scholarly journals A Protein A based Staphylococcus aureus vaccine with improved safety

2021 ◽  
Author(s):  
Miaomiao Shi ◽  
Xinhai Chen ◽  
Yan Sun ◽  
Hwan Keun Kim ◽  
Olaf Schneewind ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
B Cells ◽  
Immune Escape ◽  
Protective Efficacy ◽  
Protein A ◽  
Staphylococcal Protein A ◽  
Cell Responses ◽  
Binding Domains ◽  
Ige Receptors ◽  
Immunoglobulin Binding

Exposure to Staphylococcus aureus does not lead to immunity as evidenced by the persistent colonization of one third of the human population. S. aureus immune escape is mediated by factors that preempt complement activation, destroy phagocytes, and modify B and T cell responses. One such factor, Staphylococcal protein A (SpA) encompasses five Immunoglobulin binding domains (IgBDs) that associate with the Fcγ domain to block phagocytosis. IgBDs also associate with the Fab domain of VH3-idiotypic IgM which activates B cells with the resulting secretion of antibodies that cannot bind determinants of S. aureus. SpA crosslinking of VH3-idiotypic IgG and IgE receptors of mast cells and basophils promotes histamine release and anaphylaxis. Previous work demonstrated the safety, immunogenicity, and protective efficacy of SpAKKAA, a variant partially defective for VH3-idiotypic Ig cross-linking, in murine models of S. aureus. Compared to mice (10%), humans produce significantly more VH3-idiotypic B cells (50%), prompting a search for safer SpA variants that may be suitably developed as clinical-grade vaccines for efficacy testing in humans. Here, we report the identification of such variants.

scholarly journals Protein A-Specific Monoclonal Antibodies and Prevention of Staphylococcus aureus Disease in Mice

2012 ◽  
Vol 80 (10) ◽  
pp. 3460-3470 ◽  
Author(s):  
Hwan Keun Kim ◽  
Carla Emolo ◽  
Andrea C. DeDent ◽  
Fabiana Falugi ◽  
Dominique M. Missiakas ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Monoclonal Antibodies ◽  
Immune Responses ◽  
B Cell ◽  
Protein A ◽  
Abscess Formation ◽  
Staphylococcal Protein A ◽  
Content Type ◽  
Humoral Immune ◽  
Binding Domains

ABSTRACTStaphylococcus aureusis a leading cause of human soft tissue infections and bacterial sepsis. The emergence of antibiotic-resistant strains (methicillin-resistantS. aureus[MRSA]) has prompted research into staphylococcal vaccines and preventive measures. The envelope ofS. aureusis decorated with staphylococcal protein A (SpA), which captures the Fcγ portion of immunoglobulins to prevent opsonophagocytosis and associates with the Fab portion of VH3-type B cell receptors to trigger B cell superantigen activity. Nontoxigenic protein A (SpAKKAA), when used as an immunogen in mice, stimulates humoral immune responses that neutralize the Fcγ and the VH3+Fab binding activities of SpA and provide protection from staphylococcal abscess formation in mice. Here, we isolated monoclonal antibodies (MAbs) against SpAKKAAthat, by binding to the triple-helical bundle fold of its immunoglobulin binding domains (IgBDs), neutralize the Fcγ and Fab binding activities of SpA. SpAKKAAMAbs promoted opsonophagocytic killing of MRSA in mouse and human blood, provided protection from abscess formation, and stimulated pathogen-specific immune responses in a mouse model of staphylococcal disease. Thus, SpAKKAAMAbs may be useful for the prevention and therapy of staphylococcal disease in humans.

scholarly journals Nontoxigenic protein A vaccine for methicillin-resistant Staphylococcus aureus infections in mice

2010 ◽  
Vol 207 (9) ◽  
pp. 1863-1870 ◽  
Author(s):  
Hwan Keun Kim ◽  
Alice G. Cheng ◽  
Hye-Young Kim ◽  
Dominique M. Missiakas ◽  
Olaf Schneewind
Keyword(s):  
Staphylococcus Aureus ◽  
B Cell ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Protein A ◽  
Staphylococcal Protein A ◽  
Methicillin Resistant ◽  
Adaptive Immune ◽  
Binding Domains ◽  
Mrsa Strains ◽  
Prior Infection

The current epidemic of hospital- and community-acquired methicillin-resistant Staphylococcus aureus (MRSA) infections has caused significant human morbidity, but a protective vaccine is not yet available. Prior infection with S. aureus is not associated with protective immunity. This phenomenon involves staphylococcal protein A (SpA), an S. aureus surface molecule that binds to Fcγ of immunoglobulin (Ig) and to the Fab portion of VH3-type B cell receptors, thereby interfering with opsonophagocytic clearance of the pathogen and ablating adaptive immune responses. We show that mutation of each of the five Ig-binding domains of SpA with amino acid substitutions abolished the ability of the resulting variant SpAKKAA to bind Fcγ or Fab VH3 and promote B cell apoptosis. Immunization of mice with SpAKKAA raised antibodies that blocked the virulence of staphylococci, promoted opsonophagocytic clearance, and protected mice against challenge with highly virulent MRSA strains. Furthermore, SpAKKAA immunization enabled MRSA-challenged mice to mount antibody responses to many different staphylococcal antigens.

scholarly journals Role of Protein A in the Evasion of Host Adaptive Immune Responses by Staphylococcus aureus

mBio ◽  
2013 ◽  
Vol 4 (5) ◽  
Author(s):  
Fabiana Falugi ◽  
Hwan Keun Kim ◽  
Dominique M. Missiakas ◽  
Olaf Schneewind
Keyword(s):  
Staphylococcus Aureus ◽  
B Cells ◽  
B Cell ◽  
Cell Function ◽  
Protein A ◽  
Immune Surveillance ◽  
Staphylococcal Protein A ◽  
Wild Type ◽  
Content Type ◽  
Host Immune Surveillance

ABSTRACTHeritable defects in human B cell/antibody development are not associated with increased susceptibility toStaphylococcus aureusinfection. Protein A (SpA), a surface molecule ofS. aureus, binds the Fcγ domain of immunoglobulin (Ig) and cross-links the Fab domain of VH3-type B cell receptors (IgM). Here we generatedS. aureus spavariants harboring amino acid substitutions at four key residues in each of the five Ig-binding domains of SpA. Wild-typeS. aureusrequired SpA binding to Ig to resist phagocytosis and SpA-mediated B cell receptor cross-linking to block antibody development in mice. ThespaKKAAmutant, which cannot bind Ig or IgM, was phagocytosed and elicited B cell responses to key virulence antigens that protected animals against lethalS. aureuschallenge. The immune evasive attributes ofS. aureusSpA were abolished in µMT mice lacking mature B cells and antibodies. Thus, while wild-typeS. aureusescapes host immune surveillance, thespaKKAAvariant elicits adaptive responses that protect against recurrent infection.IMPORTANCEStaphylococcus aureuscauses recurrent skin and bloodstream infections without eliciting immunity. Heritable defects in neutrophil and T cell function, but not B cell or antibody development, are associated with increased incidence ofS. aureusinfection, and efforts to develop antibody-basedS. aureusvaccines have thus far been unsuccessful. We show here that the Fcγ and VH3-type Fab binding activities of staphylococcal protein A (SpA) are essential forS. aureusescape from host immune surveillance in mice. The virulence attributes of SpA in mice required mature B cells and immunoglobulin. These results suggest that antibodies and B cells play a key role in the pathogenesis of staphylococcal infections and provide insights into the development of a vaccine againstS. aureus.

scholarly journals Immunoglobulin-binding domains: Protein L from Peptostreptococcus magnus

2003 ◽  
Vol 31 (3) ◽  
pp. 716-718 ◽  
Author(s):  
N.G. Housden ◽  
S. Harrison ◽  
S.E. Roberts ◽  
J.A. Beckingham ◽  
M. Graille ◽  
...  
Keyword(s):  
Binding Sites ◽  
Protein A ◽  
Cell Wall Protein ◽  
Protein G ◽  
Protein L ◽  
Heavy Chains ◽  
Binding Domains ◽  
Peptostreptococcus Magnus ◽  
Immunoglobulin Binding

Protein L is a multidomain cell-wall protein isolated from Peptostreptococcus magnus. It belongs to a group of proteins that contain repeated domains that are able to bind to Igs without stimulating an immune response, the most characterized of this group being Protein A (Staphylococcus aureus) and Protein G (Streptococcus). Both of these proteins bind predominantly to the interface of CH2-CH3 heavy chains, while Protein L binds exclusively to the VL domain of the κ-chain. The function of these proteins in vivo is not clear but it is thought that they enable the bacteria to evade the host's immune system. Two binding sites for κ-chain on a single Ig-binding domain from Protein L have recently been reported and we give evidence that one site has a 25–55-fold higher affinity for κ-chain than the second site.

Multilocus Sequence Typing and Staphylococcal Protein A Typing Revealed Novel and Diverse Clones of Methicillin-Resistant Staphylococcus aureus in Seafood and the Aquatic Environment

2017 ◽  
Vol 80 (3) ◽  
pp. 476-481 ◽  
Author(s):  
V. Murugadas ◽  
C. Joseph Toms ◽  
Sara A. Reethu ◽  
K. V. Lalitha
Keyword(s):  
Staphylococcus Aureus ◽  
Aquatic Environment ◽  
Multilocus Sequence Typing ◽  
Methicillin Resistant Staphylococcus Aureus ◽  
Protein A ◽  
Staphylococcal Protein A ◽  
Spa Typing ◽  
Methicillin Resistant ◽  
Staphylococcal Protein ◽  
Mrsa Strains

ABSTRACT Methicillin-resistant Staphylococcus aureus (MRSA) has been a global health concern since the 1960s, and isolation of this pathogen from food-producing animals has been increasing. However, little information is available on the prevalence of MRSA and its clonal characteristics in seafood and the aquatic environment. In this study, 267 seafood and aquatic environment samples were collected from three districts of Kerala, India. Staphylococcal protein A (spa) typing and multilocus sequence typing (MLST) was performed for 65 MRSA strains isolated from 20 seafood and aquatic environment samples. The MRSA clonal profiles were t657-ST772, t002-ST5, t334-ST5, t311-ST5, t121-ST8, t186-ST88, t127-ST1, and two non-spa assignable strains. Whole spa gene sequence analysis along with MLST confirmed one strain as t711-ST6 and another as a novel MRSA clone identified for the first time in seafood and the aquatic environment with a t15669 spa type and a new MLST profile of ST420-256-236-66-82-411-477. The MRSA strains were clustered into five clonal complexes based on the goeBURST algorithm, indicating high diversity among MRSA strains in seafood and the aquatic environment. The novel clone formed a separate clonal complex with matches to three loci. This study recommends large-scale spa typing and MLST of MRSA isolates from seafood and the aquatic environment to determine the prevalence of new MRSA clones. This monitoring process can be useful for tracing local spread of MRSA isolates into the seafood production chain in a defined geographical area.

scholarly journals The Synergistic Effect of Nicotine and Staphylococcus aureus on Peri-Implant Infections

2021 ◽  
Vol 9 ◽  
Author(s):  
Yao Hu ◽  
Wen Zhou ◽  
Chengguang Zhu ◽  
Yujie Zhou ◽  
Qiang Guo ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Synergistic Effects ◽  
Protein A ◽  
Treated Group ◽  
Combination Group ◽  
Staphylococcal Protein A ◽  
Receptor Activator ◽  
And Staphylococcus Aureus

Smoking is considered a key risk factor for implant survival; however, how it interacts with the pathogens in peri-implant infections is not clear. Here, we identified that nicotine, the key component of cigarette smoking, can interact with Staphylococcus aureus and synergistically induce peri-implant infections in a rat osteolysis model. The nicotine–S. aureus combination group increased the gross bone pathology, osteolysis, periosteal reactions, and bone resorption compared to the nicotine or S. aureus single treated group (p < 0.05). Nicotine did not promote the proliferation of S. aureus both in vitro and in vivo, but it can significantly upregulate the expression of staphylococcal protein A (SpA), a key virulence factor of S. aureus. The nicotine–S. aureus combination also synergistically activated the expression of RANKL (receptor activator of nuclear factor-kappa B ligand, p < 0.05) to promote the development of peri-implant infections. The synergistic effects between nicotine and S. aureus infection can be a new target to reduce the peri-implant infections.

scholarly journals Diversity of Functionally Distinct Clonal Sets of Human Conventional Memory B Cells That Bind Staphylococcal Protein A

2021 ◽  
Vol 12 ◽  
Author(s):  
Emily E. Radke ◽  
Zhi Li ◽  
David N. Hernandez ◽  
Hanane El Bannoudi ◽  
Sergei L. Kosakovsky Pond ◽  
...  
Keyword(s):  
Immune System ◽  
B Cells ◽  
B Cell ◽  
Binding Site ◽  
Protein A ◽  
Memory B Cells ◽  
Host Immune System ◽  
Staphylococcal Protein A ◽  
Staphylococcal Protein ◽  
Circulating Antibodies

Staphylococcus aureus, a common cause of serious and often fatal infections, is well-armed with secreted factors that disarm host immune defenses. Highly expressed in vivo during infection, Staphylococcal protein A (SpA) is reported to also contribute to nasal colonization that can be a prelude to invasive infection. Co-evolution with the host immune system has provided SpA with an Fc-antibody binding site, and a Fab-binding site responsible for non-immune superantigen interactions via germline-encoded surfaces expressed on many human BCRs. We wondered whether the recurrent exposures to S. aureus commonly experienced by adults, result in the accumulation of memory B-cell responses to other determinants on SpA. We therefore isolated SpA-specific class-switched memory B cells, and characterized their encoding VH : VL antibody genes. In SpA-reactive memory B cells, we confirmed a striking bias in usage for VH genes, which retain the surface that mediates the SpA-superantigen interaction. We postulate these interactions reflect co-evolution of the host immune system and SpA, which during infection results in immune recruitment of an extraordinarily high prevalence of B cells in the repertoire that subverts the augmentation of protective defenses. Herein, we provide the first evidence that human memory responses are supplemented by B-cell clones, and circulating-antibodies, that bind to SpA determinants independent of the non-immune Fc- and Fab-binding sites. In parallel, we demonstrate that healthy individuals, and patients recovering from S. aureus infection, both have circulating antibodies with these conventional binding specificities. These findings rationalize the potential utility of incorporating specially engineered SpA proteins into a protective vaccine.

scholarly journals Whole-Genome Epidemiology and Characterization of Methicillin-Susceptible Staphylococcus aureus ST398 From Retail Pork and Bulk Tank Milk in Shandong, China

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaonan Zhao ◽  
Ming Hu ◽  
Cui Zhao ◽  
Qing Zhang ◽  
Lulu Li ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Protein A ◽  
Whole Genome ◽  
Staphylococcal Protein A ◽  
Sequencing Analysis ◽  
Bulk Tank Milk ◽  
Predominant Type ◽  
Bulk Tank ◽  
The One

Staphylococcus aureus (S. aureus) is now regarded as a zoonotic agent. Methicillin-susceptible S. aureus (MSSA) ST398 is a livestock-associated bacterium that is most prevalent in China, but there are currently no data available for Shandong. Therefore, the aim of this study was to investigate the epidemiology and characterization of MSSA ST398 from retail pork and bulk tank milk (BTM) in Shandong. A total of 67 S. aureus isolates were collected from retail pork between November 2017 and June 2018. Among the isolates, high antimicrobial resistance rates were observed for penicillin (97.0%), and 92.5% of the isolates were multi-drug resistant (MDR). Eight sequence types (STs) were identified in the retail pork isolates, and the predominant type was ST15 (n=26), which was followed by ST398 (n=14). Staphylococcal protein A gene (spa) typing identified spa types t034 and t1255 in MSSA ST398 from retail pork. Using whole-genome sequencing analysis, we described the phylogeny of 29 MSSA ST398 isolates that were obtained from retail pork (n=14) and BTM (n=15). The phylogenetic tree showed that the MSSA ST398 isolates from different sources had the same lineage. Among the 29 MSSA ST398 isolates, five resistance genes were detected, and all isolates carried DHA-1. Fifteen toxin genes were detected, and all isolates carried eta, hla, and hlb. In conclusion, this study found that a high risk for MSSA ST398 was present in retail pork and BTM. These findings have major implications for how investigations of MSSA ST398 outbreaks should be conducted in the One-Health context.

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