Influenza A viruses cause recurrent outbreaks of local or global scale with potentially severe consequences for human health and the global economy. Recently, a new strain of influenza A virus was detected that causes disease in and transmits among humans, probably owing to little or no pre-existing immunity to the new strain. On June 11, 2009, the WHO declared that the infections caused by the new strain had reached pandemic proportion. Characterized as an influenza A virus of the H1N1 subtype, the genomic segments of the new strain were most closely related to swine viruses1. Most human infections with swine-origin H1N1 influenza viruses (S-OIVs) appear to be mild; however, more than 50% of hospitalized individuals do not have underlying health issues, attesting to the pathogenic potential of S-OIVs. To better assess the risk posed by the new virus, we characterized one of the first US S-OIV isolates, A/California/04/09 (H1N1; CA04), as well as several other S-OIV isolates, in vitro and in vivo. In mice and ferrets, CA04 and other S-OIV isolates tested replicate more efficiently than a currently circulating human H1N1 virus. In addition, CA04 replicates efficiently in nonhuman primates, causes more severe pathologic lesions in the lungs of infected mice, ferrets, and nonhuman primates than a currently circulating human H1N1 virus, and transmits among ferrets. In specific-pathogen free miniature pigs, CA04 replicates without clinical symptoms. The assessment of human sera from different age groups suggests that infection with human H1N1 viruses antigenically closely related to viruses circulating in 1918 confers neutralizing antibody activity to CA04. Finally, we show that CA04 is sensitive to approved and experimental antiviral drugs, suggesting these compounds as a first line of defence against the recently declared S-OIV pandemic.

Elevation of KL-6, a lung epithelial cell marker, in plasma and epithelial lining fluid in acute respiratory distress syndrome. Am J Physiol Lung Cell Mol Physiol 286: L1088 -L1094, 2004. First published September 5, 2003 10.1152 10. /ajplung. 00420.2002 is a pulmonary epithelial mucin more prominently expressed on the surface membrane of alveolar type II cells when these cells are proliferating, stimulated, and/or injured. We hypothesized that high levels of KL-6 in epithelial lining fluid and plasma would reflect the severity of lung injury in patients with acute lung injury (ALI). Epithelial lining fluid was obtained at onset (day 0) and day 1 of acute respiratory distress syndrome (ARDS)/ALI by bronchoscopic microsampling procedure in 35 patients. On day 0, KL-6 and albumin concentrations in epithelial lining fluid were significantly higher than in normal controls (P Ͻ 0.001), and the concentrations of KL-6 in epithelial lining fluid (P Ͻ 0.002) and in plasma (P Ͻ 0.0001) were higher in nonsurvivors than in survivors of ALI/ARDS. These observations were corroborated by the immunohistochemical localization of KL-6 protein expression in the lungs of nonsurvivors with ALI and KL-6 secretion from cultured human alveolar type II cells stimulated by proinflammatory cytokines. Because injury to distal lung epithelial cells, including alveolar type II cells, is important in the pathogenesis of ALI, the elevation of KL-6 concentrations in plasma and epithelial lining fluid could be valuable indicators for poor prognosis in clinical ALI. alveolar type II cell; pulmonary edema; microsampling

Epithelial injury is a critical event in the development of acute lung injury, but the mechanisms that cause death of the alveolar epithelium are not completely understood. Epithelial death occurs by necrosis and apoptosis; more information is needed about the balance between these two types of cell death in the lungs. Direct epithelial necrosis probably occurs in response to bacterial exotoxins and over-distension of alveolar units by mechanical ventilation. Apoptosis is a regulated form of cell death that is mediated by membrane death receptors and direct mitochondrial injury. Apoptosis pathways are activated in the lungs of patients with acute lung injury, in part by activation of the membrane Fas death receptor by soluble Fas ligand (sFasL), which accumulates in biologically active form at the onset of lung injury. Accumulating evidence in humans and experimental models links sFasL and Fas pathway with lung epithelial injury and fibrosis. New strategies to inhibit Fas-mediated epithelial apoptosis need to be developed in order to develop new ways to preserve epithelial function in patients who develop acute lung injury.

Interpretation: Although the number of patients is limited, our results show that the antibody response against the first SARS-CoV-2 infection in symptomatic patients is typical of that observed in an acute viral infection.

Strategies to block apoptosis pathways could be useful in limiting some forms of acute lung injury in humans.