Abstract
The pore-forming cytotoxin α-hemolysin, or Hla, is a critical Staphylococcus aureus virulence factor that promotes infection by causing tissue damage, excessive inflammation, and lysis of both innate and adaptive immune cells, among other cellular targets. In this study, we asked whether a virus-like particle (VLP)-based vaccine targeting Hla could attenuate S. aureus Hla-mediated pathogenesis. VLPs are versatile vaccine platforms that can be used to display target antigens in a multivalent array, typically resulting in the induction of high titer, long-lasting antibody responses. In the present study, we describe the first VLP-based vaccines that target Hla. Vaccination with either of two VLPs displaying a 21 amino-acid linear neutralizing domain (LND) of Hla protected both male and female mice from subcutaneous Hla challenge, evident by reduction in lesion size and neutrophil influx to the site of intoxication. Antibodies elicited by VLP-LND vaccination bound both the LND peptide and the native toxin, effectively neutralizing Hla and preventing toxin-mediated lysis of target cells. We anticipate these novel and promising vaccines being part of a multi-component S. aureus vaccine to reduce severity of S. aureus infection.
Highlights
Staphylococcus aureus α-hemolysin (Hla) is an important secreted bacterial virulence factor whose loci is found in 99% of clinical isolates
Our findings demonstrate the efficacy of virus-like particle (VLP)-based vaccines displaying the Hla-linear neutralizing domain (LND) and suggest that these vaccines could contribute to a multi-component vaccine to prevent S. aureus pathogenesis and infection
Hla challenge in a murine model of VLP-based vaccines, individual mouse with the lowest anti-Hla antibody titer had the largest legion after Hlaincluding already in clinical use,antibodies have historically been developed against viral pathogens
Summary
Staphylococcus aureus α-hemolysin (Hla) is an important secreted bacterial virulence factor whose loci is found in 99% of clinical isolates. Hla mediates invasive infection and promotes pathogenesis associated with both primary and recurrent skin and soft tissue infection (SSTI), pneumonia (PNA), peritoneal infections, and sepsis, among others [1,2,3,4,5,6,7,8,9]. In SSTI models, S. aureus mutants lacking Hla are attenuated [10] and are more rapidly cleared by the host [3]. Hla binds to a zinc metalloprotease, ADAM10, on host cells to form a heptameric pore and initiate breach of epithelial barriers [6,9,11]. The importance of Hla to various S. aureus infections likely stems from the broad cellular distribution of ADAM10 [7]. Hla is a major toxin target for vaccines and therapeutics to limit
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