Editors' ChoiceIMMUNITY

“Heads,” Flesh-Eating Disease; “Tails,” Just a Sore Throat

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Science Translational Medicine  19 Dec 2012:
Vol. 4, Issue 165, pp. 165ec232
DOI: 10.1126/scitranslmed.3005491

Necrotizing fasciitis and toxic shock syndrome are the most feared diseases caused by Streptococcus pyogenes; however, healthy humans carry this so-called “flesh-eating bug” in their throats. Why this germ remains benign in many cases but becomes rapidly fatal in others is not well understood. Now, new evidence demonstrates that in humans, the particular way that antibodies, or immunoglobulins (IgGs), bind to this bug—either by the head region (Fab) or the tail region (Fc)—may affect the clinical course.

Nordenfelt et al. used a bed-to-benchside approach to a clinical problem. They obtained samples from a patient with severe Streptococcus pyogenes necrotizing fasciitis and examined the bacteria using negative-staining electron microscopy. The authors imaged single IgG molecules and discovered different orientations of IgG binding to bacteria, depending on the anatomical site. Salivary bacteria from the throat bound the IgG-Fc tail, whereas the IgG-Fab head bound blood bacteria. In blood, the IgG formed a complex with fibrinogen and the previously described IgG-Fc binding M-protein on the bug. Within necrotic tissue, bacteria were devoid of IgG binding through shedding of the M-protein, which resulted in free complexes of IgG-fibrinogen–M-protein and possibly severe vascular dysfunction and edema. At low levels of IgG, bacteria predominately bound the Fc tail, whereas at high concentrations, Fab binding dominated. These observations explain why in saliva—a low IgG environment—there is Fc binding, whereas in blood—a high IgG environment—bacteria are predominantly bound by the Fab head. Importantly, bacteria coated with Fc-binding IgG resisted phagocytosis and, if engulfed, were capable of intracellular survival. In blood, however, IgG-Fab binding to bacteria caused complement deposition, resulting in improved phagocytosis and killing. Therefore, the orientation, heads or tails, of IgG binding correlates with either benign bacterial colonization or severe infection and necrosis.

This human translational study is important for a number of reasons. First, these observations could not have been made by using animal models because only human IgG is capable of binding the streptococcal M-protein. Second, it demonstrates mechanistic differences between host-microbial interactions during colonization versus infection. And last, it highlights that nonspecific adjunctive therapy for severe streptococcal infections, such as intravenous immunoglobulin, could be further refined to improve therapeutic effectiveness.

P. Nordenfelt et al., Antibody orientation at bacterial surfaces is related to invasive infection. J. Exp. Med. 209, 2367–2381 (2012). [PubMed]

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