Category Archives: Infectous Disease

The Insanity Virus-Schizophrenia Could Be Caused By A Virus

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“Steven and David Elmore were born identical twins, but their first days in this world could not have been more different. David came home from the hospital after a week. Steven, born four minutes later, stayed behind in the ICU. For a month he hovered near death in an incubator, wracked with fever from what doctors called a dangerous viral infection. Even after Steven recovered, he lagged behind his twin. He lay awake but rarely cried. When his mother smiled at him, he stared back with blank eyes rather than mirroring her smiles as David did. And for several years after the boys began walking, it was Steven who often lost his balance, falling against tables or smashing his lip.

Those early differences might have faded into distant memory, but they gained new significance in light of the twins’ subsequent lives. By the time Steven entered grade school, it appeared that he had hit his stride. The twins seemed to have equalized into the genetic carbon copies that they were: They wore the same shoulder-length, sandy-blond hair. They were both B+ students. They played basketball with the same friends. Steven Elmore had seemingly overcome his rough start. But then, at the age of 17, he began hearing voices…”

Read the rest of this great article at Discover Magazine Online.

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Irish Researchers Fighting Fungal Infections With Bacteria

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A bacterial pathogen can communicate with yeast to block the development of drug-resistant yeast infections according to Irish scientists writing in the May issue of Microbiology. The research could be a step towards new strategies to prevent hospital-acquired infections associated with medical implants.

Read more at: http://www.scientificblogging.com/subtle_science/blog/irish_researchers_fighting_fungal_infections_bacteria_0

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Ebola-Overview and Recent Discoveries

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Transmission Electron Micrograph of the Ebola ...

Transmission Electron Micrograph of the Ebola Virus. Hemorrhagic Fever, RNA Virus.Image via WikipediaEbola

Introduction to Ebola

Ebola haemorrhagic fever (EHF) is a viral haemorrhagic fever and one of the most virulent viral diseases known to humankind.The Ebola virus was first identified in the western equatorial province of Sudan and in a nearby region of Zaire (now Democratic Republic of the Congo) in 1976 after significant epidemics in Nzara, southern Sudan and Yambuku, northern Zaire.

Species of Ebola

The Ebola virus belongs to the Filoviridae family (filovirus) and has five distinct species: Bundibugyo, Côte d’Ivoire, Reston, Sudan and Zaïre. Bundibugyo, Sudan and Zaïre species have all been associated with large outbreaks of Ebola haemorrhagic fever (EHF) in Africa causing death in 25-90% of all clinically ill cases, however Côte d’Ivoire and Reston have not.(4,5)Human infection with the Ebola Reston subtype, found in the Western Pacific, has only caused asymptomatic illness, meaning that those who contract the disease do not get sick (clinically ill).

Symptoms

Ebola has an incubation period (time between exposure and first symptoms appearing) of two to twenty one days.It is is characterized by the sudden onset of fever, intense weakness, muscle pain, headache and sore throat. This is often followed by vomiting, diarrhoea, rash, impaired kidney and liver function, and in some cases, both internal and external bleeding. Laboratory findings show low counts of white blood cells and platelets as well as elevated liver enzymes. (5)

Transmission

The Ebola virus is transmitted by direct contact with the blood, body fluids and tissues of those who are infected with it. Transmission of the Ebola virus has also occurred by handling sick or dead infected wild animals (chimpanzees, gorillas, monkeys, forest antelope, fruit bats).

Treatment

Severe cases require intensive supportive care, as patients are frequently dehydrated and in need of intravenous fluids or oral re-hydration with solutions containing electrolytes.No specific treatment or vaccine is yet available for Ebola hemorrhagic fever. Several potential vaccines are being tested but it could be several years before any is available.(5)

Natural Reservoir of Ebola

The natural reservoir of the Ebola virus is unknown despite extensive studies but it seems to reside in the rain forests of the African continent and in areas of the Western Pacific.(5)A natural reservoir or nidus is the long-term host of the pathogen (infectous agent) of an infectious disease. It is often the case that hosts do not get the disease carried by the pathogen or it is carried as a subclinical infection and so asymptomatic(no apparent symptoms) and non-lethal.Different hypotheses have been developed to explain the origin of Ebola outbreaks. Laboratory observation has shown that bats experimentally infected with Ebola do not die, and this has raised speculation that these mammals may play a role in maintaining the virus in the tropical forest.Extensive ecological studies are currently under way in the Republic of the Congo and Gabon to identify the Ebola’s natural reservoir.(5)

Life Cycle

Pathogeneis Schematic

  • Virus attaches to host receptors though the GP (glycoprotein) surface peplomer and is endocytosed into vesicles in the host cell.
  • Fusion of virus membrane with the vesicle membrane occurs; nucleocapsid is released into the cytoplasm.
  • The encapsidated, negative-sense genomic ssRNA is used as a template for the synthesis ( 3′ – 5′) of polyadenylated, monocistronic mRNAs.
  • Translation of the mRNA into viral proteins occurs using the host cell’s machinery.
  • Post-translational processing of viral proteins occurs. GP0 (glycoprotein precursor) is cleaved to GP1 and GP2, which are heavily glycosylated. These two molecules assemble, first into heterodimers, and then into trimers to give the surface peplomers. SGP (secreted glycoprotein) precursor is cleaved to SGP and delta peptide, both of which are released from the cell.
  • As viral protein levels rise, a switch occurs from translation to replication. Using the negative-sense genomic RNA as a template, a complementary +ssRNA is synthesized; this is then used as a template for the synthesis of new genomic (-)ssRNA, which is rapidly encapsidated.
  • The newly-formed nucleocapsides and envelope proteins associate at the host cell’s plasma membrane; budding occurs, and the virions are released. (7)

New Discovery

Researchers at Iowa State University have uncovered how the deadly Zaire Ebola virus decoys cells and eventually kills them.A research team led by Gaya Amarasinghe, an assistant professor of biochemistry, biophysics and molecular biology, had previously solved the structure of a critical part of an Ebola protein known as VP35 (Yiral protein 35), which is involved suppression of the hosts immune system.The results of that research were published in the journal Proceedings of the National Academy of Sciences of the United States of America last January.Amarasinghe and his research team now know how VP35 is able to do it.The current research is published in the current issue of the journal Nature Structural and Molecular Biology and is available as an advanced online publication.(1,2,3)

Mechanism of Ebola Immune Evasion

When most viruses invade a cell, they start to make RNA in order to replicate.When the healthy host cell senses the replicating RNA, the host cell starts to activate anti-viral defenses that halt replication and eventually help clear the viral infections.What Amarasinghe and his group have discovered is that Ebola virus encoded VP35 protein actually masks the replicating viral ribonucleic acid (RNA) by binding itself to short double stranded RNA(dsRNA) which results in the cell not realizing it has an invading virus.Intracellular double-stranded RNA (dsRNA) is a chief sign of replication for many viruses. Host mechanisms detect the dsRNA and initiate antiviral responses.(6)

Conserved basic residues in VP35 IID (Interferon Inhibitory Domain)recognize the dsRNA backbone, whereas the dsRNA blunt ends are ‘end-capped’ by a pocket of hydrophobic residues that mimic RIG-I (retinoic acid inducible gene I)–like receptor recognition of blunt-end dsRNA.(1,2)One of the reasons Ebola, in particular the strain isolated from Zaire, is so deadly is that the host cells don’t have any immune response when the virus enters the cell, said Amarasinghe.(1,2)

“The question with Ebola has always been ‘Why can’t host cells mount an immune response against the Ebola virus, like they do against other viruses?’” said Gaya. (2)

“The answer is, ‘If the cell doesn’t know that there’s an infection, it cannot build up any response.’ So our work really gets at the mechanism Ebola infection and immune evasion.(2)

Research

The collaborative approach taken by Amarasinghe enabled him to team up with virologist Christopher Basler at the Mt. Sinai School of Medicine, New York City, to investigate how the structural findings match up with how these proteins function inside the cell.”Our initial structure that we solved in 2008 was key to expanding our knowledge, but the structure was just part of the equation, and when we put it together with the functional studies, everything made sense,” Amarasinghe said.In his current research, Amarasinghe focused on a specific part of the

Phylogenetic tree comparing full-length genomes of ebolavirus and marburgvirus by Bayesian analysis. Posterior probabilities greater than 0.5 and maximum likelihood bootstrap values greater than 50 are indicated at the nodes.

Zaire Ebola VP35 protein that he thought looked unusual.As testing results came in, he found that the suspect region of the protein was binding with, or neutralizing, the part of the host cell that triggers the immune system in the cell. (2)

“The interesting thing about the Ebola virus is that it doesn’t let cells even get started to defend themselves,” he said. “This hides the (viral) RNA from being recognized by the host cell. This is a powerful immune evasion mechanism.” (2)

Other Research Findings

It has also been found that the Ebola virus  disables a cellular protein called tetherin that normally can block the spread of virus from cell to cell.Ebola Glycoprotein (GP) possesses the ability to counteract tetherin, which is both IFN (interferon)-induced in many primary cells and constitutively expressed on the primary targets of Ebola virus infection, particularly monocytes and dendritic cells.Tetherin,also known as Bst-2 or CD317, is one of the immune system’s responses to a viral infection. If working properly, tetherin stops the infected cell from releasing the newly made virus, thus shutting down spread to other cells.(8)Thus when it is antagonized it can no longer block the spread of the virus to other cells.

Ebola also possesses several strategies to antagonize IFN production and signaling. Ebola VP35 prevents IFN production by blocking activation of IFN regulatory factor 3, and VP24 (Viral Protein 24)inhibits IFN responsiveness by blocking the nuclear accumulation of tyrosine-phosphorylated STAT1(signal transducer and activator of transcription 1) . These proteins likely suppress de novo IFN-induced synthesis of viral restriction factors, but constitutive (always on) expression in various cell types remains a restrictive barrier to viral infection. (6,8)

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Further Information

Amarasinghe, along with Daisy Leung, associate scientist; Mina Farahbakhsh, undergraduate student; Eshwar Ramanan, graduate student; Luke Helgeson, undergraduate student; and Richard Honzatko, professor; all from Iowa State’s biochemistry, biophysics and molecular biology department, together with Kathleen Prins, graduate student, and Basler, associate professor; from Mount Sinai School of Medicine; JoAnn Tufariello; assistant clinical professor of the Albert Einstein College of Medicine, New York City; Dominika Borek, instructor; and Zbyszek Otwinowski from the University of Texas Southwestern Medical Center, Dallas; and Jay Nix from the Berkeley National Laboratory, Calif., co-authored this study.

Work in the Amarasinghe laboratory was funded in part by the Roy J. Carver Charitable Trust, National Institutes of Health, and the Midwest Regional Center for Excellence for Biodefense and Emerging Infectious Disease Research. X-ray crystallographic data were collected at the Advanced Light Source beamline 4.2.2., and the Advanced Photon Source Structural Biology Center Sector 19 beamlines.

Sources

1.Leung,Daisy W, Prins,Kathleen C ,Borek,Dominika M , et al (2010)’Structural basis for dsRNA recognition and interferon antagonism by Ebola VP35′ Nature Structural & Molecular Biology [17 January 2010]  doi:10.1038/nsmb.1765

2.http://www.eurekalert.org/pub_releases/2010-01/isu-isu011910.php

References

3.Daisy W. Leunga,Nathaniel D. Gindera,D. Bruce Fultona,Jay Nixb,Christopher F. Baslerc,Richard B. Honzatkoa andGaya K. Amarasinghea1 Structure of the Ebola VP35 interferon inhibitory domain [January 2, 2009], doi: 10.1073/pnas.0807854106

4.WHO ‘Ebola Hemorrhagic Fever’ :http://www.who.int/csr/disease/ebola/en/

5.http://www.who.int/mediacentre/factsheets/fs103/en/index.html

6.Ebola virus VP35 protein binds double-stranded RNA and inhibits alpha/beta interferon production induced by RIG-I signaling.http://www.ncbi.nlm.nih.gov/pubmed/16698997

7.http://biomarker.cdc.go.kr:8080/pathogen/pathogen_view_en.jsp?pclass=2&id=44

8.Rachel L. KaletskyJoseph R. Francica et al (2008)Tetherin-mediated restriction of filovirus budding is antagonized by the Ebola glycoprotein,PNAS,doi: 10.1073/pnas.0811014106

Further Reading

http://www.rcsb.org/pdb/explore/explore.do?structureId=3FKE

http://esciencenews.com/articles/2009/01/27/penn.study.identifies.how.ebola.virus.avoids.immune.system

http://www.cdc.gov/ncidod/dvrd/spb/mnpages/dispages/Ebola.htm

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