Staphylococcus aureus host interactions and adaptation

Abstract

Invasive Staphylococcus aureus infections are common, causing high mortality, compounded by the propensity of the bacterium to develop drug resistance. S. aureus is an excellent case study of the potential for a bacterium to be commensal, colonizing, latent or disease-causing; these states defined by the interplay between S. aureus and host. This interplay is multidimensional and evolving, exemplified by the spread of S. aureus between humans and other animal reservoirs and the lack of success in vaccine development. In this Review, we examine recent advances in understanding the S. aureus-host interactions that lead to infections. We revisit the primary role of neutrophils in controlling infection, summarizing the discovery of new immune evasion molecules and the discovery of new functions ascribed to well-known virulence factors. We explore the intriguing intersection of bacterial and host metabolism, where crosstalk in both directions can influence immune responses and infection outcomes. This Review also assesses the surprising genomic plasticity of S. aureus, its dualism as a multi-mammalian species commensal and opportunistic pathogen and our developing understanding of the roles of other bacteria in shaping S. aureus colonization.

Fig. 1. New insights into Staphylococcus aureus immune evasion.

a, Recruitment of neutrophils and phagocytic cells to the site of infection. Vascular neutrophils and phagocytic cells, such as macrophages, are actively recruited by chemotaxis to Staphylococcus aureus infection site following chemokine gradients and sensing pathogen-associated molecular patterns and bacterial-derived ligands of the formyl-peptide receptors released by S. aureus. b, Recently described S. aureus immune evasion molecules. S. aureus secretes phenol-soluble modulins (PSMs) that cause neutrophil lysis through interaction with formyl-receptor 2 (FPR2). Secreted neutrophil serine proteases (NSPs) degrade PSMs, but this process is inhibited by S. aureus extracellular adherence protein (Eap; or orthologues EapH1 and EapH2). S. aureus secretes a range of superantigens including staphylococcal superantigen (SElW) and the bifunctional staphylococcal enterotoxin-like toxin X (SElX) that lead to T cell proliferation and immune dysregulation. SElX also binds to neutrophil surface receptors and inhibits phagocytosis. Within the phagosome, myeloperoxidase (MPO) contributes to phagosomal killing through the generation of reactive oxygen species (ROS). However, S. aureus secretes staphylococcal peroxidase inhibitor (SPIN) that inhibits this process. c, Disruption of macrophage efferocytosis. S. aureus can indirectly interfere with macrophage efferocytosis of neutrophils undergoing formation of neutrophil extracellular traps (NETosis), whereby S. aureus neutralizes the bactericidal activity of neutrophil extracellular traps (NETs) using staphylococcal nuclease (Nuc) and adenosine synthase A (AdsA). The activities of these enzymes generate deoxyadenosine (dAdo), which triggers macrophage apoptosis. d, Genetic heterogeneity in virulence factors can alter their function. Clonal complex-specific sequence heterogeneity in the leukocidin AB (LukAB) leukotoxin alters phagocyte receptor tropism and cytotoxicity profile. This is exemplified by the strains belonging to CC30(CC45), which gained the ability to bind human hydrogen voltage-gated channel 1 (HVCN1). e, S. aureus biofilms secrete immune evasion factors to promote and inhibit NETosis. Secreted factors from S. aureus biofilms include leukocidins Panton–Valentine leukocidin (PVL) and S. aureus γ-haemolysin (HlgAB) that promote NETosis as well as nucleases that degrade NET DNA. CD11b, cluster of differentiation molecule 11B; ECM, extracellular matrix; Mϕ, macrophage.

Fig. 2. Evasion of immunoglobulin and complement-mediated immunity.

Binding of IgG Fc domain by secreted protein A (SpA) and staphylococcal immunoglobulin-binding protein (Sbi) protects Staphylococcus aureus from phagocytosis and inhibits complement activation. Protein A also functions as a B cell superantigen, binding to the Fab domain of IgM and cross-linking V_H3-type B cell receptors (BCRs). In conjunction with aureolysin, the secreted protease serine protease-like protein B (SplB) degrades complement components, thus hampering complement activation and opsonophagocytosis. C1q, complement component 1q.

Fig. 3. Staphylococcus aureus biofilm shapes the phenotype of leukocytes.

The left panel shows metabolic reprogramming, characterized by increased glycolysis, in macrophages infected with live planktonic bacteria or stimulated with pathogen-associated molecular patterns such as lipopolysaccharide (LPS) recognized by pathogen recognition receptor (PRR). This skews the macrophage towards a pro-inflammatory phenotype (that is, the production of the pro-inflammatory cytokine IL-1β), which promotes bacterial clearance. The right panel shows two different strategies through which staphylococcal biofilms evade innate immunity. These include either rewiring host metabolism or epigenetic changes. S. aureus biofilm, which is induced by host-derived itaconate, promotes mitochondrial oxidative phosphorylation (OXPHOS) in macrophages and an anti-inflammatory phenotype. The mechanism remains unknown (indicated by the question mark). Lactate produced by S. aureus biofilms is transported into macrophages and myeloid-derived suppressor cells (MDSCs) through the monocarboxylate transporter 1 (MCT1), inhibits histone deacetylase 11 (HDAC11) and promotes IL-10 production. Ac, acetylation; CoA, coenzyme A; TCA, tricarboxylic acid.

Fig. 4. Staphylococcus aureus host species adaptation over time.

a, Host-switching modelling of Staphylococcus aureus between species identified humans as a major transmission hub. Overlayed are reported host-specific mobile genetic elements (MGEs) in pigs^,, cows^,, small ruminants^,, horses, birds and hedgehogs; and their major associated clonal complexes (CCs). MGEs belonging to the non-dominant S. aureus lineages in pigs and cows have been reported, these CCs and sequence types (STs) are denoted in superscript. S. aureus infecting rabbits has no unique MGEs. A single nucleotide polymorphism (C338A) in chromosomal gene, dtlB, causes a non-synonymous mutation required for infection of rabbits by CC121 (see Supplementary Fig. 3c for all CC121 rabbit adaptations). No unique S. aureus MGEs have been described in rodents or carnivora. Globally disseminated, multihost lineage CC398 has been reported in rodents and carnivora, but no CCs are recognized as dominant in these species (see Supplementary Fig. 3d for the mechanism of broad host distribution for CC398). Human S. aureus strains possess the ϕSa3 prophage (β-haemolysin-converting phage) encoding a human-specific evasion cluster that integrates into hlb, causing loss of β-toxin production. Many animal-adapted S. aureus strains have lost ϕSa3, resulting in restored β-toxin production and increased fitness. Linewidth represents frequency of host jumps. b, Function of S. aureus genes carried on animal-adapted MGEs. S. aureus superantigens are virulence factors that cause nonspecific T cell activation and massive cytokine release. This excessive activation of the host immune system paradoxically promotes infection; antibiotic resistance is conferred by multiple resistance determinants; species-adapted leukodicins, encoded by luk, cause host neutrophil lysis. von Willebrand-binding protein (vWbp) causes host-specific plasma coagulation; adhesion protein (Bap) promotes S. aureus adhesion to bovine mammary mucosa and biofilm production resulting in colonization, contributing to the pathogenesis of bovine mastitis. Putative adhesin, LPXTG-surface protein promotes colonization (see Supplementary Fig. 3a for bovine-specific S. aureus adaptions); staphylococcal complement inhibitor (SCIN) encoded by scn blocks the activation of the host complement system; Avian-specific scpA encodes the thiol protease staphopain A, which is associated with enhanced pathogenicity through the inhibition of host neutrophil activation and chemotaxis (see Supplementary Fig. 3b for S. aureus CC5 adaptations in chickens). ^#Putative adhesin. ϕSabov-vSa, bacteriophage ϕ-S. aureus bovine in genomic island v-S. aureus; LPXTG, conserved peptide motif in surface linked proteins cleaved between the threonine and glycine residues and covalently attached to cell wall peptidoglycan; SCCmecC, staphylococcal cassette chromosome methicillin C resistance gene; TSST-1, toxic shock syndrome toxin-1; vSaα, genomic island v-S. aureus-α.