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Tag words: Streptococcus pneumoniae, S pneumoniae, pneumococcus, lobar pneumonia, pneumococcal pneumonia, otitis media, meningitis, pneumococcal vaccine.

Streptococcus pneumoniae

Kingdom: Bacteria
Phylum: Firmicutes
Class: Bacilli
Order: Lactobacillales
Family: Streptococcaceae
Genus: Streptpcoccus
Species: S. pneumoniae

Kenneth Todar currently teaches Microbiology 100 at the University of Wisconsin-Madison.  His main teaching interests include general microbiology, bacterial diversity, microbial ecology and pathogenic bacteriology.

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Streptococcus pneumoniae (page 3)

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Pneumococci spontaneously cause disease in humans, monkeys, rabbits, horses, mice and guinea pigs. Nasopharyngeal colonization occurs in approximately 40% of the population. Pneumonia and otitis media are the most common infections, meningitis being much more variable. The rabbit and the mouse have been used extensively as animal models of disease, leading to a reasonable understanding of many of the pneumococcal determinants of virulence.

Pneumococci adhere tightly to the nasopharyngeal epithelium by multiple mechanisms that, for most individuals, appears to result in an immune response that generates type-specific immunity. For some people, however, progression into the lungs or middle ear occurs. Passage of pneumococci up the eustachian tube is accompanied by bacterial induced changes in the surface receptors of the epithelial cell, particularly by neuraminidase. Inflammation in the middle ear is caused by pneumococcal cell wall components, and pneumolysin inflicts major cytotoxicity on ciliated cells of the cochlea.

Upon reaching the lower respiratory tract by aerosol, pneumococci bypass the ciliated upper respiratory epithelial cells unless there is damage to the epithelium. Instead, they progress to the alveolus and associate with specific alveolar cells which produce a choline-containing surfactant.

Experimentally, in healthy tissues, it requires approximately 100,000 bacteria/ml to trigger an inflammatory response. However, if a proinflammatory signal is supplied, inflammation ensues with as few as 10 bacteria. This signal is a cytokine in experimental systems or an intercurrent viral infection in clinical situations. The inflammatory response can cause considerable tissue damage.

The bacteria invade and grow primarily due to their resistance to the host phagocytic response. The cell wall components directly activate multiple inflammatory cascades, including the alternative pathway of complement activation, the coagulation cascade and the cytokine cascade, inducing interleukin-1, interleukin-6 and tumor necrosis factor (TNF) from macrophages and other cells.

In addition, as pneumococci begin to lyse due to autolysis or in response to host defensins and antimicrobial agents, they release cell wall components, pneumolysin and other substances that lead to greater inflammation and cytotoxic effects. Pneumolysin and hydrogen peroxide produced by the bacteria kill cells and induce production of nitric oxide which may play a key role in septic shock.

During invasion, the interaction between the bacterial cell wall choline and the host PAF receptor G-protein contributes to a state of altered vascular permeability. In the lung, this leads to arrival of an inflammatory exudate. At first, a serous exudate forms. This is followed by the arrival of leukocytes, thereby making the switch from a serous to a purulent exudate. Sites of pneumococcal infection are particularly noted for the intensity of the purulent response.

Pneumococci occasionally are able to directly invade endothelial cells. The ligands by which pneumococci bind to activated human cells include choline located on the cell wall teichoic acid that can serve as a direct ligand to the PAF receptor, and the choline-binding protein, CbpA, which binds to a specific carbohydrate on the alveolar cell surface. When bound to the PAF receptor, the pneumococcus enters a vacuole in a receptor-mediated endocytic process, and the vacuole moves across the cell expelling the bacteria on the ablumenal surface. In vitro, pneumococci will adhere to and traverse an endothelial barrier over approximately 4 hours.

If bacteremia occurs, the risk of meningitis increases. Pneumococci can adhere specifically to cerebral capillaries using the same pairings of choline to PAF receptor and CbpA to carbohydrate receptor. Thus, the bacteria subvert the endocytosis/recycling pathway of the PAF receptor for cellular transmigration. Once in the cerebrospinal fluid, a variety of pneumococcal components, particularly cell wall components, incite the inflammatory response.

Bacterial Determinants of Virulence

The initial event in invasive pneumococcal disease is the attachment of encapsulated pneumococci to epithelial cells in the upper respiratory tract. Recently, it has been shown that initial bacterial adhesion and subsequent ability to cause invasive disease is enhanced by pili, which were previously unknown to exist in pneumococci. These adhesive pili-like appendages are encoded by the rlrA islet, present in some, but not all, clinical isolates. Introduction of the rlrA islet into an encapsulated rlrA-negative isolate allowed pilus expression, enhances adherence to lung epithelial cells, and provides a competitive advantage upon mixed intranasal challenge of mice. Furthermore, pilus-expressing rlrA islet-positive clinical isolates are more virulent than nonpiliated deletion mutants, and they out-compete the mutants in murine models of colonization, pneumonia, and bacteremia. Additionally, piliated pneumococci evoke a higher TNF response during systemic infection compared with nonpiliated derivatives, suggesting that pneumococcal pili not only contribute to adherence and virulence but also stimulate the host inflammatory response.


The bacterial capsule interferes with phagocytosis by leukocytes, a property dependent on its chemical composition. Apparently, resistance to phagocytosis is brought about by interference with binding of complement C3b to the cell surface.

During invasion of the mucosal surface, encapsulated strains are 100,000 times more virulent than unencapsulated strains. The polysaccharide is nontoxic and noninflammatory, and the capsule does not appear to engage any host defenses except for the induction of antibody-mediated immunity. The pneumococcal capsule is not an antigenic disguise, and it does not impede the activities of underlying components, such as the cell wall and surface proteins, to engage the host defense systems. However, C-reactive protein or antibodies to teichoic acid, both of which bind to the cell wall under the capsule, fail to opsonize encapsulated strains.

Cell Wall Components
The pneumococcal cell wall is a collection of potent inflammatory stimuli. Challenge with cell wall components alone can recreate many of the symptoms of pneumonia, otitis media and meningitis in experimental models. The phosphorylcholine decorating the teichoic acid and the lipoteichoic acid is a key molecule enabling invasion, and acts both as an adhesin and as a docking site for the choline-binding proteins (CBPs). Other respiratory pathogens such as Haemophilus, Pseudomonas, Neisseria and Mycoplasma also have phosphorylcholine on lipopolysaccharide, proteins or pili, suggesting a shared mechanism for invasion of the respiratory tract.  Two host-derived elements that recognize choline are platelet activating factor (PAF) receptor and the C-reactive protein. Since respiratory pathogens may be recognized and cleared by the C-reactive protein response as part of the innate defenses, respiratory pathogens may share this invasive mechanism to subvert the signaling cascade of endogenous PAF.

The peptidoglycan/teichoic acid complex of the pneumococcus is highly inflammatory. Smaller components of peptidoglycan progressively lose specific inflammatory activity. The cell wall directly activates the alternative pathway of the complement cascade, generating chemotaxins for leukocytes, and the coagulation cascade, which promotes a "procoagulant state" favoring thrombosis. In addition, peptidoglycan binds to CD14, a cell surface receptor known to initiate the inflammatory response for endotoxin. This induces a cytokine cascade resulting in production of interleukin-1, interleukin-6 and tumor necrosis factor from human cells.

Choline Binding Proteins
The CBP family includes such important determinants as PspA (protective antigen), LytA, B, and C (three autolysins), and CbpA (an adhesin).

The protective antigen (PspA) is a 6 kDa protein with 10 choline-binding repeats. PspA appears to inhibit complement-mediated opsonization of pneumococci, and mutants lacking PspA have reduced virulence. Antibodies against PspA confer passive protection in mice.

Autolysin LytA is responsible for pneumococcal lysis in stationary phase as well as in the presence of antibiotics. The protein has two functional domains: a C-terminal domain with six choline-binding repeats that anchor the protein on the cell wall, and an N-terminal domain that provides amidase activity. Autolysin LytB is a glucosaminidase involved in cell separation, and LytC exhibits lysozyme-like activity.

CbpA is a major pneumococcal adhesin. It has eight choline-binding repeats. The adhesin interacts with carbohydrates on the pulmonary epithelial surface carbohydrates. CbpA-deficient mutants are defective in colonization of the nasopharynx and fail to bind to various human cells in vitro. CbpA also has been reported to bind secretory IgA and complement component C3.

In addition to surface-associated virulence determinants, pneumococci secrete exotoxins. Two hemolysins have been described, the most potent of which is pneumolysin. Pneumolysin is a 53kDa protein that can cause lysis of host cells and activate complement. It is stored intracellularly and is released upon lysis of pneumococci. Pneumolysin binds to cholesterol and thus can indiscriminately bind to all cells without restriction to a receptor. The protein assembles into oligomers to form transmembrane pores which ultimately lead to cell lysis. Pneumolysin can also stimulate the production of inflammatory cytokines, inhibit beating of the epithelial cell cilia, inhibit lymphocyte proliferation, decrease the bactericidal activity of neutrophils, and activate complement. A second hemolysin activity has been described but has not been identified. In addition, pneumococci also produce hydrogen peroxide in amounts greater than human leukocytes produce. This small molecule is also a potent hemolysin.

As mentioned above, pili contribute to colonization of upper respiratory tract and increase the formation of large amounts of tumor necrosis factor.

Hydrogen peroxide
H2O2 produced by the pneumococcus causes damage to host cells (e.g. can cause apoptosis in neuronal cells during meningitis) and has bactericidal effects against competing bacteria such as Staphylococcus aureus.

Neuraminidase and IgA protease
These exoenzymes produced by the bacteria have a presumptive role in virulence as they do in other pathogens.

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Kenneth Todar is an emeritus lecturer at University of Wisconsin-Madison. He has taught microbiology to undergraduate students at The University of Texas, University of Alaska and University of Wisconsin since 1969.

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