scholarly journals Abscess Formation and Alpha-Hemolysin Induced Toxicity in a Mouse Model of Staphylococcus aureus Peritoneal Infection

2012 ◽  
Vol 80 (10) ◽  
pp. 3721-3732 ◽  
Author(s):  
Sabine Rauch ◽  
Andrea C. DeDent ◽  
Hwan Keun Kim ◽  
Juliane Bubeck Wardenburg ◽  
Dominique M. Missiakas ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Mouse Model ◽  
Passive Immunization ◽  
Active Immunization ◽  
Abscess Formation ◽  
Content Type ◽  
Alpha Hemolysin ◽  
Protective Antigens ◽  
Stage Renal Disease ◽  
End Stage

ABSTRACTStaphylococcus aureusis a frequent cause of skin infection and sepsis in humans. Preclinical vaccine studies withS. aureushave used a mouse model with intraperitoneal challenge and survival determination as a measure for efficacy. To appreciate the selection of protective antigens in this model, we sought to characterize the pathological attributes ofS. aureusinfection in the peritoneal cavity. Testing C57BL/6J and BALB/c mice, >109CFU ofS. aureusNewman were needed to produce a lethal outcome in 90% of animals infected via intraperitoneal injection. Both necropsy and histopathology revealed the presence of intraperitoneal abscesses in the vicinity of inoculation sites. Abscesses were comprised of fibrin as well as collagen deposits and immune cells with staphylococci replicating at the center of these lesions. Animals that succumbed to challenge harbored staphylococci in abscess lesions and in blood. The establishment of lethal infections, but not the development of intraperitoneal abscesses, was dependent onS. aureusexpression of alpha-hemolysin (Hla). Active immunization with nontoxigenic HlaH35Lor passive immunization with neutralizing monoclonal antibodies protected mice against early lethal events associated with intraperitonealS. aureusinfection but did not affect the establishment of abscess lesions. These results characterize a mouse model for the study of intraperitoneal abscess formation byS. aureus, a disease that occurs frequently in humans undergoing continuous ambulatory peritoneal dialysis for end-stage renal disease.

scholarly journals Improved Protection in a Rabbit Model of Community-Associated Methicillin-Resistant Staphylococcus aureus Necrotizing Pneumonia upon Neutralization of Leukocidins in Addition to Alpha-Hemolysin

2016 ◽  
Vol 60 (10) ◽  
pp. 6333-6340 ◽  
Author(s):  
Binh An Diep ◽  
Vien T. M. Le ◽  
Zehra C. Visram ◽  
Harald Rouha ◽  
Lukas Stulik ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Human Monoclonal Antibody ◽  
Rabbit Model ◽  
Passive Immunization ◽  
Severe Pneumonia ◽  
Phagocytic Cells ◽  
Methicillin Resistant ◽  
Content Type ◽  
Alpha Hemolysin ◽  
Full Protection

ABSTRACTCommunity-associated methicillin-resistantStaphylococcus aureus(CA-MRSA), especially the USA300 pulsotype, is a frequent cause of skin and soft tissue infections and severe pneumonia. Despite appropriate antibiotic treatment, complications are common and pneumonia is associated with high mortality.S. aureusstrains express multiple cytotoxins, including alpha-hemolysin (Hla) and up to five bicomponent leukocidins that specifically target phagocytic cells for lysis. CA-MRSA USA300 strains carry the genes for all six cytotoxins. Species specificity of the leukocidins greatly contributes to the ambiguity regarding their role inS. aureuspathogenesis. We performed a comparative analysis of the leukocidin susceptibility of human, rabbit, and mouse polymorphonuclear leukocytes (PMNs) to assess the translational value of mouse and rabbitS. aureusmodels. We found that mouse PMNs were largely resistant to LukSF-PV, HlgAB, and HlgCB and susceptible only to LukED, whereas rabbit and human PMNs were highly sensitive to all these cytotoxins. In the rabbit pneumonia model with a USA300 CA-MRSA strain, passive immunization with a previously identified human monoclonal antibody (MAb), Hla-F#5, which cross-neutralizes Hla, LukSF-PV, HlgAB, HlgCB, and LukED, provided full protection, whereas an Hla-specific MAb was only partially protective. In the mouse USA300 CA-MRSA pneumonia model, both types of antibodies demonstrated full protection, suggesting that Hla, but not leukocidin(s), is the principal virulence determinant in mice. As the rabbit recapitulates the high susceptibility to leukocidins characteristic of humans, this species represents a valuable model for assessing novel, cytotoxin-targeting anti-S. aureustherapeutic approaches.

scholarly journals Role of Antibodies in Protection Elicited by Active Vaccination with Genetically Inactivated Alpha Hemolysin in a Mouse Model of Staphylococcus aureus Skin and Soft Tissue Infections

2014 ◽  
Vol 21 (5) ◽  
pp. 622-627 ◽  
Author(s):  
Christopher P. Mocca ◽  
Rebecca A. Brady ◽  
Drusilla L. Burns
Keyword(s):  
Staphylococcus Aureus ◽  
Soft Tissue ◽  
Murine Model ◽  
Bacterial Colonization ◽  
Passive Immunization ◽  
The United States ◽  
Soft Tissue Infections ◽  
Content Type ◽  
Alpha Hemolysin ◽  
Active Vaccination

ABSTRACTDue to the emergence of highly virulent community-associated methicillin-resistantStaphylococcus aureus(CA-MRSA) infections,S. aureushas become a major threat to public health. A majority of CA-MRSA skin and soft tissue infections in the United States are caused byS. aureusUSA300 strains that are known to produce high levels of alpha hemolysin (Hla). Therefore, vaccines that contain inactivated forms of this toxin are currently being developed. In this study, we sought to determine the immune mechanisms of protection for this antigen using a vaccine composed of a genetically inactivated form of Hla (HlaH35L). Using a murine model of skin and soft tissue infections (SSTI), we found that BALB/c mice were protected by vaccination with HlaH35L; however, Jh mice, which are deficient in mature B lymphocytes and lack IgM and IgG in their serum, were not protected. Passive immunization with anti-HlaH35L antibodies conferred protection against bacterial colonization. Moreover, we found a positive correlation between the total antibody concentration induced by active vaccination and reduced bacterial levels. Animals that developed detectable neutralizing antibody titers after active vaccination were significantly protected from infection. These data demonstrate that antibodies to Hla represent the major mechanism of protection afforded by active vaccination with inactivated Hla in this murine model of SSTI, and in this disease model, antibody levels correlate with protection. These results provide important information for the future development and evaluation ofS. aureusvaccines.

scholarly journals Phase IIa Study of the Immunogenicity and Safety of the Novel Staphylococcus aureus Vaccine V710 in Adults with End-Stage Renal Disease Receiving Hemodialysis

2012 ◽  
Vol 19 (9) ◽  
pp. 1509-1516 ◽  
Author(s):  
Moustafa Moustafa ◽  
George R. Aronoff ◽  
Chandra Chandran ◽  
Jonathan S. Hartzel ◽  
Steven S. Smugar ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Renal Disease ◽  
End Stage Renal Disease ◽  
Geometric Mean ◽  
Surface Protein ◽  
Chronic Hemodialysis ◽  
Content Type ◽  
Primary Hypothesis ◽  
Stage Renal Disease ◽  
End Stage

ABSTRACTBacteremia is the second leading cause of death in patients with end-stage renal disease who are on hemodialysis. A vaccine eliciting long-term immune responses againstStaphylococcus aureusin patients on chronic hemodialysis may reduce the incidence of bacteremia and its complications in these patients. V710 is a vaccine containing iron surface determinant B (IsdB), a highly conservedS. aureussurface protein, which has been shown to be immunogenic in healthy subjects. In this blinded phase II immunogenicity study, 206 chronic hemodialysis patients between the ages of 18 and 80 years old were randomized to receive 60 μg V710 (with or without adjuvant), 90 μg V710 (with adjuvant), or a placebo in various combinations on days 1, 28, and 180. All 201 vaccinated patients were to be followed through day 360. The primary hypothesis was that at least 1 of the 3 groups receiving 2 V710 doses on days 1 and 28 would have a ≥2.5 geometric mean fold rise (GMFR) in anti-IsdB IgG titers over the baseline 28 days after the second vaccination (day 56). At day 56, all three groups receiving 2 doses of V710 achieved a ≥2.5 GMFR in anti-IsdB antibodies compared to the baseline (Pvalues of <0.001 for all 3 groups), satisfying the primary immunogenicity hypothesis. None of the 33 reported serious adverse experiences were considered vaccine related by the investigators. V710 induced sustained antibody responses for at least 1 year postvaccination in patients on chronic hemodialysis.

scholarly journals Protective Efficacy of Monoclonal Antibodies Neutralizing Alpha-Hemolysin and Bicomponent Leukocidins in a Rabbit Model of Staphylococcus aureus Necrotizing Pneumonia

2019 ◽  
Vol 64 (3) ◽  
Author(s):  
Trang T. T. Vu ◽  
Nhu T. Q. Nguyen ◽  
Vuvi G. Tran ◽  
Emmanuelle Gras ◽  
Yanjie Mao ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Protective Efficacy ◽  
Rabbit Model ◽  
Passive Immunization ◽  
Necrotizing Pneumonia ◽  
Partial Protection ◽  
Content Type ◽  
Alpha Hemolysin ◽  
Wide Range ◽  
Panton Valentine Leukocidin

ABSTRACT Staphylococcus aureus is a major human pathogen that causes a wide range of infections by producing an arsenal of cytotoxins. We found that passive immunization with either a monoclonal antibody (MAb) neutralizing alpha-hemolysin or a broadly cross-reactive MAb neutralizing Panton-Valentine leukocidin, leukocidin ED, and gamma-hemolysins HlgAB and HlgCB conferred only partial protection, whereas the combination of those two MAbs conferred significant protection in a rabbit model of necrotizing pneumonia caused by the USA300 methicillin-resistant S. aureus epidemic clone.

scholarly journals Targeting Surface Protein SasX by Active and Passive Vaccination To Reduce Staphylococcus aureus Colonization and Infection

2015 ◽  
Vol 83 (5) ◽  
pp. 2168-2174 ◽  
Author(s):  
Qian Liu ◽  
Xin Du ◽  
Xufen Hong ◽  
Tianming Li ◽  
Bing Zheng ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Passive Immunization ◽  
Surface Protein ◽  
Lung Infection ◽  
Active Immunization ◽  
Human Neutrophils ◽  
Infection Model ◽  
Nasal Colonization ◽  
Content Type ◽  
Infection Models

SasX is a recently described surface protein ofStaphylococcus aureusthat is linked to the epidemic success of hospital-associated methicillin-resistant clones, in particular in Asia. It enhances nasal colonization and virulence in skin and lung infection models. Here, we evaluated the potential of SasX as a vaccine component in passive and active immunization efforts using mouse infection models. We found that SasX induced a specific immune response predominantly based on IgG1 antibodies. Active immunization with recombinant SasX or passive immunization with rabbit polyclonal anti-SasX IgG significantly decreased the size of lesions caused byS. aureusin a skin infection model. Furthermore, active immunization reduced acute lung injury in a lung infection model. Moreover, active or passive immunization significantly reducedS. aureuscolonization in a nasal colonization model. Finally, anti-SasX IgG enhanced the susceptibility ofS. aureusto killing by human neutrophils. We conclude that SasX is a potential target for therapeutics or vaccines designed to moderate colonization and infection bysasX-positive epidemic strains ofS. aureus.

Diabetic kidney disease in thedb/dbmouse

2003 ◽  
Vol 284 (6) ◽  
pp. F1138-F1144 ◽  
Author(s):  
Kumar Sharma ◽  
Peter McCue ◽  
Stephen R. Dunn
Keyword(s):  
Diabetic Nephropathy ◽  
Kidney Disease ◽  
Mouse Model ◽  
Renal Disease ◽  
Mouse Models ◽  
Diabetic Kidney Disease ◽  
Diabetic Kidney ◽  
Matrix Expansion ◽  
Stage Renal Disease ◽  
End Stage

Diabetic nephropathy is increasing in incidence and is now the number one cause of end-stage renal disease in the industrialized world. To gain insight into the genetic susceptibility and pathophysiology of diabetic nephropathy, an appropriate mouse model of diabetic nephropathy would be critical. A large number of mouse models of diabetes have been identified and their kidney disease characterized to various degrees. Perhaps the best characterized and most intensively investigated model is the db/ db mouse. Because this model appears to exhibit the most consistent and robust increase in albuminuria and mesangial matrix expansion, it has been used as a model of progressive diabetic renal disease. In this review, we present the findings from various studies on the renal pathology of the db/ db mouse model of diabetes in the context of human diabetic nephropathy. Furthermore, we discuss shortfalls of assessing functional renal disease in mouse models of diabetic kidney disease.

scholarly journals NSC828779 Alleviates Renal Tubulointerstitial Lesions Involving Interleukin-36 Signaling in Mice

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3060
Author(s):  
Shin-Ruen Yang ◽  
Szu-Chun Hung ◽  
Lichieh Julie Chu ◽  
Kuo-Feng Hua ◽  
Chyou-Wei Wei ◽  
...  
Keyword(s):  
Mouse Model ◽  
Nlrp3 Inflammasome ◽  
Renal Tissue ◽  
Drug Candidate ◽  
Therapeutic Effects ◽  
Tubulointerstitial Lesions ◽  
Cytokine Levels ◽  
Renal Tubular ◽  
Stage Renal Disease ◽  
End Stage

Renal tubulointerstitial lesions (TILs), a common pathologic hallmark of chronic kidney disease that evolves to end-stage renal disease, is characterized by progressive inflammation and pronounced fibrosis of the kidney. However, current therapeutic approaches to treat these lesions remain largely ineffectual. Previously, we demonstrated that elevated IL-36α levels in human renal tissue and urine are implicated in impaired renal function, and IL-36 signaling enhances activation of NLRP3 inflammasome in a mouse model of TILs. Recently, we synthesized NSC828779, a salicylanilide derivative (protected by U.S. patents with US 8975255 B2 and US 9162993 B2), which inhibits activation of NF-κB signaling with high immunomodulatory potency and low IC50, and we hypothesized that it would be a potential drug candidate for renal TILs. The current study validated the therapeutic effects of NSC828779 on TILs using a mouse model of unilateral ureteral obstruction (UUO) and relevant cell models, including renal tubular epithelial cells under mechanically induced constant pressure. Treatment with NSC828779 improved renal lesions, as demonstrated by dramatically reduced severity of renal inflammation and fibrosis and decreased urinary cytokine levels in UUO mice. This small molecule specifically inhibits the IL-36α/NLRP3 inflammasome pathway. Based on these results, the beneficial outcome represents synergistic suppression of both the IL-36α-activated MAPK/NLRP3 inflammasome and STAT3- and Smad2/3-dependent fibrogenic signaling. NSC828779 appears justified as a new drug candidate to treat renal progressive inflammation and fibrosis.

scholarly journals Clearance of Staphylococcus aureus from In Vivo Models of Chronic Infection by Immunization Requires Both Planktonic and Biofilm Antigens

2019 ◽  
Vol 88 (1) ◽  
Author(s):  
Janette M. Harro ◽  
Yvonne Achermann ◽  
Jeffrey A. Freiberg ◽  
Devon L. Allison ◽  
Kristen J. Brao ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Protective Efficacy ◽  
Passive Immunization ◽  
Quadrivalent Vaccine ◽  
Bacterial Populations ◽  
In Vivo Models ◽  
Content Type ◽  
Pentavalent Vaccine ◽  
And Control

ABSTRACT Staphylococcus aureus is a causative agent of chronic biofilm-associated infections that are recalcitrant to resolution by the immune system or antibiotics. To combat these infections, an antistaphylococcal, biofilm-specific quadrivalent vaccine against an osteomyelitis model in rabbits has previously been developed and shown to be effective at eliminating biofilm-embedded bacterial populations. However, the addition of antibiotics was required to eradicate remaining planktonic populations. In this study, a planktonic upregulated antigen was combined with the quadrivalent vaccine to remove the need for antibiotic therapy. Immunization with this pentavalent vaccine followed by intraperitoneal challenge of BALB/c mice with S. aureus resulted in 16.7% and 91.7% mortality in pentavalent vaccine and control groups, respectively (P < 0.001). Complete bacterial elimination was found in 66.7% of the pentavalent cohort, while only 8.3% of the control animals cleared the infection (P < 0.05). Further protective efficacy was observed in immunized rabbits following intramedullary challenge with S. aureus, where 62.5% of the pentavalent cohort completely cleared the infection, versus none of the control animals (P < 0.05). Passive immunization of BALB/c mice with serum IgG against the vaccine antigens prior to intraperitoneal challenge with S. aureus prevented mortality in 100% of mice and eliminated bacteria in 33.3% of the challenged mice. These results demonstrate that targeting both the planktonic and biofilm stages with the pentavalent vaccine or the IgG elicited by immunization can effectively protect against S. aureus infection.

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