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How Deadly Marburg Virus Silences Immune System: Breakthrough Findings Point to Targets for Drugs and Vaccines

September 30, 2012 Leave a comment

Scientists at The Scripps Research Institute have determined the structure of a critical protein from the Marburg virus, a close cousin of Ebola virus. These viruses cause similar diseases and are some of the deadliest pathogens on the planet, each killing up to 90 percent of those infected.

The Marburg virus VP35 protein (beige) surrounds the virus’s double-stranded RNA (blue), masking it from immune system detection. (Credit: Image by Christina Corbaci, The Scripps Research Institute) (up)

Described in the Sept. 13, 2012 publication of the journal PLoS Pathogens, the new research reveals how a key protein component of the Marburg virus, called VP35, blocks the human immune system, allowing the virus to grow unchecked. The structure provides a major step forward in understanding how the deadly virus works, and may be useful in the development of potential treatments for those infected.

“The immune system is designed to recognize certain hallmarks of virus infection,” said Erica Ollmann Saphire, the Scripps Research scientist who led the effort. “When these are sensed, an immediate antiviral defense is launched. However, the Marburg and Ebola viruses mask the evidence of their own infection. By doing so, the viruses are able to replicate rapidly and overwhelm the patient’s ability to launch an effective defense.”

Deadly Outbreaks

Ebola virus outbreaks have occurred in the last month in both Uganda and the Democratic Republic of the Congo, while Marburg virus broke out in Angola in 2005 to 2006 and again in Uganda in 2007. The Angolan Marburg virus outbreak began in a pediatric ward and killed 88 percent of those it infected. The virus has since been imported into the United States (Colorado) and the Netherlands by tourists who had visited Africa.

There is currently no cure for Marburg hemorrhagic fever. The virus is spread when people come into contact with the bodily fluids of a person or animal who is already infected. The best treatment consists of administering fluids and taking protective measures to ensure containment, like isolating the patient and washing sheets with bleach.

Most people, however, die within two weeks of exposure from a combination of dehydration, massive bleeding, and shock. A smaller number of people have stronger and immediate immune responses against the virus and survive.

A New Roadmap for Defense

The breakthrough described in the PLoS Pathogens article explains a key reason why the viruses are so deadly and provides the necessary templates to develop drugs to treat the infection.

The study’s lead author, Research Associate Shridhar Bale, explains that a key signature of Marburg virus infection is the double-stranded RNA that results from its replication inside cells. When human immune system proteins detect this virus-specific RNA, they sound an alarm to signal the rest of the immune system to respond. The new research describes how the VP35 protein of the Marburg virus binds to the viral double-stranded RNA and hides it to prevent the alarm from being sounded.

The new research also revealed a surprise. Images from the Marburg virus reveal the VP35 protein spirals around the double-stranded RNA, enveloping it completely. This is in contrast to previous images of the similar VP35 protein from Ebola virus that showed it only capping the ends of the RNA, leaving the center of the RNA helix exposed for possible recognition.

In addition to Ollmann Saphire and Bale, the article, “Marburg virus VP35 can both fully coat the backbone and cap the ends of dsRNA for interferon antagonism,” was authored by Jean-Philippe Julien, Zachary A. Bornholdt, Michelle A. Zandonatti, Gerard J.A. Kroon, Christopher R. Kimberlin, Ian J. MacRae, and Ian A. Wilson of The Scripps Research Institute, and Peter Halfmann, John Kunert, and Yoshihiro Kawaoka of the University of Wisconsin.

Support for the research was provided by grants from the Burroughs Wellcome Fund and The Skaggs Institute for Chemical Biology at Scripps Research.

Source:

The above story is reprinted from materials provided by Scripps Research Institute, via ScienceDaily

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

Bale S, Julien J-P, Bornholdt ZA, Kimberlin CR, Halfmann P, et al. Marburg Virus VP35 Can Both Fully Coat the Backbone and Cap the Ends of dsRNA for Interferon Antagonism. PLoS Pathog. PLoS Pathogens, 2012; 8(9): e1002916 DOI: 10.1371/journal.ppat.1002916

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Pathogenesis and Epidemiology of Orthomyxoviruses

February 3, 2012 Leave a comment

Pathogenesis and Immunity

Influenza initially establishes a local upper respiratory tract infection. To do so, the virus first targets and kills mucus-secreting, ciliated, and other epithelial cells, causing the loss of this primary defense system. NA facilitates the development of the infection by cleaving sialic acid residues of the mucus, thereby providing access to tissue. Preferential release of the virus at the apical surface of epithelial cells and into the lung promotes cell-to-cell spread and transmission to other hosts. If the virus spreads to the lower respiratory tract, the infection can cause severe desquamation (shedding) of bronchial or alveolar epithelium down to a single-cell basal layer or to the basement membrane.

In addition to compromising the natural defenses of the respiratory tract, influenza infection promotes bacterial adhesion to the epithelial cells. Pneumonia may result from a viral pathogenesis or from a secondary bacterial infection. Influenza may also cause a transient or low-level viremia but rarely involves tissues other than the lung.

Histologically, influenza infection leads to an inflammatory cell response of the mucosal membrane, which consists primarily of monocytes and lymphocytes and few neutrophils. Submucosal edema is present. Lung tissue may reveal hyaline membrane disease, alveolar emphysema, and necrosis of the alveolar walls

Interferon and cytokine responses peak at almost the same time as virus in nasal washes and are concomitant with the febrile phase of disease. T-cell responses are important for effecting recovery and immunopathogenesis. However, influenza infection depresses macrophage and T-cell function, hindering immune resolution. Interestingly, recovery often precedes detection of antibody in serum or secretions.

Protection against reinfection is primarily associated with the development of antibodies to HA, but antibodies to NA are also protective. The antibody response is specific for each strain of influenza, but the cell-mediated immune response is more general and is capable of reacting to influenza strains of the same type (influenza A or B virus). Antigenic targets for T-cell responses include peptides from HA but also from the nucleocapsid proteins (NP, PB2) and M1 protein. The NP, PB2, and M1 proteins differ considerably for influenza A and B but not between strains of these viruses; hence T-cell memory may provide future protection against infection by different strains of either influenza A or B.

The symptoms and time course of the disease are determined by interferon and T-cell responses and the extent of epithelial tissue loss. Influenza is normally a self-limited disease that rarely involves organs other than the lung.Many of the classic “flu” symptoms (e.g., fever, malaise, headache, and myalgia) are associated with interferon induction. Repair of the compromised tissue is initiated within 3 to 5 days of the start of symptoms but may take as long as a month or more, especially for elderly people.

To read more click on this link to the full article: Pathogenesis and Epidemiology of Orthomyxoviruses