Immunological Mechanisms Underlying the Genetic Predisposition to Severe Staphylococcus aureus Infection in the Mouse Model

Köckritz-Blickwede, Maren von; Rohde, Manfred; Oehmcke, Sonja; Miller, Lloyd S.; Cheung, Ambrose L.; Herwald, Heiko; Foster, Simon J.; Medina, Eva

doi:10.2353/ajpath.2008.080337

Cited by 121 publications

(144 citation statements)

References 64 publications

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“…Furthermore, our data suggest a new mechanism by which IL-1␤ exerts its acute host defense function against S. aureus (23), identifying IL-6 as an important downstream mediator of IL-1 signaling. IL-6, in turn, can activate the killing capacity of neutrophils as critical early effectors against the bacteria (24), a function that may be further augmented by IL-1 (25).…”

Section: Discussionmentioning

confidence: 99%

NOD2 contributes to cutaneous defense againstStaphylococcus aureusthrough α-toxin-dependent innate immune activation

Hrúz¹,

Zinkernagel

Jeníková³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

176

184

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Staphylococcus aureus is a major cause of community-acquired and nosocomial infections including the life-threatening conditions endocarditis, necrotizing pneumonia, necrotizing fasciitis, and septicemia. Toll-like receptor (TLR)-2, a membrane-bound microbial sensor, detects staphylococcal components, but macrophages lacking TLR2 or both TLR2 and TLR4 remain S. aureus responsive, suggesting that an alternative microbial recognition receptor might be involved. The cytoplasmic sensor nucleotide-binding oligomerization domain containing (NOD) 2/caspase recruitment domain (CARD) 15 detects muramyl dipeptide from bacterial peptidoglycans and mediates cytokine responses to S. aureus in vitro, but the physiological significance of these observations is not well defined. Here we show that NOD2-deficient mice exhibit a delayed but ultimately exacerbated ulcerative response and impaired bacterial clearance after s.c. infection with S. aureus. NOD2-dependent recognition of S. aureus and muramyl dipeptide is facilitated by ␣-toxin (␣-hemolysin), a pore-forming toxin and virulence factor of the pathogen. The action of NOD2 is dependent on IL-1␤-amplified production of IL-6, which promotes rapid bacterial killing by neutrophils. These results significantly broaden the physiological importance of NOD2 in innate immunity from the recognition of bacteria that primarily enter the cytoplasm to the detection of bacteria that typically reside extracellularly and demonstrate that this microbial sensor contributes to the discrimination between commensal bacteria and bacterial pathogens that elaborate poreforming toxins.Innate immunity ͉ interleukin-1 ͉ interleukin-6 ͉ microbial pathogenesis

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Section: Discussionmentioning

confidence: 99%

NOD2 contributes to cutaneous defense againstStaphylococcus aureusthrough α-toxin-dependent innate immune activation

Hrúz¹,

Zinkernagel

Jeníková³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

176

184

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“…A/J and C57BL/6 mice 6 to 8 weeks old were purchased from Jackson Laboratories or Taconic Farms. A/J mice were used to establish basic parameters of the infection system as they have enhanced susceptibility to S. aureus infections (14), whereas C57BL/6 mice were used as controls for transgenic strains backcrossed into this genetic background. Germfree C57BL/6 mice were obtained from the Harvard Digestive Diseases Center Germ Free and Gnotobiotic Microbiology Core.…”

Section: Methodsmentioning

confidence: 99%

Microbiota-Driven Immune Cellular Maturation Is Essential for Antibody-Mediated Adaptive Immunity to Staphylococcus aureus Infection in the Eye

Zaidi

Cywes‐Bentley

et al. 2014

Infect Immun

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bAs an immune-privileged site, the eye, and particularly the outer corneal surface, lacks resident mature immune effector cells. Physical barriers and innate mediators are the best-described effectors of immunity in the cornea. When the barriers are breached, infection can result in rapid tissue destruction, leading to loss of visual acuity and frank blindness. To determine the cellular and molecular components needed for effective adaptive immunity on the corneal surface, we investigated which immune system effectors were required for protection against Staphylococcus aureus corneal infections in mice, which are a serious cause of human eye infections. Both systemically injected and topically applied antibodies to the conserved cell surface polysaccharide poly-N-acetylglucosamine (PNAG) were effective at mediating reductions in corneal pathology and bacterial levels. Additional host factors impacting protection included intercellular adhesion molecule 1 (ICAM-1)-dependent polymorphonuclear leukocyte (PMN) recruitment, functional CD4 ؉ T cells, signaling via the interleukin-17 (IL-17) receptor, and IL-22 production. In germfree mice, there was no protective efficacy of antibody to PNAG due to the lack of LY6G ؉ inflammatory cell coeffector recruitment to the cornea. Protection was manifest after 3 weeks of exposure to conventional mice and acquisition of a resident microbiota. We conclude that in the anterior eye, ICAM-1-mediated PMN recruitment to the infected cornea along with endogenous microbiota-matured CD4 ؉ T cells producing both IL-17 and IL-22 is required for antibody to PNAG to protect against S. aureus infection.

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“…8 Several reports have described contact system activation in various animal models of infection with different pathogens. [9][10][11][12][13] Contact activation has been seen in all animal species tested, including baboons and rats 9,11 and also in mice, where the degree of activation varies between mouse strains. 13 Thus, animal models of infection may be useful tools to study contact system inhibition for therapeutic purposes.…”

Section: Introductionmentioning

confidence: 99%

“…9-13 Contact activation has been seen in all animal species tested, including baboons and rats 9,11 and also in mice, where the degree of activation varies between mouse strains. 13 Thus, animal models of infection may be useful tools to study contact system inhibition for therapeutic purposes.The present study investigates whether a peptide (HKH20) derived from a region of HK known to interact with bacterial surfaces could be used to block the activation of the contact system and to treat experimental S pyogenes infections. The results show that HKH20 is a potent inhibitor of the contact system.…”

mentioning

confidence: 99%

Treatment of invasive streptococcal infection with a peptide derived from human high-molecular weight kininogen

Oehmcke

Shannon

Köckritz-Blickwede

et al. 2009

Blood

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Sepsis and septic shock remain an important medical problem, emphasizing the need to identify novel therapeutic opportunities. Hypovolemic hypotension, coagulation dysfunction, disturbed microcirculation, and multiorgan failure resulting from vascular leakage are often observed in these severe conditions. In the present study, we find that HKH20, a peptide derived from human high-molecularweight kininogen (HK), down-regulates inflammatory reactions caused by Streptococcus pyogenes in a mouse model of sepsis. HK is a component of the proinflammatory and procoagulant contact system. Activation of the contact system in the bloodstream by S pyogenes leads to massive tissue damage in the lungs of the infected mice, which eventually results in the death of the animals. HKH20 inhibits activation of the contact system and protects mice with invasive S pyogenes infection from lung damage. In combination with clindamycin treatment, the peptide also significantly prolongs the survival of infected mice. IntroductionSepsis and septic shock are complications of bacterial infections that are, despite treatment with antibiotics and improved intensive care, associated with high mortality rates. Streptococcus pyogenes is a major human pathogen that mainly causes skin and throat infections. These infections are normally superficial and selflimiting, but they occasionally develop into the serious and life-threatening conditions streptococcal toxic shock syndrome and necrotizing fasciitis. 1 The molecular mechanisms behind the pathogenesis of these critical conditions are still not fully understood. However, a growing body of evidence suggests that they are the result of an uncontrolled host inflammatory response induced by the pathogen. A systemic activation of proteolytic host cascades, such as the complement, coagulation, and contact systems, plays an important role, together with a massive release of proinflammatory cytokines. 2 Previous work has shown that S pyogenes is able to assemble and activate the human contact system on its surface. 3 The contact system, also known as the intrinsic pathway of coagulation or the kallikrein-kinin system, is involved in normal hemostasis and inflammation. [4][5][6] It is composed of 4 components: factor XI (FXI), FXII, plasma kallikrein (PK), and high-molecular-weight kininogen (HK). Under physiologic conditions, these factors circulate in their inactive forms in the bloodstream or are bound to the surface of different cell types, such as endothelial cells, platelets, and polymorphonuclear neutrophils (PMNs). On activation, the contact system triggers the intrinsic pathway of coagulation via activation of FXI by FXII and evokes the release of bradykinin (BK) from the HK precursor by the action of PK. BK, a peptide consisting of 9 amino acids, is a potent proinflammatory mediator. Thus, BK has been shown to evoke the generation of nitric oxide and other inflammatory substances (eg, prostaglandins and leukotrienes), reduce blood pressure, and induce fever. Notably, and probably more importan...

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Immunological Mechanisms Underlying the Genetic Predisposition to Severe Staphylococcus aureus Infection in the Mouse Model

Cited by 121 publications

References 64 publications

NOD2 contributes to cutaneous defense againstStaphylococcus aureusthrough α-toxin-dependent innate immune activation

NOD2 contributes to cutaneous defense againstStaphylococcus aureusthrough α-toxin-dependent innate immune activation

Microbiota-Driven Immune Cellular Maturation Is Essential for Antibody-Mediated Adaptive Immunity to Staphylococcus aureus Infection in the Eye

Treatment of invasive streptococcal infection with a peptide derived from human high-molecular weight kininogen

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