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Frequent Use of the IgA Isotype in Human B Cells Encoding Potent Norovirus-Specific Monoclonal Antibodies That Block HBGA Binding.
Sapparapu G, Czakó R, Alvarado G, Shanker S, Prasad BV, Atmar RL, Estes MK, Crowe JE
(2016) PLoS Pathog 12: e1005719
MeSH Terms: Antibodies, Monoclonal, B-Lymphocytes, Blood Group Antigens, Blotting, Western, Caliciviridae Infections, Cell Line, Enzyme-Linked Immunosorbent Assay, Gastroenteritis, Humans, Hybridomas, Immunoglobulin A, Immunoglobulin G, Norwalk virus, Polymerase Chain Reaction
Show Abstract · Added April 13, 2017
Noroviruses (NoV) are the most common cause of non-bacterial acute gastroenteritis and cause local outbreaks of illness, especially in confined situations. Despite being identified four decades ago, the correlates of protection against norovirus gastroenteritis are still being elucidated. Recent studies have shown an association of protection with NoV-specific serum histo-blood group antigen-blocking antibody and with serum IgA in patients vaccinated with NoV VLPs. Here, we describe the isolation and characterization of human monoclonal IgG and IgA antibodies against a GI.I NoV, Norwalk virus (NV). A higher proportion of the IgA antibodies blocked NV VLP binding to glycans than did IgG antibodies. We generated isotype-switched variants of IgG and IgA antibodies to study the effects of the constant domain on blocking and binding activities. The IgA form of antibodies appears to be more potent than the IgG form in blocking norovirus binding to histo-blood group antigens. These studies suggest a unique role for IgA antibodies in protection from NoV infections by blocking attachment to cell receptors.
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14 MeSH Terms
Salmonella Mitigates Oxidative Stress and Thrives in the Inflamed Gut by Evading Calprotectin-Mediated Manganese Sequestration.
Diaz-Ochoa VE, Lam D, Lee CS, Klaus S, Behnsen J, Liu JZ, Chim N, Nuccio SP, Rathi SG, Mastroianni JR, Edwards RA, Jacobo CM, Cerasi M, Battistoni A, Ouellette AJ, Goulding CW, Chazin WJ, Skaar EP, Raffatellu M
(2016) Cell Host Microbe 19: 814-25
MeSH Terms: Animals, Anti-Bacterial Agents, Antioxidants, Bacterial Proteins, Chelating Agents, Escherichia coli, Gastroenteritis, Intestinal Mucosa, Intestines, Leukocyte L1 Antigen Complex, Manganese, Mice, Mice, Inbred C57BL, Neutrophils, Oxidative Stress, Reactive Oxygen Species, Salmonella Infections, Salmonella typhimurium, Symbiosis, Zinc
Show Abstract · Added April 8, 2017
Neutrophils hinder bacterial growth by a variety of antimicrobial mechanisms, including the production of reactive oxygen species and the secretion of proteins that sequester nutrients essential to microbes. A major player in this process is calprotectin, a host protein that exerts antimicrobial activity by chelating zinc and manganese. Here we show that the intestinal pathogen Salmonella enterica serovar Typhimurium uses specialized metal transporters to evade calprotectin sequestration of manganese, allowing the bacteria to outcompete commensals and thrive in the inflamed gut. The pathogen's ability to acquire manganese in turn promotes function of SodA and KatN, enzymes that use the metal as a cofactor to detoxify reactive oxygen species. This manganese-dependent SodA activity allows the bacteria to evade neutrophil killing mediated by calprotectin and reactive oxygen species. Thus, manganese acquisition enables S. Typhimurium to overcome host antimicrobial defenses and support its competitive growth in the intestine.
Copyright © 2016 Elsevier Inc. All rights reserved.
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20 MeSH Terms
Etiology of childhood diarrhea after rotavirus vaccine introduction: a prospective, population-based study in Nicaragua.
Becker-Dreps S, Bucardo F, Vilchez S, Zambrana LE, Liu L, Weber DJ, Peña R, Barclay L, Vinjé J, Hudgens MG, Nordgren J, Svensson L, Morgan DR, Espinoza F, Paniagua M
(2014) Pediatr Infect Dis J 33: 1156-63
MeSH Terms: Age Factors, Caliciviridae Infections, Child, Preschool, Diarrhea, Entamoeba histolytica, Entamoebiasis, Enteropathogenic Escherichia coli, Enterotoxigenic Escherichia coli, Escherichia coli Infections, Feces, Female, Gastroenteritis, Giardia lamblia, Giardiasis, Humans, Infant, Male, Nicaragua, Norovirus, Prospective Studies, Rotavirus, Rotavirus Infections, Rotavirus Vaccines, Sapovirus
Show Abstract · Added May 18, 2016
BACKGROUND - Nicaragua was the first developing nation to implement routine immunization with the pentavalent rotavirus vaccine (RV5). In this RV5-immunized population, understanding infectious etiologies of childhood diarrhea is necessary to direct diarrhea treatment and prevention efforts.
METHODS - We followed a population-based sample of children <5 years in León, Nicaragua for diarrhea episodes through household visits. Information was obtained on RV5 history and sociodemographics. Stool samples collected during diarrhea episodes and among healthy children underwent laboratory analysis for viral, bacterial and parasitic enteropathogens. Detection frequency and incidence of each enteropathogen was calculated.
RESULTS - The 826 children in the cohort experienced 677 diarrhea episodes during 607.5 child-years of exposure time (1.1 episodes per child-year). At least 1 enteropathogen was detected among 61.1% of the 337 diarrheal stools collected. The most common enteropathogens among diarrheal stools were: norovirus (20.4%), sapovirus (16.6%), enteropathogenic Escherichia coli (11.3%), Entamoeba histolytica/dispar (8.3%), Giardia lamblia (8.0%) and enterotoxigenic E. coli (7.7%), with rotavirus detected among 5.3% of diarrheal stools. Enteropathogenic Escherichia coli and enterotoxigenic E. coli were frequently detected among stools from healthy children. Among children with diarrhea, norovirus was more commonly detected among younger children (< 2 years) and G. lamblia was more commonly detected among older children (2-4 years). The mean age of rotavirus detection was 34.6 months.
CONCLUSIONS - In this Central American community after RV5 introduction, rotavirus was not commonly detected among children with diarrhea. Prevention and appropriate management of norovirus and sapovirus should be considered to further reduce the burden of diarrheal disease.
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24 MeSH Terms
Molecular epidemiology of contemporary G2P[4] human rotaviruses cocirculating in a single U.S. community: footprints of a globally transitioning genotype.
Dennis AF, McDonald SM, Payne DC, Mijatovic-Rustempasic S, Esona MD, Edwards KM, Chappell JD, Patton JT
(2014) J Virol 88: 3789-801
MeSH Terms: Academic Medical Centers, Child, Preschool, Cluster Analysis, Evolution, Molecular, Gastroenteritis, Genome, Viral, Genotype, Humans, Infant, Infant, Newborn, Molecular Epidemiology, Molecular Sequence Data, Phylogeny, Rotavirus, Rotavirus Infections, Sequence Analysis, DNA, Tennessee
Show Abstract · Added May 28, 2014
UNLABELLED - Group A rotaviruses (RVs) remain a leading cause of childhood gastroenteritis worldwide. Although the G/P types of locally circulating RVs can vary from year to year and differ depending upon geographical location, those with G1P[8], G2P[4], G3P[8], G4P[8], G9P[8], and G12P[8] specificities typically dominate. Little is known about the evolution and diversity of G2P[4] RVs and the possible role that widespread vaccine use has had on their increased frequency of detection. To address these issues, we analyzed the 12 G2P[4] RV isolates associated with a rise in RV gastroenteritis cases at Vanderbilt University Medical Center (VUMC) during the 2010-2011 winter season. Full-genome sequencing revealed that the isolates had genotype 2 constellations typical of DS-1-like viruses (G2P[4]-I2-R2-C2-M2-A2-N2-T2-E2-H2). Phylogenetic analyses showed that the genome segments of the isolates were comprised of two or three different subgenotype alleles; this enabled recognition of three distinct clades of G2P[4] viruses that caused disease at VUMC in the 2010-2011 season. Although the three clades cocirculated in the same community, there was no evidence of interclade reassortment. Bayesian analysis of 328 VP7 genes of G2 viruses isolated in the last 39 years indicate that existing G2 VP7 gene lineages continue to evolve and that novel lineages, as represented by the VUMC isolates, are constantly being formed. Moreover, G2 lineages are characteristically shaped by lineage turnover events that introduce new globally dominant strains every 7 years, on average. The ongoing evolution of G2 VP7 lineages may give rise to antigenic changes that undermine vaccine effectiveness in the long term.
IMPORTANCE - Little is known about the diversity of cocirculating G2 rotaviruses and how their evolution may undermine the effectiveness of rotavirus vaccines. To expand our understanding of the potential genetic range exhibited by rotaviruses circulating in postvaccine communities, we analyzed part of a collection of rotaviruses recovered from pediatric patients in the United States from 2010 to 2011. Examining the genetic makeup of these viruses revealed they represented three segregated groups that did not exchange genetic material. The distinction between these three groups may be explained by three separate introductions. By comparing a specific gene, namely, VP7, of the recent rotavirus isolates to those from a collection recovered from U.S. children between 1974 and 1991 and other globally circulating rotaviruses, we were able to reconstruct the timing of events that shaped their ancestry. This analysis indicates that G2 rotaviruses are continuously evolving, accumulating changes in their genetic material as they infect new patients.
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17 MeSH Terms
Clinical profile of children with norovirus disease in rotavirus vaccine era.
Wikswo ME, Desai R, Edwards KM, Staat MA, Szilagyi PG, Weinberg GA, Curns AT, Lopman B, Vinjé J, Parashar UD, Payne DC, Hall AJ
(2013) Emerg Infect Dis 19: 1691-3
MeSH Terms: Caliciviridae Infections, Case-Control Studies, Child, Preschool, Diarrhea, Gastroenteritis, Humans, Infant, Norovirus, Rotavirus Vaccines, United States, Vaccination
Added May 28, 2014
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11 MeSH Terms
Comparison of 2 assays for diagnosing rotavirus and evaluating vaccine effectiveness in children with gastroenteritis.
Tate JE, Mijatovic-Rustempasic S, Tam KI, Lyde FC, Payne DC, Szilagyi P, Edwards K, Staat MA, Weinberg GA, Hall CB, Chappell J, McNeal M, Gentsch JR, Bowen MD, Parashar UD
(2013) Emerg Infect Dis 19: 1245-52
MeSH Terms: Acute Disease, Case-Control Studies, Child, Preschool, Enzyme-Linked Immunosorbent Assay, Gastroenteritis, Humans, Infant, Molecular Diagnostic Techniques, Real-Time Polymerase Chain Reaction, Rotavirus, Rotavirus Infections, Rotavirus Vaccines, Vaccination, Vaccine Potency
Show Abstract · Added May 28, 2014
We compared rotavirus detection rates in children with acute gastroenteritis (AGE) and in healthy controls using enzyme immunoassays (EIAs) and semiquantitative real-time reverse transcription PCR (qRT-PCR). We calculated rotavirus vaccine effectiveness using different laboratory-based case definitions to determine which best identified the proportion of disease that was vaccine preventable. Of 648 AGE patients, 158 (24%) were EIA positive, and 157 were also qRT-PCR positive. An additional 65 (10%) were qRT-PCR positive but EIA negative. Of 500 healthy controls, 1 was EIA positive and 24 (5%) were qRT-PCR positive. Rotavirus vaccine was highly effective (84% [95% CI 71%-91%]) in EIA-positive children but offered no significant protection (14% [95% CI -105% to 64%]) in EIA-negative children for whom virus was detected by qRT-PCR alone. Children with rotavirus detected by qRT-PCR but not by EIA were not protected by vaccination, suggesting that rotavirus detected by qRT-PCR alone might not be causally associated with AGE in all patients.
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14 MeSH Terms
Etiology of viral gastroenteritis in children <5 years of age in the United States, 2008-2009.
Chhabra P, Payne DC, Szilagyi PG, Edwards KM, Staat MA, Shirley SH, Wikswo M, Nix WA, Lu X, Parashar UD, Vinjé J
(2013) J Infect Dis 208: 790-800
MeSH Terms: Child, Preschool, Feces, Female, Gastroenteritis, Humans, Infant, Infant, Newborn, Male, Molecular Typing, Phylogeny, United States, Virus Diseases, Viruses
Show Abstract · Added May 28, 2014
BACKGROUND - Although rotavirus and norovirus cause nearly 40% of severe endemic acute gastroenteritis (AGE) in children <5 years of age in the United States, there are limited data on the etiologic role of other enteric viruses in this age group.
METHODS - We conducted active population-based surveillance in children presenting with AGE to hospitals, emergency departments, and primary care clinics in 3 US counties. Stool specimens from these children and from age-matched healthy controls collected between October 2008 and September 2009 were tested for enteric adenovirus, astrovirus, sapovirus, parechovirus, bocavirus, and aichivirus. Typing was performed by sequencing and phylogenetic analysis.
RESULTS - Adenovirus, astrovirus, sapovirus, parechovirus, bocavirus, and aichivirus were detected in the stool specimens of 11.8%, 4.9%, 5.4%, 4.8%, 1.4%, and 0.2% of patients with AGE and 1.8%, 3.0%, 4.2%, 4.4%, 2.4%, and 0% of healthy controls, respectively. Adenovirus (type 41), astrovirus (types 1, 2, 3, 4, and 8), sapovirus (genogroups I and II), parechovirus (types 1, 3, 4, and 5), and bocavirus (types 1, 2, and 3) were found cocirculating.
CONCLUSIONS - Adenovirus, astrovirus, and sapovirus infections were detected in 22.1% of the specimens from children <5 years of age who had medical visits for AGE and tested negative for rotavirus and norovirus. No causal role for parechovirus and bocavirus was found.
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13 MeSH Terms
Determining the effectiveness of the pentavalent rotavirus vaccine against rotavirus hospitalizations and emergency department visits using two study designs.
Donauer S, Payne DC, Edwards KM, Szilagyi PG, Hornung RW, Weinberg GA, Chappell J, Hall CB, Parashar UD, Staat MA
(2013) Vaccine 31: 2692-7
MeSH Terms: Case-Control Studies, Child, Child, Preschool, Cohort Studies, Emergency Service, Hospital, Female, Gastroenteritis, Hospitalization, Humans, Infant, Male, New York, Ohio, Proportional Hazards Models, Prospective Studies, Rotavirus, Rotavirus Infections, Rotavirus Vaccines, Tennessee, Vaccines, Attenuated
Show Abstract · Added May 28, 2014
The objective of this study is to determine the vaccine effectiveness (VE) of the pentavalent rotavirus vaccine (RV5) for preventing rotavirus-related hospitalizations and emergency department (ED) visits during the 2006-07 and 2007-08 rotavirus seasons using two study designs. Active, prospective population-based surveillance was conducted to identify cases of laboratory-confirmed rotavirus-related hospitalizations and ED visits to be used in case-cohort and case-control designs. VE was calculated using one comparison group for the case-cohort method and two comparison groups for the case-control method. The VE estimates produced by the three analyses were similar. Three doses of RV5 were effective for preventing rotavirus-related hospitalizations and ED visits in each analysis, with VE estimated as 92% in all three analyses. Two doses of RV5 were also effective, with VE ranging from 79% to 83%. A single dose was effective in the case-cohort analysis, but was not significant in either of the case-control analyses. The case-cohort and the case-control study designs produced the same VE point estimates for completion of the three dose series. Two and three doses of RV5 were effective in preventing rotavirus-related hospitalizations and ED visits.
Copyright © 2013 Elsevier Ltd. All rights reserved.
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20 MeSH Terms
Norovirus and medically attended gastroenteritis in U.S. children.
Payne DC, Vinjé J, Szilagyi PG, Edwards KM, Staat MA, Weinberg GA, Hall CB, Chappell J, Bernstein DI, Curns AT, Wikswo M, Shirley SH, Hall AJ, Lopman B, Parashar UD
(2013) N Engl J Med 368: 1121-30
MeSH Terms: Acute Disease, Ambulatory Care, Caliciviridae Infections, Child, Preschool, Emergency Service, Hospital, Female, Gastroenteritis, Health Care Costs, Hospitalization, Humans, Infant, Male, Norovirus, Population Surveillance, Prospective Studies, Rotavirus, Rotavirus Infections, United States
Show Abstract · Added May 28, 2014
BACKGROUND - Cases of rotavirus-associated acute gastroenteritis have declined since the introduction of rotavirus vaccines, but the burden of norovirus-associated acute gastroenteritis in children remains to be assessed.
METHODS - We conducted active surveillance for laboratory-confirmed cases of norovirus among children younger than 5 years of age with acute gastroenteritis in hospitals, emergency departments, and outpatient clinical settings. The children resided in one of three U.S. counties during the years 2009 and 2010. Fecal specimens were tested for norovirus and rotavirus. We calculated population-based rates of norovirus-associated acute gastroenteritis and reviewed billing records to determine medical costs; these data were extrapolated to the U.S. population of children younger than 5 years of age.
RESULTS - Norovirus was detected in 21% of young children (278 of 1295) seeking medical attention for acute gastroenteritis in 2009 and 2010, with norovirus detected in 22% (165 of 742) in 2009 and 20% (113 of 553) in 2010 (P=0.43). The virus was also detected in 4% of healthy controls (19 of 493) in 2009. Rotavirus was identified in 12% of children with acute gastroenteritis (152 of 1295) in 2009 and 2010. The respective rates of hospitalization, emergency department visits, and outpatient visits for the norovirus were 8.6, 146.7, and 367.7 per 10,000 children younger than 5 years of age in 2009 and 5.8, 134.3, and 260.1 per 10,000 in 2010, with an estimated cost per episode of $3,918, $435, and $151, respectively, in 2009. Nationally, we estimate that the average numbers of annual hospitalizations, emergency department visits, and outpatient visits due to norovirus infection in 2009 and 2010 among U.S. children in this age group exceeded 14,000, 281,000, and 627,000, respectively, with more than $273 million in treatment costs each year.
CONCLUSIONS - Since the introduction of rotavirus vaccines, norovirus has become the leading cause of medically attended acute gastroenteritis in U.S. children and is associated with nearly 1 million health care visits annually. (Funded by the Centers for Disease Control and Prevention.).
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18 MeSH Terms
Effectiveness of pentavalent and monovalent rotavirus vaccines in concurrent use among US children <5 years of age, 2009-2011.
Payne DC, Boom JA, Staat MA, Edwards KM, Szilagyi PG, Klein EJ, Selvarangan R, Azimi PH, Harrison C, Moffatt M, Johnston SH, Sahni LC, Baker CJ, Rench MA, Donauer S, McNeal M, Chappell J, Weinberg GA, Tasslimi A, Tate JE, Wikswo M, Curns AT, Sulemana I, Mijatovic-Rustempasic S, Esona MD, Bowen MD, Gentsch JR, Parashar UD
(2013) Clin Infect Dis 57: 13-20
MeSH Terms: Ambulatory Care, Child, Preschool, Enzyme-Linked Immunosorbent Assay, Feces, Female, Gastroenteritis, Genotype, Hospitalization, Humans, Infant, Male, Rotavirus, Rotavirus Infections, Rotavirus Vaccines, United States, Vaccines, Attenuated
Show Abstract · Added May 28, 2014
BACKGROUND - We assessed vaccine effectiveness (VE) for RotaTeq (RV5; 3 doses) and Rotarix (RV1; 2 doses) at reducing rotavirus acute gastroenteritis (AGE) inpatient and emergency department (ED) visits in US children.
METHODS - We enrolled children <5 years of age hospitalized or visiting the ED with AGE symptoms from November 2009-June 2010 and from November 2010-June 2011 at 7 medical institutions. Fecal specimens were tested for rotavirus by enzyme immunoassay and genotyped. Vaccination among laboratory-confirmed rotavirus cases was compared with rotavirus-negative AGE controls. Regression models calculated VE estimates for each vaccine, age, ethnicity, genotype, and clinical setting.
RESULTS - RV5-specific analyses included 359 rotavirus cases and 1811 rotavirus-negative AGE controls. RV1-specific analyses included 60 rotavirus cases and 155 rotavirus-negative AGE controls. RV5 and RV1 were 84% (95% confidence interval [CI], 78%-88%) and 70% (95% CI, 39%-86%) effective, respectively, against rotavirus-associated ED visits and hospitalizations combined. By clinical setting, RV5 VE against ED and inpatient rotavirus-associated visits was 81% (95% CI, 70%-84%) and 86% (95% CI, 74%-91%), respectively. RV1 was 78% (95% CI, 46%-91%) effective against ED rotavirus disease; study power was insufficient to evaluate inpatient RV1 VE. No waning of immunity was evident during the first 4 years of life for RV5, nor during the first 2 years of life for RV1. RV5 provided genotype-specific protection against each of the predominant strains (G1P[8], G2P[4], G3P[8], G12P[8]), while RV1 VE was statistically significant for the most common genotype, G3P[8].
CONCLUSIONS - Both RV5 and RV1 significantly protected against medically attended rotavirus gastroenteritis in this real-world assessment.
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16 MeSH Terms