In the late nineteenth century, pairs of micrococci were first recognized in the blood of rabbits injected with human saliva by both Louis Pasteur working in France and George Sternberg, an American army physician. The important role of these micrococci in human disease was not appreciated at that time. By 1886, when the organism was designated “pneumokokkus” and Diplococcus pneumoniae, the pneumococcus had been isolated by many independent investigators, and its role in the etiology of pneumonia was well known. In the 1930s, pneumonia was the third leading cause of death in the United States (after heart disease and cancer) and was responsible for ∼7% of all deaths both in the United States and in Europe. While pneumonia was caused by a host of pathogens, lobar pneumonia—a pattern more likely to be caused by the pneumococcus—accounted for approximately one-half of all pneumonia deaths in the United States in 1929. In 1974, the organism was reclassified as Streptococcus pneumoniae.
Pneumococci are spherical gram-positive bacteria of the genus Streptococcus. Within this genus, cell division occurs along a single axis, and bacteria grow in chains or pairs—hence the name Streptococcus, from the Greek streptos, meaning “twisted,” and kokkos, meaning “berry.” At least 22 streptococcal species are recognized and are divided further into groups based on their hemolytic properties. S. pneumoniae belongs to the α-hemolytic group that characteristically produces a greenish color on blood agar because of the reduction of iron in hemoglobin (Fig. 134-1). The bacteria are fastidious and grow best in 5% CO2 but require a source of catalase (e.g., blood) for growth on agar plates, where they develop mucoid (smooth/shiny) colonies. Pneumococci without a capsule produce colonies with a rough surface. Unlike that of other α-hemolytic streptococci, their growth is inhibited in the presence of optochin (ethyl hydrocuprein hydrochloride), and they are bile soluble.
Pneumococci growing on blood agar, illustrating α hemolysis and optochin sensitivity (zone around optochin disk). Inset: Gram's stain, illustrating gram-positive diplococci. (Photographs courtesy of Paul Turner, Shoklo Malaria Research Unit, Thailand.)
In common with other gram-positive bacteria, pneumococci have a cell membrane beneath a cell wall, which in turn is covered by a polysaccharide capsule. Pneumococci are divided into serogroups or serotypes based on capsular polysaccharide structure, as distinguished with rabbit polyclonal antisera; capsules swell in the presence of specific antiserum (the Quellung reaction). The 91st and 92nd serotypes, 6C and 6D, have most recently been identified with monoclonal antibodies and by serologic, genetic, and biochemical means, respectively. Within the 92 serotypes there are 21 serogroups, each containing two to five serotypes with closely related capsules. The capsule protects the bacteria from phagocytosis by host cells in the absence of type-specific antibody and is arguably the most important determinant of pneumococcal virulence. Unencapsulated variants tend not to cause invasive disease.
Within the cytoplasm, cell membrane, and cell wall, many molecules that may play a role in pneumococcal pathogenesis and virulence have been identified (Fig. 134-2). These proteins are often involved in direct interactions with host tissues or in concealment of the bacterial surface from host defense mechanisms. Pneumolysin is a secreted cytotoxin thought to result in cytolysis of cells and tissues, and LytA enhances pathogenesis. A number of cell wall proteins interfere with the complement pathway, thus inhibiting complement deposition and preventing lysis and/or opsonophagocytosis. The pneumococcal H inhibitor (Hic) impedes the formation of C3 convertase, while pneumococcal surface protein C (PspC), also known as choline-binding protein A (CbpA), binds factor H and is thought to accelerate the breakdown of C3. PspA and CbpA inhibit the deposition of or degrade C3b. The numerous pneumococcal proteins thought to be involved in adhesion include the ubiquitous surface-anchored sialidase (neuraminidase) NanA, which cleaves sialic acid on host cells and proteins, and pneumococcal surface adhesin A (PsaA). Pili recently recognized by electron microscopy may also play an important role in binding to cells. Some of the antigens mentioned above are potential vaccine candidates (see “Prevention,” below).
Schematic diagram of the pneumococcal cell surface, with key antigens and their roles highlighted.
Although the capsule surrounding the cell wall of S. pneumoniae is the basis for categorization by serotype, the behavior and pathogenic potential of a serotype may also be related to the genetic origin of the strain. Molecular typing is therefore of considerable interest. Initially, techniques such as pulsed-field gel electrophoresis were used to determine genetic relatedness; such techniques have been superseded by sequencing of housekeeping genes to define a clone (multilocus sequence typing, MLST). For S. pneumoniae, alleles at each of the loci aroE, gdh, gki, recP, spi, xpt, and ddl are sequenced and compared with all of the known alleles at that locus. Sequences identical to a known allele are assigned the same allele number, whereas those differing from any known allele—even at a single nucleotide site—are assigned new numbers. Software for assignment of alleles at each locus is available on the pneumococcal MLST web site (http://spneumoniae.mlst.net/), and the allelic profile of each isolate and its consequent sequence type are generated. With the advent of high-throughput and relatively inexpensive sequencing techniques, whole-genome sequencing will soon supersede MLST.
Pneumococcal infections remain a significant global cause of morbidity and death, particularly among children and the elderly. Rapid and dramatic changes in the epidemiology of this disease during the past decade in several developed countries followed the licensure and routine childhood administration of pneumococcal polysaccharide–protein conjugate vaccine (PCV). With PCV introduction ...