Abstract
Lower respiratory tract infections are among the top five leading causes of human death. Fighting these infections is therefore a world health priority. Searching for induced alterations in host gene expression shared by several relevant respiratory pathogens represents an alternative to identify new targets for wide-range host-oriented therapeutics. With this aim, alveolar macrophages were independently infected with three unrelated bacterial (Streptococcus pneumoniae, Klebsiella pneumoniae, and Staphylococcus aureus) and two dissimilar viral (respiratory syncytial virus and influenza A virus) respiratory pathogens, all of them highly relevant for human health. Cells were also activated with bacterial lipopolysaccharide (LPS) as a prototypical pathogen-associated molecular pattern. Patterns of differentially expressed cellular genes shared by the indicated pathogens were searched by microarray analysis. Most of the commonly up-regulated host genes were related to the innate immune response and/or apoptosis, with Toll-like, RIG-I-like and NOD-like receptors among the top 10 signaling pathways with over-expressed genes. These results identify new potential broad-spectrum targets to fight the important human infections caused by the bacteria and viruses studied here.
Highlights
According to the World Health Organization, lower respiratory tract infections are the fourth leading cause of human death worldwide (3.1 million deaths in 2012), only behind ischemic heart disease, stroke and chronic obstructive pulmonary disease (COPD)
In this report we explored the possibility of finding host genes collectively de-regulated by various respiratory pathogens
Cells of the alveolar macrophage murine cell line MH-S were independently infected with RSV, IAV, K. pneumoniae, S. pneumoniae, or S. aureus (Table 1), followed by microarray analysis of cellular gene expression at different times after infection
Summary
According to the World Health Organization, lower respiratory tract infections are the fourth leading cause of human death worldwide (3.1 million deaths in 2012), only behind ischemic heart disease, stroke and chronic obstructive pulmonary disease (COPD) (http://www.who.int/mediacentre/factsheets/fs310/ en/). Acute respiratory infections are the most frequent cause of visits to health services around the world, and account for 20–40% of children hospitalizations, with pneumonia being the leading global killer of children under five (UNICEF and WHO, 20061; Forum of International Respiratory Societies, 20132) respiratory infections constitute an enormous global health burden, complicated by the existence of different etiologic agents that frequently co-infect the same individual, the emergence of drug-resistant variants, and the emergence and re-emergence of new human respiratory pathogens. Classical approaches to combat these infections have focused on targeting distinctive processes of each pathogen’s infectious cycle with specific drugs. The rationale behind this approach is that the more specific the target, the less likely the drug will cause host toxicity. Despite the unquestionable success of this approach in different areas, the high economic cost of developing multiple pathogen-specific treatments and the emergence of drug resistance have compelled searching for alternative therapeutic approaches
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