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Activators of innate immunity may have the potential to combat a broad range of infectious agents. We report that treatment with bacterial flagellin prevented rotavirus (RV) infection in mice and cured chronically RV-infected mice. Protection was independent of adaptive immunity and interferon (IFN, type I and II) and required flagellin receptors Toll-like receptor 5 (TLR5) and NOD-like receptor C4 (NLRC4). Flagellin-induced activation of TLR5 on dendritic cells elicited production of the cytokine interleukin-22 (IL-22), which induced a protective gene expression program in intestinal epithelial cells. Flagellin also induced NLRC4-dependent production of IL-18 and immediate elimination of RV-infected cells. Administration of IL-22 and IL-18 to mice fully recapitulated the capacity of flagellin to prevent or eliminate RV infection and thus holds promise as a broad-spectrum antiviral agent.
Copyright © 2014, American Association for the Advancement of Science.
BACKGROUND - Healthcare-associated transmission of respiratory viruses is a concerning patient safety issue.
DESIGN - Surveillance for influenza virus among a cohort of healthcare workers (HCWs) was conducted in a tertiary care children's hospital from November 2009 through April 2010 using biweekly nasal swab specimen collection. If a subject reported respiratory symptoms, an additional specimen was collected. Specimens from ill HCWs and a randomly selected sample from asymptomatic subjects were tested for additional respiratory viruses by multiplex polymerase chain reaction (PCR).
RESULTS - A total of 1,404 nasal swab specimens were collected from 170 enrolled subjects. Influenza circulated at very low levels during the surveillance period, and 74.2% of subjects received influenza vaccination. Influenza virus was not detected in any specimen. Multiplex respiratory virus PCR analysis of all 119 specimens from symptomatic subjects and 200 specimens from asymptomatic subjects yielded a total of 42 positive specimens, including 7 (16.7%) in asymptomatic subjects. Viral shedding was associated with report of any symptom (odds ratio [OR], 13.06 [95% confidence interval, 5.45-31.28]; [Formula: see text]) and younger age (OR, 0.96 [95% confidence interval, 0.92-0.99]; [Formula: see text]) when controlled for sex and occupation of physician or nurse. After the surveillance period, 46% of subjects reported working while ill with an influenza-like illness during the previous influenza season.
CONCLUSIONS - In this cohort, HCWs working while ill was common, as was viral shedding among those with symptoms. Asymptomatic viral shedding was infrequent but did occur. HCWs should refrain from patient care duties while ill, and staffing contingencies should accommodate them.
Intestinal bacteria aid host health and limit bacterial pathogen colonization. However, the influence of bacteria on enteric viruses is largely unknown. We depleted the intestinal microbiota of mice with antibiotics before inoculation with poliovirus, an enteric virus. Antibiotic-treated mice were less susceptible to poliovirus disease and supported minimal viral replication in the intestine. Exposure to bacteria or their N-acetylglucosamine-containing surface polysaccharides, including lipopolysaccharide and peptidoglycan, enhanced poliovirus infectivity. We found that poliovirus binds lipopolysaccharide, and exposure of poliovirus to bacteria enhanced host cell association and infection. The pathogenesis of reovirus, an unrelated enteric virus, also was more severe in the presence of intestinal microbes. These results suggest that antibiotic-mediated microbiota depletion diminishes enteric virus infection and that enteric viruses exploit intestinal microbes for replication and transmission.
Respiratory syncytial virus (RSV) infects polarized epithelia, which have tightly regulated trafficking because of the separation and maintenance of the apical and basolateral membranes. Previously we established a link between the apical recycling endosome (ARE) and the assembly of RSV. The current studies tested the role of a major ARE-associated protein, Rab11 family interacting protein 2 (FIP2) in the virus life cycle. A dominant-negative form of FIP2 lacking its N-terminal C2 domain reduced the supernatant-associated RSV titer 1,000-fold and also caused the cell-associated virus titer to increase. These data suggested that the FIP2 C2 mutant caused a failure at the final budding step in the virus life cycle. Additionally, truncation of the Rab-binding domain from FIP2 caused its accumulation into mature filamentous virions. RSV budding was independent of the ESCRT machinery, the only well-defined budding mechanism for enveloped RNA viruses. Therefore, RSV uses a virus budding mechanism that is controlled by FIP2.
Mammalian reoviruses infect respiratory and gastrointestinal epithelia and cause disease in neonates. Junctional adhesion molecule-A (JAM-A) is a serotype-independent receptor for reovirus. JAM-A localizes to tight junctions and contributes to paracellular permeability in polarized epithelia. To investigate the mechanisms of reovirus infection of polarized epithelial cells, we assessed reovirus replication, release, and spread after apical and basolateral adsorption to primary human airway epithelial cultures. Reovirus infection of human airway epithelia was more efficient after adsorption to the basolateral surface than after adsorption to the apical surface, and it was dependent on JAM-A. Reovirus binding to carbohydrate coreceptor sialic acid inhibited apical infection, which was partially ameliorated by treatment of the cultures with neuraminidase. Despite the preference for basolateral infection, reovirus was released from the apical surface of respiratory epithelia and did not disrupt tight junctions. These results establish the existence of an infectious circuit for reovirus in polarized human respiratory epithelial cells.
To examine oral shedding of vaccinia in volunteers who were recently vaccinated against smallpox, pharyngeal swabs were collected for viral culture between days 3 and 5 and days 6 and 8 after vaccination with diluted Sanofi Pasteur smallpox vaccine. From 102 adult volunteers (48 vaccinia-naive, 54 vaccinia-experienced), vaccinia was not detected in any specimen (0/201, 95% confidence interval, 0-1.8), which suggests a lack of oral shedding of vaccinia after immunization. This supports recommendations that individuals who were recently vaccinated against smallpox do not require placement in airborne or droplet precautions.
We previously demonstrated the susceptibility of pheasants to infection with influenza A viruses of 15 hemagglutinin (HA) subtypes: 13/23 viruses tested were isolated for >or=14 days, all in the presence of serum-neutralizing antibodies; one virus (H10) was shed for 45 days postinfection. Here we confirmed that 20% of pheasants shed low-pathogenic influenza viruses for prolonged periods. We aimed to determine why the antibody response did not clear the virus in the usual 3 to 10 days, because pheasants serve as a long-term source of influenza viruses in poultry markets. We found evidence of virus replication and histological changes in the large intestine, bursa of Fabricius, and cecal tonsil. The virus isolated 41 days postinfection was antigenically distinct from the parental H10 virus, with corresponding changes in the HA and neuraminidase. Ten amino acid differences were found between the parental H10 and the pheasant H10 virus; four were in potential antigenic sites of the HA molecule. Prolonged shedding of virus by pheasants results from a complex interplay between the diversity of virus variants and the host response. It is often argued that vaccination pressure is a mechanism that contributes to the generation of antigenic-drift variants in poultry. This study provided evidence that drift variants can occur naturally in pheasants after prolonged shedding of virus, thus strengthening our argument for the removal of pheasants from live-bird retail markets.
OBJECTIVE - To characterize the probability and duration of viral shedding among adults given trivalent live attenuated influenza vaccine (LAIV).
DESIGN - Prospective surveillance study.
METHODS - Nasal wash samples were collected from adult volunteers at baseline and on days 3, 7, and 10 and between days 17 and 21 following intranasal LAIV vaccination. The presence, titer, and identification of each specific strain of influenza virus shed were determined by standard methodology.
RESULTS - Twenty subjects received LAIV. No samples were positive for influenza virus at baseline. After LAIV vaccination, influenza virus was recovered from 10 of 20 vaccinees on day 3, from 1 of 18 vaccinees on day 7, and from none of the samples on days 10 or 17 through 21. Vaccinees who shed vaccine virus were significantly younger than those who did not (mean age, 26.4 vs 38.6 years; P < .01). Although the presence of specific mucosal immunoglobulin A to influenza B was associated with significantly less shedding of influenza B after vaccination (P = .02), associations of shedding with other measures of immunity were not detected.
CONCLUSION - The duration of shedding of vaccine virus after LAIV in adults i s limited and may be associatedwith an individual's prior influenza vaccination history.
Epstein-Barr virus is ubiquitous and is causally implicated in lymphoid and epithelial malignancies. Virus invades oropharyngeal mucosa and establishes latency in B lymphocytes. Reactivating lymphocytes shed virus into saliva for spread to new hosts. A complex of three virus glycoproteins, gH, gL and gp42, is essential for entry. B-cell entry requires binding of gp42 to human leukocyte antigen (HLA) class II whereas entry into epithelial cells lacking HLA class II requires complexes without gp42. To accommodate infection of each, the virus carries both three-part and two-part complexes. We show here that HLA class II in the virus-producing cell alters the ratio of three-part to two-part complexes. As a consequence, virus originating in epithelial cells efficiently infects B cells whereas B-cell derived virus better infects epithelial cells. This molecular switch is a novel strategy that could alter tropism of virus from epithelium to B cells and then back to epithelium in a new host.