Richard J. Jaramillo

Impaired NLRP3 Inflammasome Function in Elderly Mice during Influenza Infection Is Rescued by Treatment with Nigericin

The NLRP3 inflammasome is activated in the lung during influenza viral infection; however, the impact of aging on inflammasome function during influenza infection has not been examined. In this study, we show that elderly mice infected with a mouse-adapted strain of influenza produced lower levels of IL-1β during in vitro and in vivo infection. Dendritic cells from elderly mice exhibited decreased expression of ASC, NLRP3, and capase-1 but increased expression of pro–IL-1β, pro–IL-18, and pro–IL-33 compared with dendritic cells from young infected mice. Treatment with nigericin during influenza infection augmented IL-1β production, increased caspase-1 activity, and decreased morbidity and mortality in elderly mice. Our study demonstrates for the first time, to our knowledge, that during influenza viral infection, elderly mice have impaired NLRP3 inflammasome activity and that treatment with nigericin rescues NLRP3 activation in elderly hosts.

Integrative "omic" analysis of experimental bacteremia identifies a metabolic signature that distinguishes human sepsis from systemic inflammatory response syndromes.

RATIONALE Sepsis is a leading cause of morbidity and mortality. Currently, early diagnosis and the progression of the disease are difficult to make. The integration of metabolomic and transcriptomic data in a primate model of sepsis may provide a novel molecular signature of clinical sepsis. OBJECTIVES To develop a biomarker panel to characterize sepsis in primates and ascertain its relevance to early diagnosis and progression of human sepsis. METHODS Intravenous inoculation of Macaca fascicularis with Escherichia coli produced mild to severe sepsis, lung injury, and death. Plasma samples were obtained before and after 1, 3, and 5 days of E. coli challenge and at the time of killing. At necropsy, blood, lung, kidney, and spleen samples were collected. An integrative analysis of the metabolomic and transcriptomic datasets was performed to identify a panel of sepsis biomarkers. MEASUREMENTS AND MAIN RESULTS The extent of E. coli invasion, respiratory distress, lethargy, and mortality was dependent on the bacterial dose. Metabolomic and transcriptomic changes characterized severe infections and death, and indicated impaired mitochondrial, peroxisomal, and liver functions. Analysis of the pulmonary transcriptome and plasma metabolome suggested impaired fatty acid catabolism regulated by peroxisome-proliferator activated receptor signaling. A representative four-metabolite model effectively diagnosed sepsis in primates (area under the curve, 0.966) and in two human sepsis cohorts (area under the curve, 0.78 and 0.82). CONCLUSIONS A model of sepsis based on reciprocal metabolomic and transcriptomic data was developed in primates and validated in two human patient cohorts. It is anticipated that the identified parameters will facilitate early diagnosis and management of sepsis.

Human metapneumovirus inhibits the IL-6-induced JAK/STAT3 signalling cascade in airway epithelium.

The host cytokine IL-6 plays an important role in host defence and prevention of lung injury from various pathogens, making IL-6 an important mediator in the hosts susceptibility to respiratory infections. The cellular response to IL-6 is mediated through a Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signal transduction pathway. Human metapneumovirus (hMPV) is an important causative agent of viral respiratory infections known to inhibit the IFN-mediated activation of STAT1. However, little is known about the interactions between this virus and other STAT signalling cascades. Herein, we showed that hMPV can attenuate the IL-6-mediated JAK/STAT3 signalling cascade in lung epithelial cells. HMPV inhibited a key event in this pathway by impeding the phosphorylation and nuclear translocation of STAT3 in A549 cells and in primary normal human bronchial epithelial cells. Further studies established that hMPV interrupted the IL-6-induced JAK/STAT pathway early in the signal transduction pathway by blocking the phosphorylation of JAK2. By antagonizing the IL-6-mediated JAK/STAT3 pathway, hMPV perturbed the expression of IL-6-inducible genes important for apoptosis, cell differentiation and growth. Infection with hMPV also differentially regulated the effects of IL-6 on apoptosis. Thus, hMPV regulation of these genes could usurp the protective roles of IL-6, and these data provide insight into an important element of viral pathogenesis.