Pneumococcal disease

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University of Oklahoma Study Abroad Microbiology in Arezzo, Italy[1]
Scanning electron microscope image of Yersinia pestis. From: [2]



| Domain = Bacteria | Phylum = Firmicutes | Class = Bacilli | Order = Lactobacillales | Family = Streptococcaceae | Genus = Streptococcus | Species = S. pneumoniae (1)

NCBI: Taxonomy Genome: Genome



Streptococcus pneumoniae is a Gram-positive, non-motile, non-spore-forming bacterium (2). S. pneumoniae cells appear as lance-shaped cocci and typically form in pairs (diplococci) but can also appear as single cocci or cocci chains (2, 3). Single S. pneumoniae cells range from 0.5-1.25 µm in diameter (2). Pneumococcal cells lack the M protein on its surface as virulence factor, distinguishing it from other streptococci (2). The cell wall of pneumococci contains peptidoglycan and techoic acid, with the techoic acid attached to every third N-acetylmuramic acid (2). The cell membrane of S. pneumoniae has lipotechoic acid attached to it through a lipid moiety (2). S. pneumoniae contains an estimated 500 proteins on its surface, and many strains exhibit pili (2). A polysaccharide capsule also covers the exterior of S. pneumoniae (2). Serotypes of S. pneumoniae are determined by the structure of the capsule, 93 of which have been presently identified (15).


S. pneumoniae is a fastidious bacterium that grows optimally at 35-37°C with approximately 5% carbon dioxide (CO2 ) (3). Pneumococcal cultures require a source of catalase in order to neutralize the hydrogen peroxide (H2O2) produced by the bacterium as a means of competing with other commensal bacteria (2). Because of this, it is typically grown on blood agar (as a source for catalase) but can also be cultured on a chocolate agar plate (2, 3). S. pneumoniae is an alpha-hemolytic bacterium and will produce a green-colored zone on blood agar (2, 3). On this medium, S. pneumoniae colonies appear as small, grey, and moist colonies (3). Serotypes 3 and 37 appear mucoid on blood agar (2). S. pneumoniae is also a fermentative aerotolerant anaerobe (2). The generation time of S. pneumoniae on blood agar is 20-30 minutes (2). Pneumococcal colonies appear raised during the first 24 hours of growth, but between 24-48 hours, the colonies flatten, and the central portion of the colonies depress (3).



Transmission of S. pneumoniae occurs through coughing, sneezing, or person-person oral contact via microaerosol droplets from the nasopharynx of human carriers (4, 5). In addition, transmission can occur through autoinoculation in those who carry S. pneumoniae in their upper respiratory tract (5). Crowding, season, and upper respiratory infection or pneumococcal disease in the host are factors that influence the transmission of the bacterium (5). Though transmission is common, infection is infrequent due to the ability of hosts to asymptomatically carry S. pneumoniae in the nasopharyngeal region (6).

Infectious dose, incubation, colonization

The infectious dose (ID50) of S. pneumoniae is unknown for humans (7). However, research on animal models has shown that S. pneumoniae is able to cross the blood-brain barrier at 104 bacteria and can cause sepsis or pneumonia at 107 and 108 bacteria, respectively (7). The incubation period S. pneumoniae is one to three days (5). S. pneumoniae colonizes the nasopharyngeal and upper respiratory airway mucosae (8). In the nasopharynx, S. pneumoniae enables Staphylococcus aureus and Haemophilus influenzae to colonize, while competing for nutrients as well (10). If S. pneumoniae is allowed to uncontrollably colonize the lung, meninges, or middle ear, the bacterium will lyse and trigger inflammation (9).


S. pneumoniae is an endemic pathogen worldwide and causes serious disease in children living within developing countries (11). Diseases caused by S. pneumoniae include: acute otitis media, sinusitis, pneumonia, and bacterial meningitis (12, 13). In developing countries, it is estimated that pneumococcal pneumonia kills more than one million children under the age of five per year (11). The most susceptible age groups to S. pneumoniae are children less than two years of age and adults over 65 (14). Though the incidence of pneumococcal pneumonia did not significantly change during the 20th century, the discovery of antibiotics decreased the fatality rate significantly (12). In the Western world, yearly pneumonia incidence is 1% (14). Serotypes of S. pneumoniae are capable of exchanging genetic material with each other to recombine their genomes (16). Because of this, antibiotic resistance has developed worldwide, particularly in the serotypes that most commonly affect children (14).

Virulence factors


The capsule and pili contribute to the virulence of S. pneumoniae. The first step in pneumococcal invasion of the host is attachment via pili to epithelial cells of the upper respiratory tract (2). Pili are encoded by the rlrA islet, and experiments on nonpilated vs. pilated pneumococci have demonstrated that the pilated bacteria adhere to the host cells in greater numbers than nonpilated bacteria (2).


The polysaccharide capsule of S. pneumoniae serves as a protective mechanism from the host immune response (2). When the complement pathway is activated, the capsule resists phagocytosis by interfering with the binding of the complement protein C3b to the pneumococcal surface (2).

Pneumococcal surface protein A

Pneumococcal Surface Protein A (PspA) is surface protein located on the cell wall of S. pneumoniae (17, 18). The function of PspA is to inhibit opsonization and phagocytosis of pneumococci by the host’s complement system (2). PspA carries a highly polar electrostatic charge (19). The negatively charged end of the protein inhibits complement activation (19). Mice that received antibodies against PspA acquired passive protection to S. pneumoniae, demonstrating the effect of PspA on the virulence of S. pneumoniae (2).

Hyaluronate lyase

Hyaluronate Lyase (Hyl) is another surface protein expressed by most strains of S. pneumoniae (20). Hyl is a member of the hyaluronidase enzyme group, which enables tissue invasion of pathogens mainly through the hydrolysis of extracellular matrix components (21, 22). In S. pneumoniae, Hyl degrades hyaluronan in connective tissues, which increases tissue permeability and ease of pneumococcal entry to the host (23). Increased tissue permeability through the action of Hyl has been linked to wound infections, pneumonia, bacteremia, and meningitis (24).


Pneumolysin (Ply) is a cytoplasmic enzyme that contributes to the evasion of host physical barriers by S. pneumoniae. Ply kills ciliated bronchial epithelial cells through cytotoxicity, slows ciliary beating, and disrupts tight junctions of the bronchial epithelial monolayer (25, 26). Because of this, it is more difficult for the host to clear mucus from the lower respiratory tract, which enables the spread and infection by S. pneumoniae (24). Ply also has a cytotoxic effect on alveolar epithelial cells and pulmonary endothelial cells (27). The disruption of the alveolar-capillary boundary causes edema and hemorrhage and subsequent alveolar flooding, which provides nutrients for the pneumococci (27). In addition, the alveolar flooding allows S. pneumoniae to enter the pulmonary interstitium and then the bloodstream (27). Ply also interferes with the immune response by inhibiting neutrophil and monocyte activity as well as antibody and cytokine production (27).


Autolysins, which are enzymes that degrade bacterial cell walls and lead to cell lysis, contribute to the pathogenicity of S. pneumoniae (28). Pneumococci utilize three main autolysins: LytA, LytB, and LytC (24). By lysing cell walls, LytA causes the cell wall components to trigger inflammation in the host (29). In addition, LytA releases cytoplasmic bacterial proteins to the host environment, including additional virulence factors such as Ply, whose activity is dependent on autolysin activity (24, 30). The functions of LytB and LytC have been less studied than that of LytA, but it is known that LytB is a glucosaminidase that causes cell separation, and that LytC functions similarly to a lysozyme (2).

Pneumococcal surface antigen A

Pneumococcal surface antigen A (PsaA) is a protein attached to the cell membrane of S. pneumoniae with a covalently attached lipid component (31). The function of PsaA is to transport Mn2+ and Zn2+ into the cytoplasm (32).

Choline binding protein A (CbpA)

Choline binding protein A (CbpA) is an adhesin on the surface of S. pneumoniae (24). CbpA belongs to the choline binding protein (CBP) family along with PspA and LytA due to the common choline binding motif (24). CbpA enables pneumococci to adhere to host tissues and colonize by binding the platelet-activating factor (PAF) receptor of host cells (33).


Neuraminidase is an enzyme that is theorized to enhance the colonization of S. pneumoniae to host cell surfaces (34). Host cells express glycans on their surface, which includes molecules such as mucin, glycolipids, and glycoproteins (24). Neuraminidase cleaves terminal sialic acid from the glycans, which most likely changes the glycosylation patterns of the host cells, reveals surface receptors, and enables S. pneumoniae to adhere to the host cells (35). Neuraminidase exists in two forms: NanA and NanB, though the reason behind this redundancy is unclear (24).

Immunoglobulin A (IgA) protease

Immunoglobulin A (IgA) protease is an exoenzyme of S. pneumoniae that cleaves IgA into Fab and Fc fragments (2, 38). Though the action of IgA protease has been observed in humans, its significance in the pathology of S. pneumoniae has not been well-studied due to the inability of an animal model to demonstrate IgA cleavage (38).

Clinical features


The symptoms of Yersinia pestis present in different ways, but the three most common are bubonic, septicemic, and pneumonic plague. [23]

Bubonic Plague

This type of plague usually results from the bite of an infected flea. Once infection sets, the patient has sudden onset of fever, headache, chills, weakness, and the development of swollen nodes known as buboes, where isolated bacteria multiply and grow. If not treated the bacteria can spread to other areas [23] .

Septicemic Plague

This type of plague can either develop primarily or as a result from untreated bubonic plague. Symptoms from this include bleeding into the skin and other organs ranging to tissue blackening and death, especially in the fingers, toes, and the nose. [23]

Pneumonic Plague

This type of plague either develops from inhaling infectious droplets or from untreated bubonic/septicemic plague and bacteria spreading to the lungs. At this point the plague is infectious and can be spread from person to person by infectious droplets. Symptoms from this type of plague include fever, headache, weakness, and a developing pneumonia that heightens symptoms of cough, chest pain and shortness of breath. [23]

Morbidity and Mortality

Worldwide, the number of cases reported to the World Health Organization range between 1000 and 2000 per year. However, according to WHO, the real number is likely much higher. Because of this, it is difficult to assess mortality rate, especially in developing countries with poor diagnostics and under reporting. The mortality rate cited by WHO, is between 8-10%, but again, the predicted percentage is expected to be much higher. [24]


Diagnoses of the plague are usually reported to a state public health lab. The most common sign of the plague is the development of bubo, swollen lymph nodes, after a fleabite. Usually, blood from the patient and parts of the swollen lymph nodes are submitted to a Level A lab for testing. For a culture ID, blood is checked for a positive blood culture, with BACTEC Media and SEPTI-CHEK BHI. Next, it is cultured on TSA w/5% Sheep Blood/MacConkey II Agar, and incubated for 24 hours at 28°C. The colonies should be gray-white, translucent, little to no hemolysis, and be non-lactose fermentor. Afterwards, it should test positive for catalase, but negative for oxidase and Christensen’s Urea Slant.[25]



Individuals suspected of infection from Yesinia pestis should be immediately admitted to hospitals for isolation and proper management. A number of powerful antibiotics are used to treat the illness, with streptomycin usually prescribed as the primary drug of choice. Other possible antibiotics include gentamicin, chloramphenicol, tetracyclines, and fluoroquinolones. [26] The antibiotic levofloxacin has also been recently approved by the Food and Drug Administration as appropriate treatment.[27] Antibiotic dosages are typically administered for the full period of ten days or for three days after the fever has subsided. However, the selection of antibiotic therapy is crucial, as several classes of antibiotics have proven to be ineffective in treatment for the plague. These include penicillins, cephalosporins, and macrolides.[28]


Prophylactic therapy is a common mode of treatment for individuals who have been exposed to potentially infected individuals. Patients with possible exposure to Y. pestis should be administered antibiotics if the exposure occurred within the span of six days as a means of preventative therapy.

The usage of prophylactic therapy may also be used as a preventative measure for individuals who must be, for short periods of time, involved in circumstances where the potential of infection may be unavoidable.[28]


Yersinia pestis can be transmitted to humans from the bites of inflected fleas or handling of plague-infected tissues. In the case of plague pneumonia, transmission can occur via inhalation of the cough droplets from another infected individual. While no available vaccine currently exists, several effective means of prevention are to diminish the possibility of rodent infestation around homes by clearing away cluttered debris within the vicinity and to apply flea control products for pets that roam freely in the open. The application of insect repellent for individuals in outdoor areas is an effective measure for protection against flea bites. Any contact with potentially infected animals should be limited, and the usage of gloves as a barrier against possible transmission should be utilized when necessary.[26]

Means of prevention can also be applied in hospital settings where the possibility of transmission can be high. Standardized procedures of handwashing and utilization of gowns, latex gloves, and protective devices should be followed to protect all body orifices from coming into contact with Y. pestis. Restrictions of patients suspected with plague should be enacted to prevent the spread of disease to other individuals. This includes isolated treatment of infected patient as well as the inhibition of movement of the patient outside of the isolation room until the infection ceases to exist.[28]

Host Immune Response

The host innate immune response involves macrophages, inflammation, and the activation of the complement cascade. However, Yersinia pestis has evolved different mechanisms for evading this immune response, both in the innate and adaptive immune response.[29]

Attack on Innate Immune Response

Most of the Y. pestis bacteria are killed off by encounter with neutrophils and many that survive manage are a special subtype (facultative Y. pestis). Using the macrophages, they are then able to proliferate and express different virulence factors, before the spread systemically throughout the body. In addition, the LPS (lipopolysaccharide) structure in this organism allows the bacteria to become resistant to serum-mediated lysis during its transition from its flea vector to animal host. The bacteria coming from the macrophages, therefore, are resistant to phagocytosis and can inhibit the production of proinflammatory cytokines, which in turn attenuates the adaptive immune response of the host. Yet another immune response that is affected is the complement pathways. The complement cascade of the innate immune response (which is initiated by macrophages binding to foreign antigen) has three different effector functions: opsonization (which leads to phagocytosis), inflammation, and the formation of a membrane-attack complex (which leads to direct killing of the pathogen). However, Y. pestis has developed a resistance to complement-mediated lysis in an effort to survive transmission between flea and animal. In addition, during replication within a macrophage, the bacteria form a needle-like complex that (once released from the macrophage) they use to inject six different effector proteins into different cells to further inhibit the immune response. These proteins are called Yops proteins and have different functions that benefit the pathogen. Targets for this injection include macrophages, dendritic cells, and neutrophils. Besides paralyzing these phagocytic cells, these proteins also target the proinflammatory recruitment response initiated by infected cells. Finally, these proteins also target NK cells, which further inhibit the innate immune response. [29]

Attack on Adaptive Immune Response

Because the innate immune response has been so severely affected, the adaptive immune system cannot be properly initiated. Dendritic cells (which are the cells that link between the innate and adaptive immune response) are targeted early on, and as a result the activation of the adaptive immune response is hindered because dendritic cells cannot mature and start T-cell mediated immune response. Because of this, the humoral response (B-cell response) cannot be properly triggered.[29,[30].

Host Immune Response

In order to combat the Y. pestis infection, the host cell must reactivate its specific humoral and cellular response mechanisms to establish a protective immunity. This involves neutralizing virulence factors and delivering antibody/antigen complexes to B cells, macrophages, and dendritic cells (which promotes T-cell activation).[30] Often times, this activation is a result of the very pathology of the organism. Although the bacterium attenuates the inflammatory response and causes apoptosis of naïve macrophages, activated macrophages are killed by a process known as pyroptosis. Interestingly, this process has the opposite effect and activates the previously attenuated inflammatory response, and benefits the host further by accelerating and amplifying this response to combat the bacterial infection and stimulate proper immune response pathways. Hyper-inflammation, however can result in tissue damage and organ malfunction.[30]