Staphylococcus aureus bloodstream infections: pathogenesis and regulatory mechanisms

Abstract

Staphylococcus aureus is an opportunistic pathogen that normally colonizes the human anterior nares. At the same time, this pathogen is one of the leading causes of life-threatening bloodstream infections, such as sepsis and endocarditis. In this review we will present the current understanding of the pathogenesis of these invasive infections, focusing on the mechanisms of S. aureus clearance from the bloodstream by the immune system, and how this pathogen hijacks the host defense and coagulation systems and further interacts with the blood vessel endothelium. Additionally, we will delve into the regulatory mechanisms S. aureus employs during an invasive infection. These new insights into host-pathogen interactions show promising avenues for the development of novel therapies for treating bloodstream infections.

Figure 1.. The role of the immune system in clearance and systemic spread of S. aureus in the bloodstream.

S. aureus is initially cleared from the bloodstream by Kupffer cells (liver macrophages). While Kupffer cells can kill the majority of phagocytosed bacteria, a small fraction of S. aureus survives and proliferates intracellularly, eventually killing the cells and being released back into the bloodstream and peritoneum. Subsequently, S. aureus is phagocytosed by neutrophils in liver circulation and by peritoneal macrophages. If these host cells fail to kill bacteria, they turn into “Trojan Horses”, carrying intracellular S. aureus throughout the body and causing a disseminated infection.

Figure 2.. Virulence mechanisms of S. aureus inside the bloodstream.

After entry into the bloodstream, S. aureus hijacks the host coagulation system to create clumps of individual bacteria cross-linked by and surface coated with host fibrinogen (A). Inflammation causes endothelial cells to surface display various adhesive molecules (e.g. von Willebrand factor, vWf), which act as anchors for S. aureus aggregates with platelets and for incoming immune cells potentially carrying intracellular bacteria (B). In areas where endothelial cells are damaged, the underlying collagen-rich matrix is exposed, binding circulating vWf and initiating coagulation, which results in deposition of fibrin clots. The display of collagen, vWf and fibrin allows adhesion of circulating S. aureus cells and clumps (C). Clumps of S. aureus attached to endothelium secrete toxins (e.g. alpha-toxin and superantigens) that further activate inflammatory signaling in endothelium or cause its direct damage (D). Secreted alpha-toxin also poisons nearby platelets, causing their aggregation and formation of microthrombi, potentially clogging smaller vessels (E).

Figure 3.. S. aureus gene regulation in bloodstream infection.

When S. aureus remains planktonic in the bloodstream, the local concentration of quorum-sensing autoinducing peptide (AIP) remains low, additionally quenched by serum apolipoproteins. This keeps the Agr system turned off, resulting in high expression of surface proteins responsible for attachment to host surfaces, and a low level of toxins. When S. aureus finds itself in clumps or inside cells, the local high concentration of secreted AIP causes Agr system to activate, increasing toxin levels that target host tissues and immune cells, and decreasing surface adhesins (A). When the ArlRS – MgrA cascade remains active, it suppresses production of giant surface proteins (allowing for normal activity of surface adhesins in fibrinogen-mediated clumping and adhesion to host tissues) and drives secretion of immune-evasion factors. When the ArlRS – MgrA cascade is off, the secretion of immune evasion factors decreases, and derepressed giant surface proteins shield neighboring surface adhesins, blocking them from mediating clumping or adhesion to host tissues (B).