Respiratory Infection and the Impact of Pulmonary Immunity on Lung Health and Disease

The Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts, United States.
American Journal of Respiratory and Critical Care Medicine (Impact Factor: 13). 07/2012; 186(9). DOI: 10.1164/rccm.201206-1063PP
Source: PubMed


Acute lower respiratory tract infection is responsible for an inordinate disease burden. Pulmonary immunity determines the outcomes of these infections. The innate and adaptive immune responses to microbes in the lung are critical to maintaining a healthy respiratory system and to preventing pulmonary disease. In addition to balancing antimicrobial defense against the risk of lung injury during the immediate infection, the shaping of pulmonary immunity by respiratory infection contributes to the pathophysiology of many and even perhaps most chronic pulmonary diseases. This Perspective aims to communicate 2 inter-connected points. First, tremendous morbidity and mortality result from inadequate, misguided, or excessive pulmonary immunity. Second, our understanding of pulmonary immunity is at an exciting stage of rapid developments and discoveries, but many questions remain. Further advances in pulmonary immunity and elucidation of the cellular and molecular responses to microbes in the lung are needed in order to develop novel approaches to predicting, preventing, and curing respiratory disease.

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  • American Journal of Respiratory and Critical Care Medicine 11/2012; 186(10):943-4. DOI:10.1164/rccm.201209-1702ED · 13.00 Impact Factor
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    ABSTRACT: Pneumococcal carriage is both immunising and a pre-requisite for mucosal and systemic disease. Murine models of pneumococcal colonisation show that IL-17A-secreting CD4(+) T-cells (Th-17 cells) are essential for clearance of pneumococci from the nasopharynx. Pneumococcal-responding IL-17A-secreting CD4(+) T-cells have not been described in the adult human lung and it is unknown whether they can be elicited by carriage and protect the lung from pneumococcal infection. We investigated the direct effect of experimental human pneumococcal nasal carriage (EHPC) on the frequency and phenotype of cognate CD4(+) T-cells in broncho-alveolar lavage and blood using multi-parameter flow cytometry. We then examined whether they could augment ex vivo alveolar macrophage killing of pneumococci using an in vitro assay. We showed that human pneumococcal carriage leads to a 17.4-fold (p = 0.007) and 8-fold (p = 0.003) increase in the frequency of cognate IL-17A(+) CD4(+) T-cells in BAL and blood, respectively. The phenotype with the largest proportion were TNF(+)/IL-17A(+) co-producing CD4(+) memory T-cells (p<0.01); IFNγ(+) CD4(+) memory T-cells were not significantly increased following carriage. Pneumococci could stimulate large amounts of IL-17A protein from BAL cells in the absence of carriage but in the presence of cognate CD4(+) memory T-cells, IL-17A protein levels were increased by a further 50%. Further to this we then show that alveolar macrophages, which express IL-17A receptors A and C, showed enhanced killing of opsonised pneumococci when stimulated with rhIL-17A (p = 0.013). Killing negatively correlated with RC (r = -0.9, p = 0.017) but not RA expression. We conclude that human pneumococcal carriage can increase the proportion of lung IL-17A-secreting CD4(+) memory T-cells that may enhance innate cellular immunity against pathogenic challenge. These pathways may be utilised to enhance vaccine efficacy to protect the lung against pneumonia.
    PLoS Pathogens 03/2013; 9(3):e1003274. DOI:10.1371/journal.ppat.1003274 · 7.56 Impact Factor
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    ABSTRACT: The acute phase response is characteristic of perhaps all infections, including bacterial pneumonia. In conjunction with the acute phase response, additional biological pathways are induced in the liver and dependent on the transcription factors STAT3 or NF-κB, but these responses are poorly understood. Here, we demonstrate that pneumococcal pneumonia and other severe infections increase expression of multiple components of the cellular secretory machinery in the mouse liver, including the endoplasmic reticulum (ER) translocon complex mediating protein translation into the ER and the coat protein complexes (COPI and COPII) mediating vesicular transport of proteins to and from the ER. Hepatocyte-specific mutation of STAT3 prevented the induction of these secretory pathways during pneumonia, with similar results observed following pharmacological activation of ER stress using tunicamycin. These findings implicate STAT3 in the unfolded protein response and suggest that STAT3-dependent optimization of secretion may apply broadly. Pneumonia also stimulated the binding of phosphorylated STAT3 to promoter regions of secretion-related genes in the liver, supporting a direct role for STAT3 in their transcription. Altogether, these results identify a novel function of STAT3 during the acute phase response, the induction of secretory machinery in hepatocytes. This may facilitate the processing and delivery of newly synthesized loads of acute phase proteins, enhancing innate immunity and preventing liver injury during infection.
    Infection and immunity 03/2013; 81(5). DOI:10.1128/IAI.01332-12 · 3.73 Impact Factor
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