatal illness characterized by weight loss, bacteremia, abdominal wall necrotic lesions, and damage to the pups' thymuses, spleens, liver, lungs, and bone marrow, whereas inoculation of the animals with the KKNB100 mutant did not result in clinical disease or demonstrable bacteremia, corroborating the importance of the RTX toxin as a virulence factor and its role in the pathogenesis of disease (79). Remarkably, intraperitoneal or intra-articular inoculation of 21-day-old rats with the wild-type strain did not result in observable disease, bacteremia, or septic arthritis, indicating that the age-dependent susceptibility to invasive infections observed in humans can be closely reproduced in the animal model (79).…”

Section: Rtx Toxinmentioning

confidence: 99%

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Kingella kingae: Carriage, Transmission, and Disease

2015

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SUMMARY Kingella kingae is a common etiology of pediatric bacteremia and the leading agent of osteomyelitis and septic arthritis in children aged 6 to 36 months. This Gram-negative bacterium is carried asymptomatically in the oropharynx and disseminates by close interpersonal contact. The colonized epithelium is the source of bloodstream invasion and dissemination to distant sites, and certain clones show significant association with bacteremia, osteoarthritis, or endocarditis. Kingella kingae produces an RTX (repeat-in-toxin) toxin with broad-spectrum cytotoxicity that probably facilitates mucosal colonization and persistence of the organism in the bloodstream and deep body tissues. With the exception of patients with endocardial involvement, children with K. kingae diseases often show only mild symptoms and signs, necessitating clinical acumen. The isolation of K. kingae on routine solid media is suboptimal, and detection of the bacterium is significantly improved by inoculating exudates into blood culture bottles and the use of PCR-based assays. The organism is generally susceptible to antibiotics that are administered to young patients with joint and bone infections. β-Lactamase production is clonal, and the local prevalence of β-lactamase-producing strains is variable. If adequately and promptly treated, invasive K. kingae infections with no endocardial involvement usually run a benign clinical course.

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Section: Rtx Toxinmentioning

confidence: 73%

Section: Rtx Toxinmentioning

confidence: 99%

Section: Rtx Toxinmentioning

confidence: 99%

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Kingella kingae: Carriage, Transmission, and Disease

2015

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“…A recent study found that RtxA plays a key role in K. kingae virulence in an infant rat model (11) and is suggested to improve the organism's chances of surviving in the host and invading skeletal tissues (10). ModK-mediated switching of the RtxA toxin may enable evasion of host immune stimulation or promote invasion and inflammation at certain sites.…”

Section: Discussionmentioning

confidence: 99%

“…The major virulence factor is RtxA, a toxin that has been shown to play a key role in virulence in an animal model of infection and allows the bacteria to breach the respiratory tract and joints (10,11). The second is capsule that is speculated, based on the role of other encapsulated bacteria, to protect the bacterium from the host immune response and to enable mucosal colonization, survival of the organism in the bloodstream, and invasion of deep body sites (12)(13)(14)(15).…”

mentioning

confidence: 99%

Phasevarion-Regulated Virulence in the Emerging Pediatric Pathogen Kingella kingae

et al. 2017

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Kingella kingae is a common etiological agent of pediatric osteoarticular infections. While current research has expanded our understanding of K. kingae pathogenesis, there is a paucity of knowledge about host-pathogen interactions and virulence gene regulation. Many host-adapted bacterial pathogens contain phase variable DNA methyltransferases (mod genes), which can control expression of a regulon of genes (phasevarion) through differential methylation of the genome. Here, we identify a phase variable type III mod gene in K. kingae, suggesting that phasevarions operate in this pathogen. Phylogenetic studies revealed that there are two active modK alleles in K. kingae. Proteomic analysis of secreted and surfaceassociated proteins, quantitative PCR, and a heat shock assay comparing the wildtype modK1 ON (i.e., in frame for expression) strain to a modK1 OFF (i.e., out of frame) strain revealed three virulence-associated genes under ModK1 control. These include the K. kingae toxin rtxA and the heat shock genes groEL and dnaK. Cytokine expression analysis showed that the interleukin-8 (IL-8), IL-1␤, and tumor necrosis factor responses of THP-1 macrophages were lower in the modK1 ON strain than in the modK1::kan mutant. This suggests that the ModK1 phasevarion influences the host inflammatory response and provides the first evidence of this phase variable epigenetic mechanism of gene regulation in K. kingae.KEYWORDS Kingella kingae, gene regulation, phase variation, type III restrictionmodification systems, phasevarion K ingella kingae is a Gram-negative bacterial pathogen belonging to the Neisseriaceae family. While often carried asymptomatically in the respiratory tract, K. kingae is associated with invasive infections, including bacteremia, osteoarticular infections, meningitis, lower respiratory tract infections, and keratitis. Diagnostic advances have resulted in its recognition as a leading cause of osteoarticular infections in young children (1-3). Importantly, it is a member of the HACEK group, associated with infective endocarditis. However, unlike other HACEK organisms, K. kingae-mediated infective endocarditis can progress very rapidly (4-6) and is associated with serious complications, with an overall mortality rate of 16% (1, 6). Adults with invasive infections usually have predisposing medical ailments.Transmission occurs via close personal contact, and clusters of invasive infections have been reported among day care center attendees (7,8). Invasive disease begins with colonization of the oropharynx and is often preceded by an upper respiratory tract infection (8, 9). The disrupted respiratory mucosa may then facilitate invasion and hematogenous dissemination to the bones, joints, and heart (10).

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Bacterial toxins in musculoskeletal infections

Saeed

Sendi

Arnold

et al. 2020

Journal Orthopaedic Research

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Musculoskeletal infections (MSKIs) remain a major health burden in orthopaedics. Bacterial toxins are foundational to pathogenesis in MSKI, but poorly understood by the community of providers that care for patients with MSKI, inducing an international group of microbiologists, infectious diseases specialists, orthopaedic surgeons and biofilm scientists to review the literature in this field to identify key topics and compile the current knowledge on the role of toxins in MSKI, with the goal of illuminating potential impact on biofilm formation and dispersal as well as therapeutic strategies. The group concluded that further research is needed to maximize our understanding of the effect of toxins on MSKIs, including: further research to identify the roles of bacterial toxins in MSKIs, establish the understanding of the importance of environmental and host factors and in vivo expression of toxins throughout the course of an infection, establish the principles of drug‐ability of antitoxins as antimicrobial agents in MSKIs, have well‐defined metrics of success for antitoxins as antiinfective drugs, design a cocktail of antitoxins against specific pathogens to (a) inhibit biofilm formation and (b) inhibit toxin release. The applicability of antitoxins as potential antimicrobials in the era of rising antibiotic resistance could meet the needs of day‐to‐day clinicians.

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RTX Toxin Plays a Key Role in Kingella kingae Virulence in an Infant Rat Model

Cited by 36 publications

References 60 publications

Kingella kingae: Carriage, Transmission, and Disease

Kingella kingae: Carriage, Transmission, and Disease

Phasevarion-Regulated Virulence in the Emerging Pediatric Pathogen Kingella kingae

Bacterial toxins in musculoskeletal infections

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