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Abstract
Tumor progression locus 2 (Tpl2, MAP3K8, COT) is a serine threonine kinase known to regulate inflammation in a variety of infections, cancers, and autoimmune diseases. During infection, Tpl2 responds in a cell type-specific manner by transducing signals downstream of various pathogen recognition receptors initiating induction of pro-inflammatory mediators, which regulate the recruitment of various cell types to the site of infection. Our lab has shown previously that Tpl2-/- mice succumb to influenza infection, however the root cause of morbidity and mortality have not yet been identified. The goal of this project is to determine the cellular and molecular mechanisms by which Tpl2 genetic ablation leads to exacerbation of disease during influenza infection. We observed that a heightened immune response rather than impaired viral control was primarily responsible for increased disease severity in Tpl2-/- mice. Specifically, over-expression of interferon-β (IFN-β), interferon- (IFN-) and CCL2 along with increased recruitment of inflammatory monocytes and neutrophils characterized the lungs of influenza-infected Tpl2-/- mice at 7 days post infection (dpi). We next examined the effect of Tpl2 ablation on the immune response to influenza in the absence of type I IFN (T1 IFN) signaling using IFNAR-/- (Interferon Alpha Receptor 1 knockout) mice to determine if deregulated T1 IFN response in Tpl2-/- mice could be the sole cause of enhanced disease severity. However, the IFNAR-/-Tpl2-/- mice succumbed to influenza infection by 7 dpi, earlier than either IFNAR-/- or Tpl2-/- mice. The enhanced morbidity and mortality in IFNAR-/-Tpl2-/-, was attributed to this switch from excessive monocyte recruitment in Tpl2-/- mice to excessive neutrophil recruitment in IFNAR-/-Tpl2-/- mice, accompanied by excessive levels of IL-6, IL-1β, IFN-, IFN-λ and CXCL1. Further histological and clinical examination of Tpl2-/- mice revealed pulmonary edema and alveolar damage similar to the pathology seen in hospitalized influenza patients who develop Acute Respiratory Distress Syndrome (ARDS). Collectively, these studies demonstrate the importance of Tpl2 in preventing respiratory exacerbations caused by influenza infections by regulating the IFN response and the influx of inflammatory cells that induce pulmonary damage, which progresses to ARDS-like disease.