Human respiratory syncytial virus (RSV) is a major cause of severe respiratory illness in children and susceptible adults. RSV blocks the development of the innate antiviral immune response and can ...grow to high titers in the respiratory tract. Here we demonstrate that immunostimulatory defective viral genomes (iDVGs) that are naturally generated during RSV replication are strong inducers of the innate antiviral response to RSV in mice and humans. In mice, RSV iDVGs stimulated the expression of antiviral genes, restricted viral replication, and prevented weight loss and lung inflammation. In human cells, the antiviral response to RSV iDVGs was dominated by the expression of IFN-λ1 over IFN-β and was driven by rapid intranuclear accumulation of the transcription factor IRF1. RSV iDVGs were detected in respiratory secretions of hospitalized patients, and their amount positively correlated with the level of expression of antiviral genes in the samples. Infection of explanted human lung tissue from different donors revealed that most humans can respond to RSV iDVGs and that the rate of accumulation of iDVGs during infection directly correlates with the quality of the antiviral response. Taken together, our data establish iDVGs as primary triggers of robust antiviral responses to RSV and provide the first evidence for an important biological role for naturally occurring iDVGs during a paramyxovirus infection in humans.
Influenza viruses typically cause the most severe disease in children and elderly individuals. However, H1N1 viruses disproportionately affected middle-aged adults during the 2013–2014 influenza ...season. Although H1N1 viruses recently acquired several mutations in the hemagglutinin (HA) glycoprotein, classic serological tests used by surveillance laboratories indicate that these mutations do not change antigenic properties of the virus. Here, we show that one of these mutations is located in a region of HA targeted by antibodies elicited in many middle-aged adults. We find that over 42% of individuals born between 1965 and 1979 possess antibodies that recognize this region of HA. Our findings offer a possible antigenic explanation of why middle-aged adults were highly susceptible to H1N1 viruses during the 2013–2014 influenza season. Our data further suggest that a drifted H1N1 strain should be included in future influenza vaccines to potentially reduce morbidity and mortality in this age group.
Significance Influenza viruses typically cause a higher disease burden in children and the elderly, who have weaker immune systems. During the 2013–2014 influenza season, H1N1 viruses caused an unusually high level of disease in middle-aged adults. Here, we show that recent H1N1 strains possess a mutation that allows viruses to avoid immune responses elicited in middle-aged adults. We show that current vaccine strains elicit immune responses that are predicted to be less effective in some middle-aged adults. We suggest that new viral strains should be incorporated into seasonal influenza vaccines so that proper immunity is elicited in all humans, regardless of age and pre-exposure histories.
Respiratory RNA Viruses Hodinka, Richard L
Microbiology spectrum,
08/2016, Volume:
4, Issue:
4
Journal Article
Peer reviewed
Open access
Acute upper and lower respiratory infections are a major public health problem and a leading cause of morbidity and mortality worldwide. At greatest risk are young children, the elderly, the ...chronically ill, and those with suppressed or compromised immune systems. Viruses are the predominant cause of respiratory tract illnesses and include RNA viruses such as respiratory syncytial virus, influenza virus, parainfluenza virus, metapneumovirus, rhinovirus, and coronavirus. Laboratory testing is required for a reliable diagnosis of viral respiratory infections, as a clinical diagnosis can be difficult since signs and symptoms are often overlapping and not specific for any one virus. Recent advances in technology have resulted in the development of newer diagnostic assays that offer great promise for rapid and accurate detection of respiratory viral infections. This chapter emphasizes the fundamental characteristics and clinical importance of the various RNA viruses that cause upper and lower respiratory tract diseases in the immunocompromised host. It highlights the laboratory methods that can be used to make a rapid and definitive diagnosis for the greatest impact on the care and management of ill patients, and the prevention and control of hospital-acquired infections and community outbreaks.
Two meetings, one sponsored by the Wellcome Trust in 2012 and the other by the Global Virology Foundation in 2013, assembled academic, public health and pharmaceutical industry experts to assess the ...challenges and opportunities for developing antivirals for the treatment of respiratory syncytial virus (RSV) infections. The practicalities of clinical trials and establishing reliable outcome measures in different target groups were discussed in the context of the regulatory pathways that could accelerate the translation of promising compounds into licensed agents. RSV drug development is hampered by the perceptions of a relatively small and fragmented market that may discourage major pharmaceutical company investment. Conversely, the public health need is far too large for RSV to be designated an orphan or neglected disease. Recent advances in understanding RSV epidemiology, improved point-of-care diagnostics, and identification of candidate antiviral drugs argue that the major obstacles to drug development can and will be overcome. Further progress will depend on studies of disease pathogenesis and knowledge provided from controlled clinical trials of these new therapeutic agents. The use of combinations of inhibitors that have different mechanisms of action may be necessary to increase antiviral potency and reduce the risk of resistance emergence.
Cerebrospinal fluid (CSF) white blood cell (WBC) counts for neonates and young infants are usually interpreted on the basis of values reported in reference texts or handbooks; however, current ...reference texts either present normal CSF parameters without citation or cite studies with significant limitations. The objective of this study was to determine accurate, age-specific reference values for CSF WBC counts in a large population of neonates and young infants.
This cross-sectional study included patients who were aged < or =56 days and had a lumbar puncture performed in the emergency department from January 1, 2005, to June 30, 2007. Patients were excluded from analysis for conditions that are suspected to cause CSF pleocytosis, including traumatic lumbar puncture, serious bacterial infection, congenital infection, seizure, and presence of a ventricular shunt. Children who tested positive for enterovirus (EV) in the CSF by polymerase chain reaction were also excluded. Two-sample Wilcoxon rank-sum tests were used to compare median CSF WBC values of those who had negative EV testing with those who did not have EV testing.
A total of 380 (36%) of 1064 patients met inclusion criteria; 54% were male, 15% were preterm, and 39% presented during EV season. The median CSF WBC count was significantly higher in infants who were aged < or =28 days (3/microL, 95th percentile: 19/microL) than in infants who were aged 29 to 56 days (2/microL, 95th percentile: 9/microL; P < .001). In both age groups, infants with a negative EV PCR had a higher upper bound of the 95% confidence interval of the mean values compared with infants who did not have EV testing performed.
We determined age-specific CSF WBC reference values in a large cohort of neonates and young infants that can be used to interpret accurately the results of lumbar punctures in this population.
Prior to serological testing, influenza viruses are typically propagated in eggs or cell culture. Recent human H3N2 strains bind to cells with low avidity. Here, we isolated nine primary H3N2 viral ...isolates from respiratory secretions of children. Upon propagation in vitro, five of these isolates acquired hemagglutinin or neuraminidase mutations that increased virus binding to cell surfaces. These mutations can potentially confound serological assays commonly used to identify antigenically novel influenza viruses.
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