The Influence of Antibiotic Resistance on Innate Immune Responses to Staphylococcus aureus Infection

Abstract

Staphylococcus aureus (S. aureus) causes a broad range of infections and is associated with significant morbidity and mortality. S. aureus produces a diverse range of cellular and extracellular factors responsible for its invasiveness and ability to resist immune attack. In recent years, increasing resistance to last-line anti-staphylococcal antibiotics daptomycin and vancomycin has been observed. Resistant strains of S. aureus are highly efficient in invading a variety of professional and nonprofessional phagocytes and are able to survive inside host cells. Eliciting immune protection against antibiotic-resistant S. aureus infection is a global challenge, requiring both innate and adaptive immune effector mechanisms. Dendritic cells (DC), which sit at the interface between innate and adaptive immune responses, are central to the induction of immune protection against S. aureus. However, it has been observed that S. aureus has the capacity to develop further antibiotic resistance and acquire increased resistance to immunological recognition by the innate immune system. In this article, we review the strategies utilised by S. aureus to circumvent antibiotic and innate immune responses, especially the interaction between S. aureus and DC, focusing on how this relationship is perturbed with the development of antibiotic resistance.

Keywords: Staphylococcus aureus; antibiotic resistance; innate immunity.

Figure 1

Schematic presentation of the changes in the innate immune response coincident with the development of antibiotic resistance in S. aureus. (a) Changes in membrane phospholipid composition with the evolution of antibiotic resistance in S. aureus. Emergence of MRSA with reduced susceptibility to VCM and DAP has been associated with gain-of-function, in which lysinylation of PG is increased [217,221]. This positively charged L-PG increases net positive charge on the CM and reduced affinity for VCM and DAP [221]. Increased cell wall thickening is also suggested to cause ineffective binding of DAP/VCM to the CM [218,219]. (b) In the innate immune response, S. aureus is recognised by PRR of immune cells and phagocytosed, leading to the activation of intracellular PRRs and upregulation of costimulatory markers [222]. Cytokines produced by innate immune cells further mobilise recruitment of immune cells for pathogen clearance [222]. Among the innate immune cells, Antigen Presenting cells (APCs) induce the activation of adaptive immunity through antigen presentation [223]. However, antibiotic resistant S. aureus can evade innate immune detection, thus preventing activation. Notably, antibiotic-resistant S. aureus can modulate DC activation by avoiding recognition via TLR2 and 13 [159,224]. In response to DAP-R MRSA, DCs produced reduced proinflammatory cytokines including TNFα, IL-6, and MIP-1β as well as decreased CD80 expression compared with DAP-sensitive MRSA [225]. MRSA can also suppress DC activation by inducing the production of immunosuppressive cytokine IL-10 [226]. Neutrophils are one of the most fundamental host innate immune effectors against S. aureus [227]. During infection, neutrophils are initially recruited to the site of infection, a process termed chemotaxis, followed by adhesion and phagocytosis of S. aureus [228]. On the other hand, mutation in membrane phospholipid biosynthesis gene (cls₂) conferring DAP resistance allowed S. aureus to evade neutrophil chemotaxis and overcome the immune attack [11]. Macrophages, which are also professional phagocytes, can also successfully control and degrade S. aureus using a range of mechanisms, including TLR activation, upregulation of proinflammatory cytokines, and generation of reactive ROS and NO [135]. However, the development of antibiotic resistance in S. aureus led to a downregulation of TLR1, TLR2, TLR6, and TLR9 expression in macrophages and dampened TNFα secretion and NO synthesis, allowing them to survive and escape macrophages [229,230].