Table 2.
Summary of virulence factors explored as potential targets for S. aureus pneumonia therapeutics.
| Targeted in SAP | Virulence Factor | Research Stage a | Approach/Strategy | Main Results | Advantages of Targeting b | Disadvantages of Targeting b | References |
|---|---|---|---|---|---|---|---|
| Yes | Hla | PC | in vitro: tissue cultures in vivo: murine, rabbit, and ferret models |
Protective potential of passive and active immunization | Core virulence factor; crucial role in SAP | Complex regulation | [69,72,73,74,75,76,77,78,79,80,81] |
| C | Human clinical trials | Protective potential of passive immunization | |||||
| Hlb/Hlg | PC | in vivo: murine SAP model | Hlb-deficient S. aureus shows less severe histopathology | Prevalent in nearly all S. aureus lineages; distinct role in pathogenesis | NA | [82] | |
| PSMs | PC | in vivo: murine SAP model | Reduced mouse mortality by indirect targeting (blocking Agr system) | Distinct role in SAP | Neutrophils are more protected than macrophages | [83] | |
| SasX | PC | in vitro: cell culture; vaccination studies in mice (skin abscess and lung infection model) | Induction of antigen-specific IgG response; protection from S. aureus-induced infection and colonization | (i) active immunization induced IgG1 response and reduced acute lung injury; (ii) active and passive immunization reduced S. aureus colonization; (iii) anti-SasX IgG increased S. aureus killing by human neutrophils | NK | [84] | |
| Yes | Srt | PC | in vitro: cell culture in vivo: murine S. aureus lung infection models | Deletion of SrtB reduced mortality; reduced S.aureus adhesion to human lung epithelial cells | Anti-inflammatory effects on macrophage | NK | [85] |
| PVL | PC | in vitro: polymorphonuclear leukocytes in vivo: rabbit SAP, murine sepsis models | Neutralization of cytotoxic effects (IVIG); protective immunity | Important role in pathogenesis of necrotizing pneumonia | Low prevalence | [86,87,88,89] | |
| SEVs | PC | in vivo: murine models (SAP, systemic infection, skin infection, sepsis) | Induction of protective immunity | Nano-size; safety profile; multivalent nature; longer persistence in host; induction of innate/adaptive immune response; intrinsic adjuvanticity | Insufficient humoral response (reason for failure of passive immunization) | [90,91,92,93] | |
| LTA | PC | in vitro: cell cultures; in vivo: healthy humans |
Neutrophil recruitment; proinflammatory; pro-apoptotic effects on macrophages; affects hemostasis | Crucial S. aureus component | Weak immunogenicity | [94,95,96,97] | |
| No | SpA | PC | in vivo: murine models (skin abscess, sepsis) | Induction of protective immunity against S. aureus-induced infection | Induction of antigen-specific IgG response; protection from abscess formation and neonatal sepsis in mice; prevention of S. aureus colonization | Unexplored as single target | [98,99,100,101,102] |
| C | Vaccination study in human (S. aureus bacteremia) | Good safety profile and minimal side effects in patients | |||||
| FnBPA | PC | in vitro: cell culture in vivo: vaccination studies in mice (FnBPA/SpA bivalent fusion vaccine; murine pneumonia and bacteremia model) | Induction of protective immunity against S. aureus-induced infections; induction of S. aureus killing by neutrophils | Bivalent vaccine more promising than SpA alone | Unexplored as single target | [103] | |
| Fur | PC | in vivo: murine SAP model | S. aureus lacking Fur is less virulent and protected against killing by neutrophils | Regulates several immunomodulatory proteins | Not yet targeted | [104] | |
| No | LukAB | PC | in vitro: cell cultures in vivo: murine immunization (sepsis) |
Neutralization of cytotoxicity; prevention of cell lysis | Main contributor in human phagocyte killing | Not well described | [105,106,107] |
| LukED | PC | in vitro: cell cultures | Induction of partial resistance to killing; functional inhibition of LukED | Highly conserved in epidemic MRSA lineages | NK | [108] |
SAP: S. aureus pneumonia; Ab: Antibody; IVIG: Intravenous immunoglobulin; Hla: Alpha-toxin; Hlb: Beta-toxin; Hlg: Gamma-toxin; PSMs: Phenol soluble modulins; FnBPA: Fibronectin binding protein A; Spa: Staphylococcal protein A; SasX: S. aureus surface protein X; Srt: Staphylococcal sortases; PVL: Panton-Valentine leukocidin; SEVs: S. aureus extracellular vesicles; LTA: Lipoteichoic acid; LukAB: Leukocidin AB; LukED: Leukocidin ED; Fur: Ferric uptake regulator; NK: Not known. a PC: Preclinical; C: Clinical. b SEVs and OMVs: (Dis)advantages of therapeutic use.