Time-Course Transcriptome Analysis of the Lungs of Mice Challenged with Aerosols of Methicillin-Resistant Staphylococcus aureus USA300 Clone Reveals Inflammatory Balance.

Abstract

USA300, a dominant clone of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA), is circulating globally and can cause necrotizing pneumonia with high morbidity and mortality. To further reveal the host anti-MRSA infection immune response, we established a mouse model of acute primary MRSA pneumonia challenged with aerosols of the USA300 clone. A time-course transcriptome analysis of the lungs collected at 0, 12, 24, 48 and 96 h post-infection (hpi) was conducted using RNA sequencing (RNA-seq) and multiple bioinformatic analysis methods. The change trend of histopathology and five innate immune cell (neutrophils, mononuclear cells, eosinophils, macrophages, DC cells) proportions in the lungs after infection was also examined. We observed a distinct acute pulmonary recovery process. A rapid initiation period of inflammation was present at 12 hpi, during which the IL-17 pathway dominantly mediated inflammation and immune defense. The main stages of host inflammatory response occurred at 24 and 48 hpi, and the regulation of interferon activation and macrophage polarization played an important role in the control of inflammatory balance at this stage. At 96 hpi, cellular proliferation processes associated with host repair were observed, as well as adaptive immunity and complement system responses involving C1q molecules. More importantly, the data provide new insight into and identify potential functional genes involved in the checks and balances occurring between host anti-inflammatory and proinflammatory responses. To the best of our knowledge, this is the first study to investigate transcriptional responses throughout the inflammatory recovery process in the lungs after MRSA infection. Our study uncovers valuable research targets for key regulatory mechanisms underlying the pathogenesis of MRSA lung infections, which may help to develop novel treatment strategies for MRSA pneumonia.