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Bacterial Endocarditis

Notes

Bacterial Endocarditis

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The bacteria Staphylococcus aureus is the leading cause of infective endocarditis; it is associated with a high mortality rate due to its aggressive nature and anti-biotic resistance (other causes are addressed in detail, elsewhere).

S. aureus exists in the normal human flora, and is commonly found in the nares (aka, nostrils). However, it can travel in the blood and cause infection; individuals with compromised immune systems and/or prosthetic cardiac devices are at higher risk of developing infective endocarditis.

The aggressive nature of S. aureus is due to multiple virulence factors that enhance its ability to thrive; in the context of endocarditis, we'll focus on:
Adherence to endothelial cells and extracellular proteins via surface adhesion protein.
Invasion of endocardial cells, where it releases toxins and promotes inflammatory processes that are highly destructive to host tissues.
Evasion of host defenses via the creation of a protective biofilm and/or phenotype switching to persist as small colony variants. In this state, S. aureus "hides" from the host immune system and antibiotic treatments, enabling it to persist, and, when conditions are favorable, reemerge as a chronic infectious agent.

We draw the anatomical context of endocarditis: inflamed valves with the vegetation blocking blood flow.

We've shown infection of the atrioventricular valve, but endocarditis can also affect the walls of the heart (mural endocarditis).

Pathogenesis by S. aureus

We draw a layer of endocardial cells and subendothelium.
As part of the immune response, fibronectin is deposited.
Fibrinogen (a glycoprotein that contributes to clot formation) and fibronectin act as "connecting bridges" that adhere to host cells, platelets, and bacteria to form a thrombotic vegetation. As we discuss elsewhere, these vegetations can break free and cause an embolism.
S. aureus produces a protective biofilm (sometimes called the slime layer).
– The biofilm comprises polysaccharides and proteins that inhibit thrombus destruction, thus allowing S. aureus to proliferate and destroy underlying tissues.

If this vegetation were to break free from the valve and travel in the bloodstream, it could easily become lodged in a vessel and cause embolism, even stroke.

Virulence factors of S. aureus and its mechanisms of infection

Thrombus formation:

Fibronectin acts as a "bridge" between the endothelial cells and bacterial pathogens:

Inflammation promotes deposition of fibronectin, which adheres to the endothelial cell via alpha-5 beta-1 integrins
Fibronectin adheres to S. aureus via surface adhesion proteins such as FnBP.

Fibrinogen forms a bridge by adhering to S. aureus via Clumping factor A, and to endocardial cells via alpha-5 beta-1 integrin.

Platelets adhere to fibrinogen via integrin GPIIb/IIIa (platelets also bind to von Willebrand factor, not shown for simplicity). Multiple platelets can bind to the same strands of fibrinogen, which, in turn, adhere to S. aureus via Clumping factor A.

As these connections form a thrombus, they promote additional activity:
Platelet activation induces release of pro-inflammatory molecules, binding and stimulation of leukocytes, and release of pro-coagulation molecules. These events promote thrombus formation and further activation of the immune system.

Endocytosis:

S. aureus is particularly virulent and destructive because of its ability to enter host cells.

The S. aureus-fibronectin connection enables endocytosis into the endocardial cell.

Within the host cells, S. aureus releases toxins and acts as a superantigen to provoke immune responses that ultimately destroy the cells.

To protect itself from host defenses and/or antibiotic treatments, S. aureus employs phenotypic switching to become small colony variants; this allows it to lie dormant within the host tissues, evade host defenses, and, when conditions are favorable, reemerge as an infective pathogen.

Treatment:

Requires prolonged intravenous administration of antibiotics; S. aureus is resistant to penicillin.

Methicillin (also spelled "meticillin"), a synthetic derivative of penicillin, has been used to treat S. aureus infections since the 1960s;

However, methicillin-resistant strains (MRSA) are increasingly common in both hospital and community settings; these strains of S. aureus display changes in their penicillin-binding proteins to increase tolerance.

In these cases, vancomycin or daptomycin, sometimes in combination with other antibiotics, are administered intravenously.

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