Immunology and Infectious Diseases

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Immunology and Infectious Diseases

Calgary, Canada
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PubMed | McMaster University, Immunology and Infectious Diseases. and University of Calgary
Type: Journal Article | Journal: Open forum infectious diseases | Year: 2016

Background. Seronegative human immunodeficiency virus (HIV) infections are exceedingly rare but might inform HIV-host physiology. Methods. We investigate the cause and consequences of a patient infected with HIV who did not mount a humoral response to HIV for 4 years. Results. The patient was confirmed HIV-uninfected by nucleic acid testing 4 months before rapidly progressing to acquired immune deficiency syndrome. The patients humoral deficit was specific to HIV: he mounted robust humoral responses to all challenge vaccines including influenza A(H1N1)pdm09 and all T cell-dependent and -independent serotypes in the 23-valent pneumococcal polysaccharide vaccine. The virus had similar gp120 antigenicity to HIV-positive control serum as NL4-3 and YU2 prototype strains. Two human leukocyte antigen alleles associated with rapid progression were identified (B*08 and B*35), and a cytotoxic T-lymphocyte epitope site variant was noted: E277K. Viral decay (t 1/2 39 weeks) suggested that relatively long-lived cells were the source of ongoing viremia. Human immunodeficiency virus viremia was not suppressed until after the patient developed a humoral immune response, despite therapeutic antiretroviral levels. No resistance was detected by virtual phenotyping of virus obtained from serum or from gastrointestinal biopsies despite considerable antiretroviral selection pressure. Conclusions. Ineffective antibody production may be associated with a subgroup of extremely rapid HIV progressors. Although antiretroviral therapy may be sufficient to slow propagation of infection, it appears to be ineffective for HIV viral clearance in the absence of a humoral response.

News Article | April 1, 2016

A team led by Purdue University researchers is the first to determine the structure of the Zika virus, which reveals insights critical to the development of effective antiviral treatments and vaccines. The team also identified regions within the Zika virus structure where it differs from other flaviviruses, the family of viruses to which Zika belongs that includes dengue, West Nile, yellow fever, Japanese encephalitis and tick-borne encephalitic viruses. A paper detailing the findings was published Thursday, March 31, in the journal Science and is available online. Any regions within the virus structure unique to Zika have the potential to explain differences in how a virus is transmitted and how it manifests as a disease, said Richard Kuhn, director of the Purdue Institute for Inflammation, Immunology and Infectious Diseases (PI4D) who led the research team with Michael Rossmann, Purdue's Hanley Distinguished Professor of Biological Sciences. "The structure of the virus provides a map that shows potential regions of the virus that could be targeted by a therapeutic treatment, used to create an effective vaccine or to improve our ability to diagnose and distinguish Zika infection from that of other related viruses," said Kuhn, who also is head of Purdue's Department of Biological Sciences. "Determining the structure greatly advances our understanding of Zika - a virus about which little is known. It illuminates the most promising areas for further testing and research to combat infection." The Zika virus, a mosquito-borne disease, has recently been associated with a birth defect called microcephaly that causes brain damage and an abnormally small head in babies born to mothers infected during pregnancy. It also has been associated with the autoimmune disease Guillain-Barré syndrome, which can lead to temporary paralysis. In the majority of infected individuals symptoms are mild and include fever, skin rashes and flulike illness, according to the World Health Organization. Zika virus transmission has been reported in 33 countries. Of the countries where Zika virus is circulating 12 have reported an increased incidence of Guillain-Barré syndrome, and Brazil and French Polynesia have reported an increase in microcephaly, according to WHO. In February WHO declared the Zika virus to be "a public health emergency of international concern." "This breakthrough illustrates not only the importance of basic research to the betterment of human health, but also its nimbleness in quickly addressing a pressing global concern," said Purdue President Mitch Daniels. "This talented team of researchers solved a very difficult puzzle in a remarkably short period of time, and have provided those working on developing vaccines and treatments to stop this virus a map to guide their way." Rossmann and Kuhn collaborated with Theodore Pierson, chief of the viral pathogenesis section of the Laboratory of Viral Diseases at the National Institutes of Health National Institute of Allergy and Infectious Diseases. Additional research team members include Purdue graduate student Devika Sirohi and postdoctoral research associates Zhenguo Chen, Lei Sun and Thomas Klose. The team's paper marks the first published success of the new Purdue Institute for Inflammation, Immunology and Infectious Diseases in Purdue's Discovery Park. The university's recently announced $250 million investment in the life sciences funded the purchase of advanced equipment that allowed the team to do in a couple of months what otherwise would have taken years, Rossmann said. "We were able to determine through cryo-electron microscopy the virus structure at a resolution that previously would only have been possible through X-ray crystallography," he said. "Since the 1950s X-ray crystallography has been the standard method for determining the structure of viruses, but it requires a relatively large amount of virus, which isn't always available; it can be very difficult to do, especially for viruses like Zika that have a lipid membrane and don't organize accurately in a crystal; and it takes a long time. Now we can do it through electron microscopy and view the virus in a more native state. This was unthinkable only a few years ago." The team studied a strain of Zika virus isolated from a patient infected during the French Polynesia epidemic and determined the structure to 3.8Å. At this near-atomic resolution key features of the virus structure can be seen and groups of atoms that form specific chemical entities, such as those that represent one of 20 naturally occurring amino acids, can be recognized, Rossmann said. The team found the structure to be very similar to that of other flaviviruses with an RNA genome surrounded by a lipid, or fatty, membrane inside an icosahedral protein shell. The strong similarity with other flaviviruses was not surprising and is perhaps reassuring in terms of vaccine development already underway, but the subtle structural differences are possibly key, Sirohi said. "Most viruses don't invade the nervous system or the developing fetus due to blood-brain and placental barriers, but the association with improper brain development in fetuses suggest Zika does," Sirohi said. "It is not clear how Zika gains access to these cells and infects them, but these areas of structural difference may be involved. These unique areas may be crucial and warrant further investigation." The team found that all of the known flavivirus structures differ in the amino acids that surround a glycosylation site in the virus shell. The shell is made up of 180 copies of two different proteins. These, like all proteins, are long chains of amino acids folded into particular structures to create a protein molecule, Rossmann said. The glycosylation site where Zika virus differs from other flaviviruses protrudes from the surface of the virus. A carbohydrate molecule consisting of various sugars is attached to the viral protein surface at this site. In many other viruses it has been shown that as the virus projects a glycosylation site outward, an attachment receptor molecule on the surface of a human cell recognizes the sugars and binds to them, Kuhn said. The virus is like a menacing stranger luring an unsuspecting victim with the offer of sweet candy. The human cell gladly reaches out for the treat and then is caught by the virus, which, once attached, may initiate infection of that cell. The glycosylation site and surrounding residues on Zika virus may also be involved in attachment to human cells, and the differences in the amino acids between different flaviviruses could signify differences in the kinds of molecules to which the virus can attach and the different human cells it can infect, Rossmann said. "If this site functions as it does in dengue and is involved in attachment to human cells, it could be a good spot to target an antiviral compound," Rossmann said. "If this is the case, perhaps an inhibitor could be designed to block this function and keep the virus from attaching to and infecting human cells." The team plans to pursue further testing to evaluate the different regions as targets for treatment and to develop potential therapeutic molecules, Kuhn said. Kuhn and Rossmann have studied flaviviruses, the family of viruses to which Zika belongs, for more than 14 years. They were the first to map the structure of any flavivirus when they determined the dengue virus structure in 2002. In 2003 they were first to determine the structure of West Nile virus and now they are the first to do so with the Zika virus.

MEDFORD/SOMERVILLE (December 22, 2016) - Female fireflies have long known that the best romances are with a male firefly who offers the most nourishing and largest "nuptial gift" - a protein-packed capsule of sperm that is rich with egg-producing and life-extending nutrients for the female. However, the molecular composition of nuptial gifts has remained unknown even though the gifts offer benefits that keep a female firefly coming back for more. Now, new research at Tufts University, in collaboration with MIT scientists, reveals the mystery of this special package, offers the first peek into the content of firefly gifts, and sheds new light on post-mating sexual selection. The findings were published today in Scientific Reports. Focusing on the common Eastern firefly, Photinus pyralis, also known as the Big Dipper, researchers found more than 200 identifiable proteins within the nuptial gifts. The proteins' diverse functions can be inferred based on their resemblance to proteins known from other insects. Some are structural proteins that make up the fabric of the nuptial gift, while others are enzymes that may help unpackage the gift, allowing its contents to be released. Still other enzymes appear to be a biochemical way of nudging the female to lay more eggs. The researchers also identified enzymes that might enhance a male's paternity success by expediting sperm storage or by increasing the ability of male sperm to fertilize the female's eggs. Corresponding author Sara Lewis, Ph.D., professor of biology in the School of Arts and Sciences at Tufts University, said new technologies enabled the research group to decipher exactly what's inside these amorous bundles. Among the new advances used were studies of gene expression within the reproductive glands of male fireflies and proteomic analysis to identify specific proteins that get transferred to females during mating. "We found that firefly nuptial gifts are complex, elegant structures manufactured by a bevy of male glands," said Nooria Al-Wathiqui, who earned her Ph.D. at Tufts in 2016 and is co-first author of the study. "In fact, if you look inside a male firefly, you'll find them jam-packed with gift-making machinery." Although gene expression and proteomic studies give insight into gift protein composition, different approaches were needed to reveal other ingredients that might be contained within male gifts. So researchers conducted a high-resolution metabolomic exploration that found that firefly nuptial gifts also contain lucibufagin, a bitter-tasting toxin shown in previous work to protect firefly eggs and adults. Females might use these male-donated toxins to help defend themselves or their offspring against predators. "We knew a lot about firefly courtship, but we were still in the dark about firefly sex," said Lewis. "I think it's safe to say that adult fireflies are obsessed with sex." The Lewis Lab at Tufts has been researching firefly sex for more than two decades. The lab's previous field and laboratory studies have shown that females choose their mates based on the timing of males' bioluminescent courtship flashes and that firefly females mate with several different males across successive nights. The lab also discovered that female fireflies benefit from male nuptial gifts with higher lifetime egg production and increased longevity, while also finding that males who provide larger gifts are able to sire more of the females' offspring. Deciphering what makes certain males more successful after mating has proven to be very challenging because post-mating events transpire within the hidden recesses of the female reproductive tract. Future studies will investigate the roles played by specific components of the male gift in promoting female egg production and improving male reproductive success. More studies also are needed to determine how the anti-predator toxins donated by male fireflies contribute to protecting females and their offspring. "This study opens up so many exciting avenues for future sexual selection research in fireflies and in other gift-giving insects," said Lewis who appeared in TED2014Talks. In addition to Lewis and Al-Wathiqui, authors include: co-first author Timothy R. Fallon, a Ph.D. student at the Whitehead Institute for Biomedical Research at Massachusetts Institute of Technology; co-corresponding author Jing-Ke Weng, a member of the Whitehead Institute for Biomedical Research and associate professor of biology at Massachusetts Institute of Technology; and Adam South, who earned his Ph.D. at Tufts in 2012 and is currently a postdoctoral fellow in the Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health at Harvard University. This work was funded in part by Tufts University, the Beckman Young Investigator Program, Pew Scholars Program in the Biomedical Sciences, and the Searle Scholars Program. Tufts University, located on campuses in Boston, Medford/Somerville and Grafton, Massachusetts, and in Talloires, France, is recognized among the premier research universities in the United States. Tufts enjoys a global reputation for academic excellence and for the preparation of students as leaders in a wide range of professions. A growing number of innovative teaching and research initiatives span all Tufts campuses, and collaboration among the faculty and students in the undergraduate, graduate and professional programs across the university's schools is widely encouraged.

Santacroce L.,Immunology and Infectious Diseases | Carlaio R.G.,University of Bari | Bottalico L.,Immunology and Infectious Diseases
Endocrine, Metabolic and Immune Disorders - Drug Targets | Year: 2010

Epidemiological studies indicated that more than 15% of the population in western countries suffer because of severe forms of periodontitis. In this respect, the recognition of the relationship between oral and systemic health is growing, thus receiving remarkable interest in scientific literature. In fact, periodontitis may increase the risk for a group of life-threatening conditions such as atherosclerosis, stroke or low birth weight. The American Diabetes Association has reported that individuals with uncontrolled diabetes (defined as 200mg/dL of glucose on three consecutive readings) undergo an increased risk of infections, abnormal wound healing and consequent increased recovery time. Moreover, diabetics may be more likely to develop periodontal and cardiovascular disease than non diabetics, if note. History of poorly controlled chronic periodontal disease can alter diabetic/glycemic control. This may originate from a likely continuous passage of bacterial toxins and/or bacteria into the bloodstream, and/or from an exaggerated release of inflammatory mediators. This review is aimed at elucidating the connections between the status of oral health and glycemic control in diabetes.

News Article | April 1, 2016

The destructive Zika virus has been visualized for the first time, shedding light on similarities and differences between this and related viruses, according to a new study. The new findings may be helpful in developing effective antiviral treatments and vaccines against the Zika virus, the researchers said. "The structure of the virus provides a map that shows potential regions of the virus that could be targeted by a therapeutic treatment, used to create an effective vaccine, or [used] to improve our ability to diagnose and distinguish Zika infection from that of other related viruses," Richard Kuhn, the director of the Purdue University Institute for Inflammation, Immunology and Infectious Diseases in Indiana and a co-author on the study, said in a statement. "Determining the structure greatly advances our understanding of Zika, a virus about which little is known," he said. [Zika Virus News: Complete Coverage of The Outbreak] Although the Zika virus usually causes mild or no symptoms, health officials are concerned about a link between Zika infection in pregnant women and a birth defect called microcephaly, or an abnormally small head. The transmission of the Zika virus has so far been reported in 39 countries and territories. Of these locations, Brazil and French Polynesia have reported an increase in microcephaly, according to the World Health Organization. In addition, 12 of the locations with Zika cases have reported increases in cases of a rare neurological condition called Guillain-Barré syndrome, which causes muscle weakness and, sometimes, paralysis in kids and adults. In the new study, researchers looked at a strain of the virus isolated from a patient who had been infected with Zika during an epidemic in French Polynesia in 2013-14. The researchers found that the structure of the virus is very similar to that of other flaviviruses, a family of viruses that also includes dengue, West Nile and yellow fever. The structure of the Zika virus appeared to be particularly similar to the structure of dengue, the study said. "In essence, all these viruses have the same shape and structure, but they enter different kinds of cells," and therefore lead to different illnesses, said Michael Rossmann, a professor of biological sciences at Purdue University and a co-author on the study. However, the researchers did find a certain structural difference between Zika and these related viruses.  That difference is found in an area of the virus that may be important for how the virus attaches to human cells, which types of cells it may enter and how the resulting disease may progress. [5 Things to Know About Zika Virus] There is an equivalent of this particular area found in the dengue virus, and it is involved in how that virus attaches to human cells. If the Zika virus's version of this area serves the same function as in dengue, and is therefore also involved in attachment to human cells, that suggests a possible treatment, Rossmann said.  "Perhaps an inhibitor could be designed to block this function and keep the virus from attaching to and infecting human cells," Rossmann told Live Science. It is also possible that this area of structural difference is somehow involved in the association between Zika virus infection and improper brain development in fetuses, but more research is needed to investigate this question, the researchers said. Though the researchers now have a much better understanding of what the virus looks like, efforts to actually inhibit it may take a long time, Rossmann said. "People should not expect a sudden result," he said. The new study was published today (March 31) in the journal Science. Copyright 2016 LiveScience, a Purch company. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.

PubMed | University of Amsterdam, Immunology and Infectious Diseases. and Academic Medical Center Amsterdam
Type: Journal Article | Journal: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America | Year: 2015

Despite the declining incidence of severe neurological complications such as HIV encephalopathy, human immunodeficiency virus (HIV) infection in children is still associated with a range of cognitive problems. Although most HIV-infected children in industrialized countries are immigrants with a relatively low socioeconomic status (SES), cognitive studies comparing HIV-infected children to SES-matched controls are lacking.This cross-sectional study included perinatally HIV-infected children and controls matched for age, sex, ethnicity, and SES, who completed a neuropsychological assessment evaluating intelligence, information processing speed, attention, memory, executive function, and visual-motor function. Multivariate normative comparison was used to assess the prevalence of cognitive impairment in the HIV-infected group. Multivariable regression analyses were performed to identify HIV- and combination antiretroviral therapy-related factors associated with cognitive performance.In total, 35 perinatally HIV-infected children (median age, 13.8 years; median CD4 count, 770 10(6) cells/L; 83% with undetectable HIV RNA) and 37 healthy children (median age, 12.1 years) were included. HIV-infected children scored lower than the healthy controls on all cognitive domains (eg, intelligence quotient [IQ], 76 [standard deviation {SD}, 15.7] vs 87.5 [SD, 13.6] for HIV-infected vs healthy children; P = .002). Cognitive impairment was found in 6 HIV-infected children (17%). The Centers for Disease Control and Prevention (CDC) clinical category at HIV diagnosis was inversely associated with verbal IQ (CDC clinical category C: coefficient -22.98; P = .010).Our results show that cognitive performance of HIV-infected children is poor compared with that of SES-matched healthy controls. Gaining insight into these cognitive deficits is essential, as subtle impairments may progress to more pronounced complications that will influence future intellectual performance, job opportunities, and community participation of HIV-infected children.

Thornton C.S.,Immunology and Infectious Diseases | Brown E.L.,Immunology and Infectious Diseases | Alcantara J.,Immunology and Infectious Diseases | Rabin H.R.,Immunology and Infectious Diseases | Parkins M.D.,Immunology and Infectious Diseases
BMC Pulmonary Medicine | Year: 2015

Background: Cystic fibrosis (CF) is a genetic disease characterized by complex polymicrobial communities within the lower respiratory tract. S. pneumoniae, while a well-defined pathogen in the general population, has rarely been identified in CF. Furthermore, prevalence studies on Pneumococcus in CF have predominantly focused on the infant and pediatric populations, and outcome data is lacking. Methods: Through a review of our comprehensive clinical and microbiologic database from a single adult CF center in Canada from 1978-2013 we sought to determine the incidence, prevalence, serotype and clinical impact of Pneumococcus in adults with CF. Results: Only fifteen of 318 adult CF patients (5%) were ever found to have transient Pneumococcus colonization, and none developed persistent infection although length of carriage varied. As all isolates were stored, capsular serotyping could be performed using a multiplex PCR panel. Capsular serotyping revealed a varied distribution of several serotypes within these isolates. Lung function testing at time of incident Pneumococcus isolation was compared with values before and after isolation and showed no significant reduction in spirometry values, nor was there an increased need for rescue antibacterial therapy. Conclusion: Within our center, incident Pneumococcus infection is neither common, associated with a disproportionate clinical deterioration nor results in chronic infection. © 2015 Thornton et al.; licensee BioMed Central.

Haverman L.,Emma Childrens A3 241 Hospital | van Oers H.A.,Emma Childrens A3 241 Hospital | Maurice-Stam H.,Emma Childrens A3 241 Hospital | Kuijpers T.W.,Emma Childrens Hospital | And 2 more authors.
Pediatric Rheumatology | Year: 2014

Background: A chronic illness, such as Juvenile Idiopathic Arthritis (JIA), has an impact on the whole family, especially on parents caring for the ill child. Therefore the aim of this study is to evaluate parental Health Related Quality of Life (HRQOL) and parental perceptions of child vulnerability (PPCV) and associated variables in parents of a child with JIA.Methods: Parents of all JIA patients (0-18 years) in Amsterdam, the Netherlands, were eligible. HRQOL was measured using the TNO-AZL Questionnaire (TAAQOL) and PPCV using the Child Vulnerability Scale (CVS). The HRQOL of parents of a child with JIA was compared to a norm population, and differences between parents of a child with JIA and active arthritis versus parents of a child with JIA without active arthritis were analyzed (ANOVA). For PPCV, parents of a child with JIA were compared to a norm population, including healthy and chronically ill children (Chi2, Mann-Whitney U test). Variables associated with PPCV were identified by logistic regression analyses.Results: 155 parents (87.5% mothers) completed online questionnaires. JIA parents showed worse HRQOL than parents of healthy children on one out of twelve domains: fine motor HRQOL (p < .001). Parents of children with active arthritis showed worse HRQOL regarding daily activities (p < .05), cognitive functioning (p < .01) and depressive emotions (p < .05) compared to parents of children without active arthritis. Parents of children with JIA perceived their child as more vulnerable than parents of a healthy child (p < .001) and parents of a chronically ill child (p < .001). Parents of children with active arthritis reported higher levels of PPCV (p < .05) than parents of children without active arthritis. A higher degree of functional disability (p < .01) and shorter disease duration (p < .05) were associated with higher levels of PPCV.Conclusion: The HRQOL of JIA parents was comparable to the HRQOL of parents of a healthy child. JIA parents of a child with active arthritis showed worse HRQOL than parents of a child without active arthritis. Parents perceived their child with JIA as vulnerable. © 2014 Haverman et al.; licensee BioMed Central Ltd.

Frakking F.N.J.,Emma Childrens Hospital Academic Medical Center | Israels J.,Emma Childrens Hospital Academic Medical Center | Kremer L.C.M.,Emma Childrens Hospital Academic Medical Center | Kuijpers T.W.,Immunology and Infectious Diseases | And 2 more authors.
Pediatric Blood and Cancer | Year: 2011

Background: We determined whether mannose-binding lectin (MBL) deficiency is associated with an increased risk of febrile neutropenia (FN) and/or infection in pediatric oncology patients. Procedure: We systematically searched and reviewed all the literature on MBL and infections in children with cancer, identified from a literature search of Medline, Embase, and Central (1966-April 2010). We extracted information on the type of study, patient characteristics, definition of MBL deficiency, definition of infection and method of detection, follow-up period and the results of the outcome in different groups. The validity of each study was assessed. Results: Six cohort studies were retrieved, consisting of 581 children with leukemia (n=2) or varying types of cancer (n=4). Many different outcome definitions were used. In only one out of three genotype studies, variant MBL2 genotypes, as well as MBL levels <1,000μg/L, were associated with an increased duration of FN. In one additional MBL level study the number of FN episodes, bacteremia and severe bacterial infection were increased in patients with MBL levels <100μg/L as compared to those with MBL levels of 100-999μg/L. Sepsis, pneumonia, viral infection, and fungal infection were not associated with either MBL levels or genotypes in any of the studies. Conclusions: MBL deficiency could not be identified as an independent risk factor for FN or infection in pediatric oncology patients. A multicenter study of children with comparable chemotherapy regimens, relevant and equal outcome definitions and measuring both MBL levels and genotypes, will be required to avoid clinical and methodological inconsistencies. © 2010 Wiley-Liss, Inc.

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