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Investigating influenza

Findings about the flu virus were made by the Shoulders Lab at MIT

As winter approaches, New England can begin to anticipate cold weather and snow. But while we begin to brace ourselves against the elements, we must similarly protect ourselves from the onset of flu season.

The United States experiences annual flu outbreaks, usually starting in October or November and sometimes lasting until May. The Centers for Disease Control (CDC) monitors flu indicators such as laboratory test results, influenza hospitalizations, and deaths. Outpatient visits for flu-like symptoms such as fever, sore throat, runny nose, cough, headache, muscle and joint pain, or malaise, are also counted in order to determine the beginning of “flu season.”

The CDC recommends getting vaccinated against influenza annually. Flu viruses evolve every year, even within a “flu season.” At MIT, the Shoulders Lab, headed by Matthew Shoulders, is generally interested in protein folding and how it affects viral evolution. The lab specifically investigated the mechanisms behind influenza virus evolution and published their findings in the papers “Host proteostasis modulates influenza evolution” in eLIFE in Sept. 2017 and “Destabilized adaptive influenza variants critical for innate immune system escape are potentiated by host chaperones” in PLoS Biology in Sept. 2018. Graduate student Anna Ponomarenko and Angela Phillips PhD ’18 led the work. For Phillips, this topic “is especially appealing from the perspective of viral evolution because viruses are rapidly mutating.”

The lab currently studies viral evolution using both influenza and HIV, viruses that mutate rapidly and are able to develop resistance to antiviral therapeutics and vaccines. According to Phillips, this high mutation rate has a downside for the viruses: “these mutations can also be detrimental to the viral proteins and can hamper viral protein folding, so we were really interested in how this protein folding constrains viral evolution.”

In the initial eLIFE paper, the lab discovered that cellular factors such as chaperone proteins were involved in the evolution of influenza. Chaperone proteins exist in human cells to help proteins fold properly. Ponomarenko likens chaperones to expert furniture assembly, saying they are  “the complex network in the cells that helps its own proteins to fold and achieve proper structure that is critical to function.”

The lab sought to look into if and how this host protein folding network impacts viral evolution.

To approach this question, Phillips describes how in their recent PLoS paper, the lab used a collection of influenza viruses with mutated nucleoproteins. The library was used to infect host cells with varying levels of chaperones, and the lab then analyzed the chaperone-viral protein interactions for each mutant.

The study found experimental evidence that this host folding network of chaperones is critical for flu evolution, likely by allowing the mutant flu protein to fold. The virus “hijacks [the] systems” that human cells use to make protein, “[uses] them to resolve some defects, and that’s how it propagates,” explained Ponomarenko.

While the Shoulders Lab focuses on the fundamental research behind the evolution, Phillips and Ponomarenko see how the results could eventually be applied to treatments. A potential outcome could be using a chaperone inhibitor, in addition to an antiviral, “to prevent [viral] resistance from developing,” Phillips says. “We are very far from that, but I think it is a promising approach for the future.”

For now, our main defense against the influenza virus is vaccinations. The CDC explains how the flu vaccine is redesigned every season to protect against the strains of influenza that are most likely to circulate in a given year. The composition of a season’s flu vaccine is determined by collecting and analyzing influenza virus samples from over 100 influenza centers in over 100 countries. The World Health Organization then assembles biannually to recommend which viruses to include in flu vaccines, but ultimately, every country decides their vaccine composition for the upcoming season.

The CDC suggests getting vaccinated early, before the flu starts spreading. After getting the vaccine, it takes around two weeks for your body to develop the correct antibodies to fight against a particular flu virus strain. It is recommended to get vaccinated by the end of October.

MIT Medical began offering flu clinics starting Oct. 3 on the Cambridge campus. The vaccine for this year is quadrivalent or has four components. It protects against influenza A (H1N1 and H3N2) and two strains of influenza B. All MIT Medical patients older than 10, employees, students, affiliates, and retirees can get flu vaccines by going to walk-in clinics or calling the Flu Line at 617-253-4865 to make an appointment. The remaining campus clinics this year are Oct. 16 from 3 p.m. to 7 p.m. in the Stratton Student Center (W20), and Oct. 18 from 3 p.m. to 6 p.m. at the Tang Center (E51).