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Pneumonia Therapy Blazes a New TRAIL

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Science Translational Medicine  07 Nov 2012:
Vol. 4, Issue 159, pp. 159ec204
DOI: 10.1126/scitranslmed.3005252

Streptococcus pneumoniae is a leading cause of community-acquired pulmonary infection. Even though these bacteria are generally sensitive to antibiotics, streptococcal infection often results in severe invasive disease, such as septic shock, and mortality remains high; therefore, nonantibiotic or disease-modifying approaches are necessary. A recently discovered molecular pathway mediating cell death in the lung now looks like a promising pathway to novel therapeutics for streptococcal pneumonia.

A prevailing theory is that severe streptococcal pneumonia results from an overwhelming host inflammatory response, which causes tissue and organ damage. Steinwede et al. investigated how programmed cell death, or apoptosis, of alveolar macrophages restrains the inflammatory response, improving outcomes. Using a mouse model of pneumococcal pneumonia, the authors found a higher mortality in animals genetically deficient in the tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL). In wild-type mice, some TRAIL was bound on the outer cell surface of alveolar macrophages, but activated neutrophils were the major source of this molecule, which triggered apoptosis in macrophages infected with S. pneumoniae. In TRAIL-deficient mice, however, the alveolar macrophages became necrotic and not apoptotic, and the animals could not effectively clear bacteria from their lungs. Necrosis, a nonprogrammed form of cell death, heightened the release of the proinflammatory cytokines TNF, interleukin-6, and interferon-γ. The absence of neutrophils, via depletion by antibodies, also dramatically reduced lung TRAIL levels and subsequent macrophage apoptosis. In contrast, giving recombinant TRAIL to mice with pneumococcal pneumonia 6 hours into the infection resulted in greatly improved survival. Mice treated with TRAIL had reduced lung inflammation, enhanced bacterial killing, and evidence of improved lung tissue repair. An antibody that stimulated the TRAIL receptor also improved the animals’ survival, even when neutrophils were depleted. Therefore, either the addition of TRAIL or stimulation of the TRAIL receptor was sufficient to improve survival of mice with pneumococcal pneumonia, independent of antibiotic therapy.

The authors demonstrated that a hyperinflammatory response can be deleterious during pneumonia and that neutrophils recruited to the site of infection secrete TRAIL in order to dampen the immune response by inducing programmed cell death in macrophages. This paper showed two different antibiotic-independent approaches for treating pneumonia by inducing macrophage apoptosis, which were effective even in neutrophil-depleted hosts. The usefulness of these therapies still needs to be confirmed in humans, and in conjunction with antibiotic treatment, but the new findings of Steinwede and colleagues should lead to the development of more effective treatments for pneumococcal pneumonia and better chances of survival for patients.

K. Steinwede et al., TNF-related apoptosis-inducing ligand (TRAIL) exerts therapeutic efficacy for the treatment of pneumococcal pneumonia in mice. J. Exp. Med. 209, 1937–1952 (2012). [PubMed]

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