The pneumococcus: epidemiology, microbiology, and pathogenesis

Abstract

The pneumococcus is the classic Gram-positive extracellular pathogen. The medical burden of diseases it causes is amongst the greatest in the world. Intense study for more than 100 years has yielded an understanding of fundamental aspects of its physiology, pathogenesis, and immunity. Efforts to control infection have led to the deployment of polysaccharide vaccines and an understanding of antibiotic resistance. The inflammatory response to pneumococci, one of the most potent in medicine, has revealed the double-edged sword of clearance of infection but at a cost of damage to host cells. In virtually every aspect of the infectious process, the pneumococcus has set the rules of the Gram-positive pathogenesis game.

Figure 1.

Progression of pneumococcal disease. Spread by aerosol, pneumococci are harbored in the nasopharynx. This interaction most commonly leads to clearance and serotype-specific immunity. Progression to otitis media is very common in children. Invasive disease involves spread to the lungs and bloodstream. The most serious development is meningitis. This series of invasive steps is a pattern shared by the three major bacterial pathogens of children (pneumococcus, Haemophilus, and meningococcus) and is driven by a very basic interplay between innate invasion and innate immunity.

Figure 2.

Innate invasion versus innate immunity. The majority of respiratory pathogens have phosphorylcholine (PCho) on their surfaces. PCho is on the cell wall teichoic acid of pneumococci (pictured as blue circles on cell wall surface extensions). PCho, by mimicking the host chemokine PAF, binds to the host cell platelet-activating factor receptor (PAFr) and its scaffold of β arrestins, leading to the uptake of bacteria into a vesicle and transmigration across the epithelial or endothelial barrier. This simple invasion step is countered by innate immune elements. C-reactive protein binds to PCho on the bacteria and surfactant contains abundant PCho, both of which inhibit bacterial contact with the host cell.

Figure 3.

Pneumococcal cell wall PAMPs in disease progression. The cell wall of pneumococci is a major determinant of the course of disease. The interaction of PCho on the cell wall teichoic acid binds to PAFr and enables bacterial invasion of cells and transmigration across barriers. It also enables the cell wall itself to traffic to all organs (inset top: view through the cranial window of fluorescein-tagged cell wall pieces migrating from vasculature to brain). In the tissues, cell wall subcomponents generate intense inflammation by interacting with TLR2 and Nod2. Signaling through these receptors activates NF-κB pathways, cytokine, and chemokine production, leading to intense neutrophil recruitment (inset bottom: Gram stain of pneumococcus [blue] and neutrophils [red] in the lung).

Figure 4.

Host cell damage by pneumococcal components. During the inflammatory response, host cells are subjected to bacterial and host-derived toxic stimuli. Early in the course of disease, the bacteria produce the potent pore-forming cytotoxin pneumolysin and copious amounts of hydrogen peroxide, both of which kill host cells independent of caspases. Later in the course of the inflammatory response, when cell wall debris has induced neutrophil recruitment, host cells undergo caspase-dependent apoptosis. The caspase inhibitor z-VAD-FMK attenuates only half of the damage in infected tissues (inset: orange, dead cells; green, live cells).