Madenspacher, J.H. et al. p53 Integrates host defense and cell fate during bacterial pneumonia. J. Exp. Med. 210, 891-904

2 Cellular and Molecular Pathology Branch, 3 National Toxicology Program
Journal of Experimental Medicine (Impact Factor: 12.52). 04/2013; 210(5). DOI: 10.1084/jem.20121674
Source: PubMed

ABSTRACT Cancer and infection are predominant causes of human mortality and derive, respectively, from inadequate genomic and host defenses against environmental agents. The transcription factor p53 plays a central role in human tumor suppression. Despite its expression in immune cells and broad responsiveness to stressors, it is virtually unknown whether p53 regulates host defense against infection. We report that the lungs of naive p53(-/-) mice display genome-wide induction of NF-κB response element-enriched proinflammatory genes, suggestive of type 1 immune priming. p53-null and p53 inhibitor-treated mice clear Gram-negative and -positive bacteria more effectively than controls after intrapulmonary infection. This is caused, at least in part, by cytokines produced by an expanded population of apoptosis-resistant, TLR-hyperresponsive alveolar macrophages that enhance airway neutrophilia. p53(-/-) neutrophils, in turn, display heightened phagocytosis, Nox-dependent oxidant generation, degranulation, and bacterial killing. p53 inhibition boosts bacterial killing by mouse neutrophils and oxidant generation by human neutrophils. Despite enhanced bacterial clearance, infected p53(-/-) mice suffer increased mortality associated with aggravated lung injury. p53 thus modulates host defense through regulating microbicidal function and fate of phagocytes, revealing a fundamental link between defense of genome and host during environmental insult.

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Available from: Daniel Menendez, Sep 29, 2015
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    • "For initiating disease development, an interaction between a highly virulent pathogen and a susceptible host in a disease favourable environment is required. The environment plays a major role in modulating the virulence of the pathogen [16–18] as well as reducing the host defence [19] and thus increasing the susceptibility of the host. A pathogenic agent can certainly gain entry into the animal body and initiate disease development process but the immune system of host can phagocytise the pathogen (e.g., by secreting chemical factors) and thus check the disease progress. "
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