Evasion of the Immune System

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S. pyogenes infections are normally secondary infections; streptococci normally only infect an individual after another infection (usually viral), or after disruptions in his or her normal bacterial flora. The skin typically is able to prevent strep infections, and many host actions, such as coughing and sneezing, usually prevent the bacteria from entering the host beyond the superficial epithelium of the upper respiratory tract (Todar 2002).

Streptococci have many different mechanisms for evading the innate immune response, allowing the bacteria to successfully infect the host. Voyich et al. (2003) discovered that after only 30 minutes of in vitro incubation with S. pyogenes, approximately 33% of polymorphonuclear leukocytes phagocytosed the bacteria. However, the amount of phagocytosis leveled off at approximately 50% after 60 minutes. These observations were supported by a similar trend of the percentage of streptococci killed, which also leveled off after 30 minutes. Using microarrays and real-time RT-PCR, the investigators determined that the bacteria’s apparent resistance to polymorphonuclear leukocytes was due to changes in gene expression throughout the bacteria’s genome. Several proteins known to affect the bacteria’s virulence, such as different exotoxins, were upregulated, as were other proteins known to enable S. pyogenes to evade the immune system, such as the sic (streptococcal inhibitor of complement) protein. Also 11 other proteins were upregulated, but their functions are unknown at this time, presenting researchers with new investigation topics (Voyich et al. 2003).

DNases have also been implicated in helping GAS evade the innate immune response. After infecting mice with wild-type S. pyogenes, researchers found areas of killed polymorphonuclear leukocytes and live bacteria. However, after infecting mice with a knockout strain of S. pyogenes missing all DNases, researchers noted less necrosis, reduced numbers of bacteria, and more live leukocytes after 32 hours compared to the mice infected with wild-type bacteria. All S. pyogenes strains have multiple DNase genes in their genomes. The exact mechanism behind how DNases aid in the evasion of the innate immune response is unknown, although the researchers hypothesize that the enzyme disrupts the neutrophil extracellular traps (NETs), structures that contain chromatin and kill bacteria without phagocytosis(Sumby et al. 2005).

GAS has still more ways of evading the innate immune response. It is thought that the recently discovered ability of the bacteria to live inside macrophages evolved as a way to avoid killing by the innate immune response (Thulin et al. 2006). Also, many of the extracellular substances secreted by the bacteria counteract the innate immune response. For example, GAS produces C5a peptidase, a protein that interrupts the complement cascade. The bacteria also produce different proteins that kill neutrophils, such as streptolysins O and S (Todar 2002).

GAS is also able to evade the adaptive immune response. Because of their hyaluronic acid capsule, streptococci are able to minimize the host's humoral immune response. Due to its similarity to human connective tissue, the hyaluronic capsule is only weakly antigenic, and as a result does not cause the production of antibodies specific to the capsule. And because the capsule encloses an entire bacterium, it is able to hide most of the bacterial proteins that would otherwise result in a humoral immune response. In fact, the only antibodies that are produced against S. pyogenes are specific to the M protein, as it is actually extends through the hyaluronic acid capsule. Thus by hiding most of its antigenic proteins by the hyaluronic acid capsule, S. pyogenes is able to limit the humoral immune response of the host (Todar 2003).

Further, the amino acid sequence of the M protein is extremely variable. The M protein contains a hypervariable region (HVR) that is approximately 50 residues long and is found at the N-terminus of the protein. Because of the presence of the HVR, approximately 120 different M types have been identified (Persson et al. 2006). Even if a host does mount a humoral response against a streptococcal infection, the memory of that infection is useless if the host is infected with a different M type strain.

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