Pathogenesis and Epidemiology of Orthomyxoviruses

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

Structure and Replication of Orthomyxoviruses

Introduction

Influenza A, B, and C viruses are the only members of the Orthomyxoviridae family, and only influenza A and B viruses cause significant human disease. The orthomyxoviruses are enveloped and have a segmented negative-sense RNA genome. The segmented genome of these viruses facilitates the development of new strains through the mutation and reassortment of the gene segments among different human and animal (influenza A) strains of virus. This genetic instability is responsible for the annual epidemics (mutation: drift) and periodic pandemics (reassortment: shift) of influenza infection worldwide.

Influenza is one of the most prevalent and significant viral infections. There are even descriptions of influenza epidemics (local dissemination) that occurred in ancient times. Probably the most famous influenza pandemic (worldwide) is the Spanish influenza that swept the world in 1918 to 1919, killing 20 to 40 million people. In fact, more people died of influenza during that time than in the battles of World War I. Pandemics caused by novel influenza viruses occurred in 1918, 1947, 1957, 1968, and 1977, but fortunately none have occurred since. New virus strains have been detected since the last pandemic, including an outbreak of avian influenza first noted in Hong Kong in 1997, which has caused some human disease and fatalities. Fortunately, prophylaxis in the form of vaccines and antiviral drugs is now available for people at risk for serious outcomes.

To read more click on this link to the full article: Structure and Replication of Orthomyxoviruses.

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How Dengue Infection Hits Harder the Second Time Around

One of the most vexing challenges in the battle against dengue virus, a mosquito-borne virus responsible for 50-100 million infections every year, is that getting infected once can put people at greater risk for a more severe infection down the road.

The cluster of dark dots near the center of this micrograph shows dengue virus particles. (Credit: CDC)

Now, for the first time, an international team of researchers that includes experts from the University of California, Berkeley, has pulled apart the mechanism behind changing dengue virus genetics and dynamics of host immunity, and they are reporting their findings in the Dec. 21 issue of Science Translational Medicine.

The virus that causes dengue disease is divided into four closely related serotypes (dengue virus 1, 2, 3 and 4), and those serotypes can be further divided into genetic variants, or subtypes.

The researchers showed that a person’s prior immune response to one serotype of dengue virus could influence the interaction with virus subtypes in a subsequent infection. How that interaction plays out could mean the difference between getting a mild fever and going into a fatal circulatory failure from dengue hemorrhagic fever or dengue shock syndrome.

The findings have implications for the efforts to combat a disease that has grown dramatically in recent decades, including the development of a first-ever dengue vaccine.

According to the World Health Organization, dengue disease is now endemic in more than 100 countries around the world, and recent estimates say some 3 billion people — almost half of the world’s population — are at risk.

It was already known that upon a person’s first infection with dengue virus, the immune system reacts normally by creating antibodies to fight the viral invaders. The problem is that those antibodies can then be confused if confronted later with one of the other three types of dengue virus, and as this new study revealed, even different subtypes within the same serotype.

“With the second infection, the antibodies sort of recognize the new type of viruses, but not well enough to clear them from the system,” said study lead author Molly OhAinle, post-doctoral fellow in infectious diseases at UC Berkeley’s School of Public Health. “Instead of neutralizing the viruses, the antibodies bind to them in a way that actually helps them invade the immune system’s other cells and spread.”

The study authors noted that this Trojan horse effect has been shown before, but the new research provides an analysis of the interplay between viral genetics and immune response with unprecedented detail, going beyond the main serotype.

Putting the puzzle pieces together required UC Berkeley’s expertise in immunology and virology, the genome analysis and biostatistical capabilities at the Broad Institute of Harvard University and Massachusetts Institute of Technology, and the epidemiological and clinical field work at Nicaragua’s National Virology Laboratory.

Researchers used data from two independent, Nicaragua-based studies headed by Eva Harris, professor of infectious diseases and vaccinology and director of UC Berkeley’s Center for Global Public Health, and Dr. Angel Balmaseda, director of the National Virology Laboratory in Nicaragua. One was a hospital-based study that examined children admitted to the National Pediatric Reference hospital with dengue between 2005 and 2009. The other was a prospective study that had followed 3,800 children since 2004, with blood samples collected annually.

By following dengue cases in both studies, researchers were able to identify a dramatic increase in severe dengue disease and then sequence the virus across time. They detected genetic changes in the virus that coincided with changes in disease severity, but only in the context of pre-existing immune response to specific dengue virus serotypes.

They found that children who had antibodies to dengue virus 3, which circulated in the region from 1994-1998, were at greater risk for developing severe infections when exposed to subtype 2B of dengue virus 2. They also found that children who had antibodies to dengue virus 1, which circulated from 2002-2005, were also at increased risk of severe disease from exposure to subtype 1 of dengue virus 2 after an initial period of immunity wore off.

“We showed for dengue that both the subtype of virus you get infected with and whether your body has antibodies to another type of virus matter,” said Matthew Henn, director of viral genomics at the Broad Institute. “If you get the wrong combination of the two, you are more likely to get severe disease. This study provides a framework we can utilize to eventually predict which specific virus types will proliferate in different human populations. We lacked a good model for this previously.”

The researchers followed up with tests in the lab to confirm the complex interplay of viral genetics and immune system response.

Harris understands this risk on a personal level. She has been studying dengue in Nicaragua for 24 years, and in 1995, became infected with dengue virus type 3. That puts her at greater risk for a severe reaction should she become exposed to other dengue virus serotypes.

While no vaccine yet exists for dengue, Harris noted that the vaccines currently under development aim to immunize against all types of the virus.

“Our findings have implications for vaccine development and implementation, as the precise genetics of vaccine strains, as well as the timing and serotype sequence of infection prior to and after vaccination, play an important role in determining the outcome of infection,” she said.

Harris added that this study benefited from decades of productive collaboration between U.S. and Nicaraguan researchers. “It was the multi-disciplinary approach we took to analyzing two high-quality studies that allowed us to untangle this very complex phenomenon,” she said.

Funding from the National Institute of General Medical Sciences, the National Institute of Allergy and Infectious Diseases and the Pediatric Dengue Vaccine Initiative provided support for this research.

Story Source:

The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided byUniversity of California – Berkeley. The original article was written by Sarah Yang.

Journal Reference:

M. OhAinle, A. Balmaseda, A. R. Macalalad, Y. Tellez, M. C. Zody, S. Saborio, A. Nunez, N. J. Lennon, B. W. Birren, A. Gordon, M. R. Henn, E. Harris. Dynamics of Dengue Disease Severity Determined by the Interplay Between Viral Genetics and Serotype-Specific Immunity.Science Translational Medicine, 2011; 3 (114): 114ra128 DOI: 10.1126/scitranslmed.3003084