Researchers discover a new way that influenza can infect cells

Sep. 23, 2013 — Scientists at Fred Hutchinson Cancer Research Center have uncovered a new mechanism by which influenza can infect cells -- a finding that ultimately may have implications for immunity against the flu.

Influenza viruses have two main proteins on their surface that allow them to do their dirty work: a protein called hemagglutinin allows viruses to infect cells, while a protein called neuraminidase allows viruses to escape from cells.

Now in a paper published online ahead of the December print issue of the Journal of Virology, Jesse Bloom, Ph.D., an evolutionary biologist and assistant member of the Fred Hutch Basic Sciences Division, and Kathryn Hooper, a graduate research assistant in the Bloom Lab, describe the discovery of an influenza virus that instead uses neuraminidase to attach to cells.

The researchers discovered the new mechanism of infection after mutating the hemagglutinin of a lab-adapted strain of influenza so that it could no longer attach to cells.

"We expected that viruses with the mutated hemagglutinin wouldn't be able to infect cells," said Bloom, who also is a computational biologist and an assistant member of the Fred Hutch Public Health Sciences Division. "So we were surprised when a virus with this hemagglutinin started to grow. We were even more surprised when we sequenced the virus and discovered that it had evolved a mutation in neuraminidase."

Hooper began characterizing the new virus in detail. She discovered that the mutation allowed neuraminidase to attach the virus to cells. Hemagglutinin's ability to bind to cells -- long considered one of the protein's most crucial and conserved properties -- was no longer necessary for infection.

What does this finding mean for influenza in humans? That remains an open question, but Bloom and Hooper have already shown that the neuraminidase mutation they discovered is present in some human isolates of influenza.

"This was not a mutation we expected to find in the lab, let alone in viruses that have infected humans over the past few years," Hooper said. "It suggests there is influenza circulating in nature that may be infecting cells by a mechanism that has been overlooked by others in the field."

The researchers are now carefully characterizing human influenza isolates that have the mutation. They are also looking for other mutations that allow neuraminidase to attach viruses to cells.

They say there is a possibility that these types of mutations may have implications for immunity against influenza, since they might enable the virus to escape from antibodies that block the binding of hemagglutinin to cells.

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Study establishes human model of influenza pathogenesis

Sep. 13, 2013 — A National Institutes of Health (NIH) clinical study of healthy adult volunteers who consented to be infected with the 2009 H1N1 influenza virus under carefully controlled conditions has provided researchers with concrete information about the minimum dose of virus needed to produce mild-to-moderate illness. The study also gives a clearer picture of how much time elapses between a known time of infection, the start of viral shedding (a signal of contagiousness), the development of an immune response, and the onset and duration of influenza symptoms. The data obtained from this study provide a basis for more rapid, cost-effective clinical trials to evaluate new influenza drugs or to determine the efficacy of candidate vaccines for both seasonal and pandemic influenza.

In the study, 46 volunteers were divided into five groups and exposed to influenza virus in escalating doses. The virus, synthesized in the lab under Good Manufacturing Practice conditions, was genetically identical to the virus that caused 2009 H1N1 pandemic influenza. The volunteers all gave informed consent and subsequently were admitted to an isolation unit at the NIH Clinical Center in Bethesda, Md., for a minimum of eight days following virus exposure. The volunteers' health was closely monitored throughout their stay in the clinic and for two months afterward. The researchers sought to determine the minimum dose of virus needed to produce both shedding of live virus in nasal secretions and mild or moderate flu symptoms in 60 percent or more of dosed volunteers. When the scientists administered an influenza virus dose of 107 TCID50 (a measure of the amount of virus required to produce cell death in 50 percent of cultured cells inoculated with virus) to 13 volunteers, 9 (or 69 percent) shed virus and developed symptoms. Lower dosages did not generate responses that met this threshold, thereby establishing the minimum dose of influenza virus needed to produce mild-to-moderate illness.

Researchers from NIH's National Institute of Allergy and Infectious Diseases (NIAID) presented the preliminary study results at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) meeting in Denver in September 2013.

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The above story is based on materials provided by NIH/National Institute of Allergy and Infectious Diseases.

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