Non-Canonical Host Intracellular Niche Links to New Antimicrobial Resistance Mechanism

Abstract

Globally, infectious diseases are one of the leading causes of death among people of all ages. The development of antimicrobials to treat infectious diseases has been one of the most significant advances in medical history. Alarmingly, antimicrobial resistance is a widespread phenomenon that will, without intervention, make currently treatable infections once again deadly. In an era of widespread antimicrobial resistance, there is a constant and pressing need to develop new antibacterial drugs. Unraveling the underlying resistance mechanisms is critical to fight this crisis. In this review, we summarize some emerging evidence of the non-canonical intracellular life cycle of two priority antimicrobial-resistant bacterial pathogens: Pseudomonas aeruginosa and Staphylococcus aureus. The bacterial factors that modulate this unique intracellular niche and its implications in contributing to resistance are discussed. We then briefly discuss some recent research that focused on the promises of boosting host immunity as a combination therapy with antimicrobials to eradicate these two particular pathogens. Finally, we summarize the importance of various strategies, including surveillance and vaccines, in mitigating the impacts of antimicrobial resistance in general.

Keywords: Pseudomonas aeruginosa; Staphylococcus aureus; antibiotic resistance; non-canonical intracellular pathogen.

Figure 1

Depiction of P. aeruginosa’s ability to subvert the host cell cytoskeleton. When P. aeruginosa (PA) binds to epithelial cells (1), it results in the activation of PI3K (2) in an H2-T6SS-dependent manner [48]. PI3K subsequently activates Akt and PIP3 via phosphorylation (3), leading to cytoskeleton remodeling (4) [49,52]. Evidence has also shown that the H2-T6SS effector VgrG2b is injected into the host cell prior to P. aeruginosa invasion (5) [54]. VgrG2b is then able to interact with α/β–tubulin as well as the γ-TuRC (6) [45]. This interaction is likely to lead to cytoskeletal remodeling; however, connections between the PI3K and VgrG2b remain to be elucidated.

Figure 2

Overview of the zipper-type mechanism or FnBP-Fn-α5β1 integrin-mediated uptake, involving staphylococcal fibronectin-binding proteins A and B (FnBPA and FnBPB). S. aureus (SA) contains fibronectin-binding proteins A and B (FnBPA and FnBPB) (1). As described by Liang and colleagues [85], these proteins bind to host α5β1 integrin molecules on the surface of cells (1) where FnBPA repeats bind to Fn and encourage the clustering of α5β1 integrins. The clustering of integrins promotes the recruitment of host proteins (2), including vinculin and tensin, and will additionally promote activation of host focal adhesion kinases (FAKs) and proto-oncogene tyrosine-protein kinase Src (Src) to the bacterial attachment site. The combined activity of FAK and Src results in tyrosine phosphorylation of several host effectors that trigger cytoskeletal rearrangements and the assembly of characteristic endocytic complexes on the intracellular side of the plasma membrane to allow bacterial entry [85].

Figure 3

Alternative staphylococcal mechanisms for cellular entry. Staphylococcal protein A (SpA) directly interacts with host tumor necrosis factor α receptor 1 (TNF1a) [106], host receptor gC1qR/p33 on endothelial cells [107], and host vWF in the extracellular matrix of human umbilical vein endothelial cells (1) [108]. SpA has been shown to activate TNF1a and EGF receptor (EGFR) signaling cascades that will re-configure the cytoskeleton for staphylococcal internalization [109,110]. Staphylococcal protein EAP may also enhance attachment of SpA to the endothelium by upregulating host receptor gC1qR/p33 on endothelial cells via TNFα release in the bloodstream (2) [107]. S. aureus (SA) has been additionally shown to stimulate its own uptake by upregulating β1 integrin expression in the host cell through the secretion of α-hemolysin (HLA) (3) [111,112]. S. aureus HLA will disrupt cell-matrix adhesion by activating FAK signaling via interaction with transmembrane protein ADAM10 with the consequent acceleration of focal contact turnover to overcome the defensive barrier function of the airway epithelium (4) [113]. This FAK will also cause plasma membrane depolarization and activates p38 MAP kinase [114]. The β1 integrin is additionally involved in transient activation of the phosphatidylinositol 3-kinase/Akt signaling pathway, which might play a crucial role in β1 integrin-mediated internalization of S. aureus [115].