Editors' ChoiceHost Defense

Immune from It All

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Science Translational Medicine  05 Sep 2012:
Vol. 4, Issue 150, pp. 150ec161
DOI: 10.1126/scitranslmed.3004843

Mucosal surfaces in our guts and airways are “points of first contact” with elements of the outside world, and many of the same biological mechanisms at play in our guts are also at play in our lungs. Thus, it is no surprise that these surfaces are both equipped with immune and host defense machinery that serve to protect us against infections, both viral, bacterial, and beyond. The herpes virus entry mediator (HVEM), a member of the tumor necrosis factor receptor family, plays an important anti-inflammatory role in colitis, but its function in mucosal immunity is largely unknown. Now, Shui et al. explore the potential participation of HVEM in epithelial barrier integrity and host innate mucosal defense against pathogenic bacteria in the guts and lungs of mice.

The authors used Hvem–/–mice to assess HVEM’s role in orchestrating mucosal immune responses in colonic and lung epithelium and then delineated the underlying mechanisms of action. The most compelling finding of Shui et al. is that HVEM plays a critical role in lung host defense. The authors discovered that Hvem–/–mice were highly susceptible to infection with the bacteria Streptococcus pneumonia, which is the most common cause of community-acquired pneumonia. These mice displayed impaired early host responses, a reduced bacterial elimination in the lung, reduced activation of signal transducer and activator of transcription 3 (STAT3) (which is necessary to limit bacterial pneumonia), and a marked reduction in the expression of key epithelial host defense genes, such as those that encode interleukin-6, interferon-γ, CXCL2, CCL20, and S100A9. These animals also had significantly higher bacterial colony counts and reduced overall survival as compared with those of wild-type controls. HVEM was also shown to be a key regulator of epithelial innate responses by mediating lymphocyte-epithelial communication to optimize host defense responses.

These findings have the potential for rapid translation into the clinical realm, first through preclinical testing of HVEM agonists in animals and then potentially in clinical trials for treatment of diseases such as pneumonia, cystic fibrosis, suppurative bronchiectasis, and chronic obstructive pulmonary disease. Boosting of our mucosal defenses in lung directly with inhaled agonists might be an exciting next chapter in HVEM research.

J. W. Shui et al., HVEM signalling at mucosal barriers provides host defense against pathogenic bacteria. Nature 488, 222–225 (2012). [Full Text]

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