2 MRSA infection and its immune mechanisms
MRSA infection has three stages: colonization, adaptation and invasion. Its high pathogenicity is attributed to the invasiveness, virulence and variability [13]. MRSA has virulence factors that increase its invasiveness, allowing the bacteria to adhere and invade to host cells [14]. The variability of MRSA includes antigenic variation and phase variation. Antigenic variation enables resistance to commonly used antibiotics without reducing the pathogenicity of MRSA, and can alter the immunoreactivity of its encoded products, thereby evading the host’s immune response[15, 16]. Phase variation helps MRSA immune evasion by promoting MRSA biofilm (MRSA-BF) formation and assisting bacteria survival within the “Trojan horse”[17]. In MRSA infection, the human immune system evolves several efficient mechanisms to eliminate MRSA, and MRSA evolves immune evasion strategies against host immunity (Fig. 1)[2].
2.1 Host immune defense against MRSA infection
As shown in Fig. 1, there are three lines of defense against MRSA infection, the body’s mucosal immune system (MIS), the innate immune system (IIS) and the adaptive immune system (AIS). As a physical and immune defense barrier, MIS maintains immune homeostasis in the vast epithelial surface areas from the nasal cavity and respiratory tract to the intestine [18]. The formation of secretory IgA (SIgA) is the key strategy of the MIS [19]. SIgA is released into the nasal passage and intestinal tract, binding and “coating” offending pathogens, thus blocking pathogens invasion (Fig. 1) [20]. The IIS is rapidly triggered during infections, which involves the activation of the complement system and the recruitment and activation of dedicated immune cells such as neutrophils and macrophages (Fig. 1) [21]. The activated complement system usually exerts phagocytosis by binding with the complement receptor (CR), and it triggers serial chemotactic and proinflammatory responses to facilitate neutrophil migration to the infection site [22, 23]. Neutrophils are activated and stimulate bacterial clearance by phagocytosis and bactericide[24, 25]. As pathogens are degraded, antigenic peptides are processed by specific antigen-presenting cells such as DCs and Mφs, further triggering the AIS, which plays a major role in both the treatment and control of chronic infections (Fig. 1)[26, 27].
2.2 MRSA immune evasion
To establish infection successfully, MRSA deploys several immune evasion strategies to prevent the host’s three lines of defense. (Table 1.). The analysis of molecular structures reveals the mechanism by which a bacterial pathogen evades SIgA-mediated immunity via Staphylococcal superantigen-like protein-7 (SSL-7) in the mucosal immune response, which facilitates survival in mucosal environments and then contributes to systemic infections [28].
To evade attack from innate immune responses, MRSA secretes virulence factors that prevent complement initiation, digest complements and inhibit the cleavage of complement cleavage fragments, further evading opsonization of the complement system and causing inhibition of subsequent neutrophil effects (Table 1) [25, 29-38]. Other virulence factors prevent neutrophils from functioning by blocking them from arriving at infected sites, inhibiting their phagocytosis, and even killing them [32, 39-41]. MRSA also impairs macrophages mainly via the formation of mature MRSA-BF[40, 42]. It survives in macrophages and enters the general circulation, leading to other tissue damage, which is called the “Trojan horse” [43]. Finally, MRSA directly causes macrophage death through pore-forming toxins (PFTs), particularly PVL. MRSA also manipulates the AIS, for example, interfering with B-cell activation and proliferation, and impeding the humoral response[44, 45].