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Clumping factor B is an important virulence factor during Staphylococcus aureus skin infection and a promising vaccine target.

ABSTRACT: Staphylococcus aureus expresses a number of cell wall-anchored proteins that mediate adhesion and invasion of host cells and tissues and promote immune evasion, consequently contributing to the virulence of this organism. The cell wall-anchored protein clumping factor B (ClfB) has previously been shown to facilitate S. aureus nasal colonization through high affinity interactions with the cornified envelope in the anterior nares. However, the role of ClfB during skin and soft tissue infection (SSTI) has never been investigated. This study reveals a novel role for ClfB during SSTIs. ClfB is crucial in determining the abscess structure and bacterial burden early in infection and this is dependent upon a specific interaction with the ligand loricrin which is expressed within the abscess tissue. Targeting ClfB using a model vaccine that induced both protective humoral and cellular responses, leads to protection during S. aureus skin infection. This study therefore identifies ClfB as an important antigen for future SSTI vaccines.

SUBMITTER: Lacey KA

PROVIDER: S-EPMC6497315 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Clumping factor B is an important virulence factor during Staphylococcus aureus skin infection and a promising vaccine target.

Lacey Keenan A KA Mulcahy Michelle E ME Towell Aisling M AM Geoghegan Joan A JA McLoughlin Rachel M RM

PLoS pathogens 20190422 4

Staphylococcus aureus expresses a number of cell wall-anchored proteins that mediate adhesion and invasion of host cells and tissues and promote immune evasion, consequently contributing to the virulence of this organism. The cell wall-anchored protein clumping factor B (ClfB) has previously been shown to facilitate S. aureus nasal colonization through high affinity interactions with the cornified envelope in the anterior nares. However, the role of ClfB during skin and soft tissue infection (SS ...[more]

PMID: 31009507

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Project description:UnlabelledTreatment of Staphylococcus aureus infections has become increasingly difficult because of the emergence of multidrug-resistant isolates. Development of a vaccine to prevent staphylococcal infections remains a priority. To determine whether clumping factor A (ClfA) is a good target protein for inclusion in a multivalent vaccine, we evaluated its efficacy in a variety of relevant staphylococcal infection models, challenging with different S. aureus strains. ClfA adsorbed to Alhydrogel and mixed with Sigma Adjuvant System was more immunogenic and stimulated a more robust Th17 response than ClfA administered with alum alone. ClfA immunization induced the production of functional antibodies in rabbits and mice that blocked S. aureus binding to fibrinogen and were opsonic for S. aureus strains that produced little or no capsular polysaccharide. Mice immunized with ClfA showed a modest reduction in the bacterial burden recovered from subcutaneous abscesses provoked by S. aureus USA300 strain LAC. In addition, the ClfA vaccine reduced lethality in a sepsis model following challenge with strain Newman, but not ST80. Vaccination with ClfA did not protect against surgical wound infection, renal abscess formation, or bacteremia. Passive immunization with antibodies to ClfA did not protect against staphylococcal bacteremia in mice or catheter-induced endocarditis in rats. Some enhancement of bacteremia was observed by ClfA immunization or passive administration of ClfA antibodies when mice were challenged by the intraperitoneal route. Although rodent models of staphylococcal infection have their limitations, our data do not support the inclusion of ClfA in an S. aureus multivalent vaccine.ImportanceAntibiotics are often ineffective in eradicating Staphylococcus aureus infections, and thus, a preventative vaccine is sorely needed. Two single-component vaccines and two immunoglobulin preparations failed to meet their designated endpoints in phase III clinical trials. Importantly, recipients of an S. aureus surface protein (iron surface determinant B) vaccine who developed a staphylococcal infection experienced a higher rate of multiorgan failure and mortality than placebo controls, raising safety concerns. Multicomponent S. aureus vaccines have now been generated, and several include surface protein clumping factor A (ClfA). We immunized mice with ClfA and generated a robust T cell response and serum antibodies that were functional in vitro. Nonetheless, ClfA was not protective in a number of relevant animal models of S. aureus infection, and high levels of ClfA antibodies enhanced bacteremia when mice were challenged with community-acquired methicillin-resistant S. aureus strains. Evidence supporting ClfA as a vaccine component is lacking.

Dataset Information

Clumping factor B is an important virulence factor during Staphylococcus aureus skin infection and a promising vaccine target.

Publications

Clumping factor B is an important virulence factor during Staphylococcus aureus skin infection and a promising vaccine target.

Similar Datasets

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