Defense Wins Ball Games

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Science Translational Medicine  03 Oct 2012:
Vol. 4, Issue 154, pp. 154ec177
DOI: 10.1126/scitranslmed.3005012

“When life gives you a hundred reasons to cry, show life that you have a thousand reasons to smile.”* Bacteria heed this advice well in their responses to attack from the host immune system and to the evolutionary pressure imposed by use of antibiotics. Over and over again, physicians and scientists have observed the plasticity of infecting bacteria as they develop adaptational mechanisms that protect themselves from being killed. However, recent work by Agarwal and co-workers on the mechanism behind invasive Streptococcus pneumoniae infections reveals that we have observed just the tip of the iceberg.

The discovery and characterization of pathogen-specific evasion mechanisms and the subsequent exploitation of these pathways as therapeutic targets rank among the greatest challenges faced by biomedical scientists. Certain bacterial proteins have been shown to defend the microbes in their fight for survival against attack from the immune system. The authors found that S. pneumoniae’s enolase—a key enzyme that participates in the metabolism of sugars—allows the bacteria to avoid attack from the human complement system, a critical component of the nonspecific (innate) immune response. They demonstrated that enolase on the bacterial surface binds to and covers bacteria with host C4-binding protein (C4BP), which prevents activation of the complement system. Other proteins that bind C4BP have been found in microorganisms responsible for meningitis, diarrhea, and sexually transmitted diseases and have been shown to be critical for microbial survival. However, recruitment of C4BP to the bacterial surface is a new survival mechanism.

These results represent a breakthrough in the understanding of bacterial survival and pathogenesis and should spur further studies aimed at discovering new therapeutic interventions. The results also highlight major drawbacks for future studies: Enolase is vital in bacterial metabolism, so creating organisms with a mutated version of the enzyme is impossible. Furthermore, human and bacterial enolases are highly conserved, and the host immune system may recognize its own enolase as foreign and mount an autoimmune response. This characteristic makes enolase unlikely to be used as vaccine antigen.


V. Agarwal et al., Enolase of Streptococcus pneumoniae binds human complement inhibitor C4b-binding protein and contributes to complement evasion. J. Immunol. 189, 3575–3584 (2012). [Abstract]

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