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].