The Role of Type I and III Interferons in the Pathogenesis of Bordetella pertussis Infection and Disease.
AdvisorCarbonetti, Nicholas H.
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AbstractBordetella pertussis is a Gram-negative bacterial pathogen that infects human respiratory tracts and is the causative agent for the disease pertussis, otherwise known as whooping cough. In 2012, there were 48,277 reported cases in the United States, the most since 1955. Symptoms build up to severe paroxysmal coughing, often for 10+ weeks after onset. For infants, pertussis can be fatal due to complications including pulmonary hypertension, pneumothorax, high-level circulating lymphocytosis, and pneumonia. In adults, the disease is severe too, with long-lasting cough, lung damage, and serious symptoms resulting in hospitalization. A difficulty in treatment/prevention of pertussis is a suboptimal vaccine that confers waning immunity, and a lack of effective treatments available. Antibiotics are administered to patients to prevent transmission, but usually don’t change the clinical course of disease. Host directed therapeutics treating pertussis could benefit individuals with severe cough and save the lives of infected infants. Using RNA-sequencing transcriptomics we investigated lung gene expression responses to Bordetella pertussis infection in adult mice, revealing that type I and III interferon (IFN) responses and signaling pathways may play an important role in promoting inflammatory responses. In B. pertussis infected mice, lung type I/III IFN responses correlated with increased proinflammatory cytokine expression and lung inflammatory pathology. In mutant mouse models with increased type I IFN signaling, B. pertussis exacerbated lung inflammatory pathology, whereas knockout mice with deficiencies in type I/III IFN signaling had reduced lung inflammation compared to wild-type mice. In direct contrast, infant mice didn’t upregulate type I/III IFNs in response to B. pertussis infection and were protected from lethal infection by increased type I IFN signaling, indicating age dependent effects of type I/III IFN signaling during B. pertussis infection. The induction of type I/III IFNs was found to be MyD88 dependent, and TLR9 and STING were identified as DNA sensing pattern recognition receptors required for type I/III IFN responses, as well as for typical levels of lung inflammatory pathology. This observation, coupled with results showing DNase treatment of B. pertussis-infected mice causing reduced lung pathology, indicated a DNA dependent induction of type I/III IFNs, making these targets for therapeutic intervention.
Molecular Microbiology and Immunology
University of Maryland, Baltimore