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  Bacterial identification
  in the diagnostic 
  laboratory versus 
  taxonomy

Streptococcus pneumoniae
Drug Resistant 
  S. pneumoniae (DRSP)

Mode of Infection and 
  the Immune Response
 

Vaccine Development
Bacterial Defense against
   the Host Immune 
   Responses

Antigenic Variation



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   Streptococcus pneumoniae    

NAME: Streptococcus pneumoniae

SYNONYM OR CROSS REFERENCE: Pneumococcus, Diplococcus, Pneumococcal pneumonia

CHARACTERISTICS: Gram-positive diplococci, alpha hemolysis on blood agar, no specific group antigen

PATHOGENICITY: Sudden onset with shaking chill, pleural pain, dyspnea, a cough productive of rusty sputum and leukocytosis; clinical features include pneumonia, bacteremia, otitis media, meningitis, sinusitis, peritonitis and arthritis; onset may be less abrupt in elderly requiring x-rays for diagnosis; in infants, vomiting and convulsions may be initial manifestations; important cause of death in infants and elderly; 5-10% fatality with antimicrobial therapy, but 20-40% among patients with underlying disease; neurologic sequelae and/or learning disabilities can occur in meningitis patients

DRUG SUSCEPTIBILITY: Sensitive to penicillin and erythromycin

DRUG RESISTANCE: High level of resistance to penicillin; resistance to other therapeutic agents such as TMP/SMX, erythromycin, tetracycline, chloramphenicol, ceftriaxone, and cefotaxime

SUSCEPTIBILITY TO DISINFECTANTS: Susceptible to many disinfectants - 1% sodium hypochlorite, 70% ethanol, 2% glutaraldehyde, formaldehyde, iodines

PHYSICAL INACTIVATION: Sensitive to moist heat (121° C for at least 15 min) and dry heat (160-170° C for at least 1 hour)

SURVIVAL OUTSIDE HOST: Mouse carcass - 180-270 days; Dust - up to 25 days; Glass - 1-11 days; Sputum at room temperature - 7 days; Gauze 2-15 days

FIRST AID/TREATMENT: Penicillin G, administered parenterally (erythromycin for those hypersensitive to penicillin)

IMMUNIZATION: Polyvalent vaccine containing capsular polysaccharides for those at high risk of fatal infection (vaccine should be given only once to adults to avoid systemic reactions to a second dose); vaccine is less effective in those under 2 years of age

PROPHYLAXIS: Penicillin treatment

LABORATORY-ACQUIRED INFECTIONS: 78 recorded cases of Streptococcus spp. with 4 deaths up to 1976; 5th most common laboratory-acquired infection

SOURCES/SPECIMENS: Sputum, blood, respiratory secretions, throat swabs

PRIMARY HAZARDS: Inhalation of infectious aerosols; direct contact of mucous membranes; accidental parenteral inoculation

Due to its ability to acquire multidrug resistance, Streptococcus pneumoniae has once again become a major global public heath problem [30]. This in turn has increased the danger of pneumococcal meningitis caused by S. pneumoniae [31]. In the United States, S. pneumoniae has been on the rise since 1987 [32]. Even with antibiotics and intensive care, the bacteria causes excess morbidity and mortality in young children, the elderly and patients with medical problems [30].

Drug Resistant S. pneumoniae

There are 90 serotypes of S. pneumoniae [32]. The strains are differentiated by the capsular polysaccharide coat, which stimulates the production of serotype-specific, protective antibody. The capsule protects the pneumococci from phagocytosis by polymorphonuclear leukocytes [33]. Virulence is based upon the chemical composition of the capsule and its size. The purified capsular protein itself does not stimulate an inflammatory response when delivered directly into the lung, which suggests it is not necessary for inflammation, but contributes to the infectivity of the S. pneumoniae [33].

Initially, S. pneumoniae was found to be susceptible to penicillin [34]. In 1977 a strain highly resistant to penicillin emerged in South Africa. Penicillin resistance and multidrug resistance have spread worldwide [35]. There are actually 4 strains which are responsible for most disease and drug-resistant S. pneumoniae (DRSP). These are strains 6B, 14, 19 and 23F [32]. For example, serotype 23F, which most likely originated in Spain, is now found in Mexico, South Africa, South Korea, Portugal, Croatia, France and the United States [35]. Many penicillin resistant strains are also resistant to other drugs such as chloramphenicol, erythromycin, tetracycline and trimethoprim-sulfamethoxazole [36]. There are numerous reports regarding the failure of antibiotics to treat meningitis because the pneumococci are resistant [35]. Between 3-35% of pneumococcal illness is due to DRSP, and the bacteria causes at least 15,000 cases of meningitis annually [32].

 

Mode of Infection and the Immune Response

Figure 1: S. Pneumoniae under the microscope appears as small, dark dots. Source: University of Texas-Houston Medical School, [38].

Pneumococcal meningitis is caused by direct spreading from the nasopharynx to the meninges or by hematogenous spread [30]. In hematogenous spread the bacteria usually initially infect the lungs, causing pneumonia. Infection spreads to the blood resulting in bacteremia. From the blood the bacteria is able to traverse the blood-brain barrier and infect the meninges [30, 37]. Diagnosis may be achieved by the isolation of S. pneumoniae from body fluids such as blood, spinal fluid or urine. Sputum may be analyzed by a Gram stain; S. pneumoniae is a Gram-positive coccus [30, 37].

The mucosal epithelium of the nasopharynx is the primary site of pneumococcal colonization [33]. Binding to the nasopharynx is dependent upon introconversion between two phenotypes: opaque and transparent. Only the transparent phenotype is able to persist in the nasopharynx in vivo [33]. Colonization involves pneumococcal surface adhesins which bind those epithelial cell receptors which display glycoconjugates with the disaccharide GlcNAcl-4Gal [37].

Figure 2: The inflammatory response to pneumococcal cell walls. 
In this case the lung is the site of infection. See text for discussion. Source: The New England Journal of Medicine 332(19):1281

 

 

 

 

 

 

 

 

 

 

As stated earlier, S. pneumoniae may go directly to the meninges, or it may be aspirated into the lungs, spread to the blood and traverse the blood-brain barrier [30, 37]. The cell wall of pneumococcus bacteria is made of more than a dozen glycopeptides which are continuously inserted and released from the circumferential macromolecule [33]. Pneumococci adhere to platelet activating factor (PAF) receptors on cytokine activated cells by the phosphorylcholine in the teichoic acid component of their cell walls. Phosphorylcholine modulates the bioactivity of PAF, which results in the recruitment of leukocytes and platelets to the area [33, 37]. Leukocytes are also attracted by a selectin-CD18 integrin pathway which becomes actived during infection. The bacteria bind epithelia, endothelia and leukocytes and trigger production of interleukin-1 (IL-1), a key cytokine in the inflammatory response [33]. Among many functions, IL-1 increases vascular permeability and stimulates platelet production [39]. The cell wall is acted upon by components of the acute phase response and has the ability to fix complement. Cell wall components also enhance the permeability of the cerebral endothelia and pulmonary alveolar epithelia, stimulate cytokine production, activate the procoagulant cascade, damage neurons and affect cerebral blood flow and vascular-perfusion pressure [33].

Thus, due to the strong response created to the pneumococcal cell wall, the alternative complement pathway is activated prior to the production of specific anti-capsular antibody [37]. The result is complement fixation to pneumococci and clearance by the reticuloendothelial (RE) system (specifically the spleen). Once antibody to the capsule is formed, rapid opsonization and removal by the RE system results [37].

Figure 3: In the brain of a patient with acute meningitis from Streptococcus pneumoniae, a purulent exudate is visible beneath the meninges. Source: University of Utah School of Medicine, [40].

 

 

 

 

 

 

 

 



S.pneumoniae
does not damage by bacterial toxins, but rather because the cell wall elicits such a strong inflammatory response. In the meninges, lethal intracranial pressure builds as meningitis progresses [37]. The recruitment of leukocytes decreases the number of bacteria at the infection site, but S. pneumoniae becomes deadly due to the precipitation of the inflammatory response created when the pneumococci die, leaving their cell walls to disintegrate and releasing components such as pneumolysin [33]. The cell wall components which result from degradation by the body’s own defenses are much more effective chemoattractants than the intact cell walls. If the concentration of cell wall components exceeds 100,000 particles per milliliter, a rapid inflammatory response is initiated [33]. If a patient is able to survive this event, the decline in bacterial products will decrease the inflammatory response. The trouble is that many people, especially the elderly and very young, are unable to successfully withstand the response. The situation may be exacerbated by lysis of bacteria caused by antibiotics [33].

  

Vaccine Development

 Due to the difficulties in providing successful antibiotic treatment for S. pneumoniae, based on drug resistance and the exacerbation of the inflammatory response by bacterial lysis, vaccine development has been pursued. There currently exists a 23-valent capsular polysaccharide vaccine to protect against S. pneumoniae infection [34]. The decision to develop a capsular polysaccharide vaccine was based on the knowledge that antibodies formed against the capsule are very effective in preventing lethal S. pneumoniae infection. However, the antibodies formed against the capsule are type-specific, and as mentioned earlier, at least 90 different types of S. pneumoniae exist [34]. Thus, the vaccine was constructed using 23 of the most common strains. The vaccine has been very effective in young adults, but less successful in the elderly. Also, the vaccine does not stimulate adequate antibody responses in children under 2 years of age [34].

The possibility of creating polysaccharide-protein conjugate vaccines was proposed when work with animals found polysaccharides could be made more immunogenic if coupled to proteins. Capsular polysaccharides of pneumococcus have been joined to tetanus toxoid, diphtheria toxoid, CRM197 (a nontoxic form of diphtheria toxoid), pneumolysin and outer membrane proteins of meningococcus [34]. The tetanus and diphtheria toxoid conjugates have been the most successful. The problem in the case of S. pneumoniae remains that many different capsular types must be included. Thus, individual conjugates must be made and placed in a vaccine together [34]. A certain amount of conjugate is required to stimulate a specific immune response. Thus, the number of different strains which can be included is limited [34]. Also, as mentioned above, it has been found that children do not respond well to polysaccharides until they are over 2 years of age. Thus, it would seem that there is some disadvantage in making a vaccine which attempts to elicit such a response. This encouraged the search for substances other than capsular polysaccharides which could serve as antigens and provide protection against pneumococcal infection [34].

A number of protein antigens are exposed on or released from the surface of the pneumococcus. Antibodies to some of these proteins, pneumolysin, autolysin and neuraminidase, have demonstrated protective activity [34]. Monoclonal antibodies have been used in the detection of other potential surface antigens, one of which is pneumococcal surface protein A (PspA). The role of PspA in virulence is not clear, but it seems to retard the clearance of pneumococci from the blood, as antibody to PspA facilitates the clearance of pneumococci [34]. Further laboratory work has indicated that PspA immunization results in antibody rather than cell-mediated immunity. Immunization with PspA stimulated IgG production, and passive administration of anti-PspA IgG and IgM monoclonal antibodies prevents against fatal infection [34].

The human reservoir of pneumococci is maintained through nasopharyngeal carriage. A vaccine which would prevent carriage of the bacteria would protect in addition to immunized individuals, those who are not immunized and those who are unable to stimulate an adequate immune response [34]. It was found that immunization using the full-length of PspA prevented nasopharyngeal carriage. Conjugates of tetanus toxoid and capsular type 6B polysaccharide with cholera toxin B subunit as the adjuvant also prevented carriage [34].

Antigenic variation is a major issue in S. pneumoniae vaccine development as so many strains of the bacteria exist. PspA is actually one of the more variable gene products of S. pneumoniae [34]. However, PspA was found to be highly cross reactive as it provided cross-protection against challenge strains, though responses to some strains were more effective than to others. Also, the same PspA epitopes are present in different combinations on PspAs from different strains. PspA still remains to undergo human vaccine trials [34].

As evidenced by the preceding discussion, in the face of difficulties with vaccine treatment, a variety of vaccine possibilities are currently being researched to improve upon the 23 capsular polysaccharide vaccine against S. pneumoniae. It is hoped that by impeding the ability of S. pneumoniae to infect humans, the diseases associated with this bacteria, specifically pneumococcal meningitis in this case, may be prevented.

 

Bacterial Defense against the Host Immune Responses

© 2002 Kenneth Todar University of Wisconsin-Madison Department of Bacteriology

Bacterial Mechanisms to Overcome Host Immune Defenses

Antibody-mediated immunity (AMI) is the principal specific immune response effective against extracellular bacteria. The major protective immune response against intracellular bacteria is cell-mediated immunity (CMI).

On epithelial surfaces, the main antibacterial immune defense of the host is the protection afforded by secretory IgA. Once the epithelial surfaces have been penetrated, however, the major immune defenses of AMI and CMI are encountered.

If there is a way for an organism to successfully bypass or overcome the immune defenses, then some bacterial pathogen has probably "discovered" it. Bacteria evolve very rapidly in relation to their host, so that most of the feasible anti-host strategies are likely to have been tried out and exploited. Consequently, pathogenic bacteria have developed numerous ways to bypass or overcome the immune defenses of the host, which contribute to the virulence of the microbe and the pathology of the disease.

Antigenic Variation

One way bacteria can avoid forces of the immune response is to periodically changing antigens, i.e., to undergo antigenic variation. Some bacteria avoid the host antibody response by changing from one type of fimbriae to another, or by switching fimbrial tips. This makes the original AMI response obsolete by using new fimbriae that do not bind the previous antibodies. Pathogenic bacteria can vary (change) other surface proteins, especially outer membrane proteins, that are the targets of antibodies.

Antigens may vary or change within the host during the course of an infection, or alternatively antigens may vary among multiple strains (antigenic types) of a parasite in the population. Antigenic variation is an important mechanism used by pathogenic microorganisms for escaping the neutralizing activities of antibodies. Antigenic variation usually results from site-specific inversions or gene conversions or gene rearrangements in the DNA of the microorganisms.

Many pathogenic bacteria exist in nature as multiple antigenic types or serotypes, meaning that they are variant strains of the same pathogenic species. For example, there are multiple serotypes of Salmonella typhimurium based on differences in cell wall (O) antigens or flagellar (H) antigens. There are 80 different antigenic types of Streptococcus pyogenes based on M-proteins on the cell surface. There are over one hundred strains of Streptococcus pneumoniae depending on their capsular polysaccharide antigens. Based on minor differences in surface structure chemistry there are multiple serotypes of Vibrio cholerae, Staphylococcus aureus, Escherichia coli, Neisseria gonorrhoeae and an assortment of other bacterial pathogens. Antigenic variation is prevalent among pathogenic viruses as well.

If the immune response is the main defense against a pathogen, then being able to shed old antigens and present new ones to the immune system might allow infection or continued invasion by the pathogen to occur. Furthermore, the infected host would seem to be the ideal selective environment for the emergence of new antigenic variants of bacteria. Perhaps this explains why many bacteria exist in a great variety of antigenic types.

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