<i>Francisella tularensis</i> subsp. <i>tularensis</i> Induces a Unique Pulmonary Inflammatory Response: Role of Bacterial Gene Expression in Temporal Regulation of Host Defense Responses

<div><p>Pulmonary exposure to <i>Francisella tularensis</i> is associated with severe lung pathology and a high mortality rate. The lack of induction of classical inflammatory mediators, including IL1-β and TNF-α, during early infection has led to the suggestion that <i>F. tularensis</i> evades detection by host innate immune surveillance and/or actively suppresses inflammation. To gain more insight into the host response to <i>Francisella</i> infection during the acute stage, transcriptomic analysis was performed on lung tissue from mice exposed to virulent (<i>Francisella tularensis</i> ssp <i>tularensis</i> SchuS4). Despite an extensive transcriptional response in the lungs of animals as early as 4 hrs post-exposure, <i>Francisella tularensis</i> was associated with an almost complete lack of induction of immune-related genes during the initial 24 hrs post-exposure. This broad subversion of innate immune responses was particularly evident when compared to the pulmonary inflammatory response induced by other lethal (<i>Yersinia pestis</i>) and non-lethal (<i>Legionella pneumophila, Pseudomonas aeruginosa</i>) pulmonary infections. However, the unique induction of a subset of inflammation-related genes suggests a role for dysregulation of lymphocyte function and anti-inflammatory pathways in the extreme virulence of <i>Francisella</i>. Subsequent activation of a classical inflammatory response 48 hrs post-exposure was associated with altered abundance of <i>Francisella</i>-specific transcripts, including those associated with bacterial surface components. In summary, virulent <i>Francisella</i> induces a unique pulmonary inflammatory response characterized by temporal regulation of innate immune pathways correlating with altered bacterial gene expression patterns. This study represents the first simultaneous measurement of both host and <i>Francisella</i> transcriptome changes that occur during <i>in vivo</i> infection and identifies potential bacterial virulence factors responsible for regulation of host inflammatory pathways.</p>