Development of a vaccine against Staphylococcus aureus invasive infections: Evidence based on human immunity, genetics and bacterial evasion mechanisms

Abstract

Invasive Staphylococcus aureus infections are a leading cause of morbidity and mortality in both hospital and community settings, especially with the widespread emergence of virulent and multi-drug resistant methicillin-resistant S. aureus strains. There is an urgent and unmet clinical need for non-antibiotic immune-based approaches to treat these infections as the increasing antibiotic resistance is creating a serious threat to public health. However, all vaccination attempts aimed at preventing S. aureus invasive infections have failed in human trials, especially all vaccines aimed at generating high titers of opsonic antibodies against S. aureus surface antigens to facilitate antibody-mediated bacterial clearance. In this review, we summarize the data from humans regarding the immune responses that protect against invasive S. aureus infections as well as host genetic factors and bacterial evasion mechanisms, which are important to consider for the future development of effective and successful vaccines and immunotherapies against invasive S. aureus infections in humans. The evidence presented form the basis for a hypothesis that staphylococcal toxins (including superantigens and pore-forming toxins) are important virulence factors, and targeting the neutralization of these toxins are more likely to provide a therapeutic benefit in contrast to prior vaccine attempts to generate antibodies to facilitate opsonophagocytosis.

Keywords: Staphylococcus aureus; MRSA; evasion; genetics; immunity; vaccine.

Figure 1.

Host cell signaling pathways implicated in immunity against S. aureus infections. Toll-like receptor 2 (TLR2) (which heterodimerizes with TLR1 or TLR6 and the TLR2/6 heterodimer is activated by Staphylococcus aureus lipopeptides and LTA [lipoteichoic acid]) and interleukin–1 receptor 1 (IL–1R1) (which is activated by IL–1α and IL–1β) both signal through MyD88 (myeloid differentiation primary response protein 88) and IRAK4 (IL–1R–associated kinase 4) to trigger activation of NF–κB (nuclear factor-κB) and MAPK (mitogen-activated protein kinase) (including p38, ERK [extracellular signal–regulated kinase] and JNK [JUN N-terminal kinase]) signaling. An additional signaling adapter protein, TIRAP (Toll/interleukin-1 receptor [TIR] domain- containing adapter protein), is required for TLR2 signaling, and the IL-1 receptor accessory protein (IL-1RAcP), is required for IL-1R signaling. S. aureus also induces production of NGFβ (nerve growth factor β) that binds to its receptor TRKA (tyrosine kinase receptor A) to promote RAS/RAF/MEK and PI3K (phosphatidylinositol 3-kinase)/AKT (protein kinase B) signaling. Finally, IL-6, which binds to its receptor comprised of gp130 and the IL-6Rα activates JAK (Janus kinase) and STAT3 (signal transducer and activator of transcription 3) signaling. Each of these signaling pathways leads to transcription and translation of proinflammatory cytokines, chemokines, adhesion molecules and host defense peptides against S. aureus infections. Red arrows: The specific inflammatory mediators and signaling molecules in which loss-of-function mutations have been identified in humans that result in an increased susceptibility to S. aureus infections.

Figure 2.

T cells in immunity against S. aureus infections. In response to S. aureus infection, naïve αβ CD4⁺ T cells can differentiate into different T helper (Th) cell subsets. These include Th17 cells (induced by IL-6, IL-21 and IL-23) that express the transcription factors RORγt (retinoic acid-related-orphan receptor γ) and STAT3 (signal transducer and activator of transcription 3) and produce IL-17A and IL-17F, which activate their receptor comprised of IL-17RA (IL-17 receptor A) and IL-17RC (IL-17 receptor C) to promote phagocyte (neutrophil and monocyte) recruitment from the bloodstream to form an abscess at the site of infection. Similarly, Th1 cells (induced by IFNγ, IL-12 and IL-18) that express the transcription factor T-bet (T-box–containing protein expressed in T cells) and produce IFNγ and TNF, which also promote phagocyte (neutrophil and monocyte) recruitment from the bloodstream to form an abscess at the site of infection. In addition, Th2 cells (induced by IL-4 and IL-33) express the transcription factor GATA3 and promote antibody production by B cells. Finally, Tregs (T regulatory cells) (induced by TGFβ and IL-2) that express the transcription factor FoxP3 (forkhead box P3) downregulate immune responses by producing the anti-inflammatory cytokines TGFβ and IL-10. Unconventional T cells such as γδ T cells (induced by IL-1β, TLR2 and IL-23) and MAIT (mucosa-associated invariant T cells) (induced by IL-7, IL-12, IL-18 and IL-23) produce IL-17A, IL-17F, IFNγ and TNF, which also promote phagocyte recruitment and host defense against S. aureus infections. Red arrows: The specific inflammatory mediators and signaling molecules in which loss-of-function mutations have been identified in humans that result in an increased susceptibility of S. aureus infections.

Figure 3.

S. aureus superantigens (SAgs) and pore-forming toxins (PFTs). S. aureus produces SAgs (including Toxic shock syndrome toxin 1 [TSST-1] and Staphylococcal enterotoxins [SE]) that crosslink the Vβ chain of T cell receptors (TCRs) from tissue resident and recruited T cells to MHCII molecules on antigen-presenting cells (APCs), leading to antigen-independent stimulation of T cells and APCs with massive production and release of many different cytokines. The activity of SAgs is a S. aureus immune evasion mechanism of T cell responses as it leads to altered and skewed T cells responses and exhaustion. Staphylococcus aureus also produce single component α-toxin, bicomponent leukocidins (luk) and phenol soluble modulins (PSMs) that result in host cell lysis and inflammatory activation. The activity of PFTs is a S. aureus immune evasion mechanism to counter the host defense activity of epithelial, stromal and immune cells.

Figure 4.

Serum cytokines levels in patients with S. aureus bacteremia (SAB) and their correlation with clinical outcome. ↑ (up arrow) = relatively increased cytokine level. ↓ (down arrow) = relatively decreased cytokine level. Green text = protective clinical outcome. Red text = deleterious clinical outcome. Early = the cytokine level within the first 3 days following the diagnosis of SAB. Late = the cytokine level after the first 3 days following the diagnosis of SAB. IL = interleukin. IL-1RA = interleukin-1 receptor antagonist. TNF = tumor necrosis factor. IFN-γ = interferon γ. CCR2 = C-C chemokine receptor type 2.

Figure 5.

Serum antibody titers against S. aureus superantigens (SAgs) and pore-forming toxins (PFTs) in patients with S. aureus bacteremia (SAB) and their correlation with clinical outcome. ↑ (up arrow) = relatively increased antibody titers. ↓ (down arrow) = relatively decreased antibody titers. Green text = protective clinical outcome. Red text = deleterious clinical outcome. TSST-1 = Toxic shock syndrome toxin 1. SE = Staphylococcal enterotoxin. Hl = hemolysin. PVL = Panton-Valentine leukocidin.