Influenza papers published!
18/11/11 13:26
I’m excited to report that two new papers have recently been published describing my lab’s work on influenza immunity and pathogenesis. Both of these studies were conducted in collaboration with my UW colleague Yoshi Kawaoka.
The first, led by my lab, shows that cross-reactive T cell responses play a role in rapid clearance of 2009 H1N1 influenza viruses from the upper and lower respiratory tract in nonhuman primates. This observation is important because it establishes a role for T cells in protective immunity against influenza in a humanlike model system. Such “heterosubtypic” T cell responses were known to protect mice against divergent influenza viruses, but scientists have disagreed on the significance of heterosubtypic immunity to influenza in humans.
Our results showed that monkeys “primed” to make flu-specific T cell responses by prior infection with a seasonal virus were able to clear a challenge with the 2009 H1N1 pandemic virus more rapidly than naive animals. This enhanced clearance was associated with rapid recall of memory T cell responses and occurred before the emergence of neutralizing antibodies specific for the 2009 H1N1 virus.
These results suggest that cross-reactive T cells could play a similar role in humans, allowing for the rapid containment of infection even in the absence of neutralizing antibodies. Since current influenza vaccines are designed specifically to induce antibodies, we speculate that adding vaccine components designed to elicit T cells could would enhance influenza vaccine efficacy, particularly against emerging viruses. These results were published in PLoS Pathogens.
The second study, led by Yoshi’s group, investigates the impact of a mutation in the hemagglutinin (HA) protein of the 2009 H1N1 influenza virus on virus tropism and disease severity. This was a major collaborative study in which my group contributed expertise in nonhuman primate virology. It was based on the observation that pandemic viruses isolated from some patients with unusually severe (sometimes fatal) disease had a particular mutation in HA, frequently referred to as D222G or D225G. (The numbers differ depending on which virus strain is used for reference, but they refer to the same mutation.)
Together, our experiments showed that the D222G mutation altered the tropism of the virus, allowing it to bind to both human- and avian-type receptors. As a result, the mutant virus binds to different types of cells in the respiratory tract than the wild type virus does. Specifically, the mutant virus can infect Type II pneumocytes. These cells are not directly involved in gas exchange in the lungs, but they are the progenitors of gas-exchanging Type I pneumocytes. At least one strain of D222G virus caused much more severe disease in infected monkeys than wild type viruses did, suggesting that the D222G mutation can indeed increase influenza virus virulence. We speculate that viral destruction of Type II pneumocytes may limit the lung’s ability to repair damage, which could explain the increased severity of disease seen in monkeys and humans infected with D222G variant viruses. This study is now in press at the Journal of Virology.
The first, led by my lab, shows that cross-reactive T cell responses play a role in rapid clearance of 2009 H1N1 influenza viruses from the upper and lower respiratory tract in nonhuman primates. This observation is important because it establishes a role for T cells in protective immunity against influenza in a humanlike model system. Such “heterosubtypic” T cell responses were known to protect mice against divergent influenza viruses, but scientists have disagreed on the significance of heterosubtypic immunity to influenza in humans.
Our results showed that monkeys “primed” to make flu-specific T cell responses by prior infection with a seasonal virus were able to clear a challenge with the 2009 H1N1 pandemic virus more rapidly than naive animals. This enhanced clearance was associated with rapid recall of memory T cell responses and occurred before the emergence of neutralizing antibodies specific for the 2009 H1N1 virus.
These results suggest that cross-reactive T cells could play a similar role in humans, allowing for the rapid containment of infection even in the absence of neutralizing antibodies. Since current influenza vaccines are designed specifically to induce antibodies, we speculate that adding vaccine components designed to elicit T cells could would enhance influenza vaccine efficacy, particularly against emerging viruses. These results were published in PLoS Pathogens.
The second study, led by Yoshi’s group, investigates the impact of a mutation in the hemagglutinin (HA) protein of the 2009 H1N1 influenza virus on virus tropism and disease severity. This was a major collaborative study in which my group contributed expertise in nonhuman primate virology. It was based on the observation that pandemic viruses isolated from some patients with unusually severe (sometimes fatal) disease had a particular mutation in HA, frequently referred to as D222G or D225G. (The numbers differ depending on which virus strain is used for reference, but they refer to the same mutation.)
Together, our experiments showed that the D222G mutation altered the tropism of the virus, allowing it to bind to both human- and avian-type receptors. As a result, the mutant virus binds to different types of cells in the respiratory tract than the wild type virus does. Specifically, the mutant virus can infect Type II pneumocytes. These cells are not directly involved in gas exchange in the lungs, but they are the progenitors of gas-exchanging Type I pneumocytes. At least one strain of D222G virus caused much more severe disease in infected monkeys than wild type viruses did, suggesting that the D222G mutation can indeed increase influenza virus virulence. We speculate that viral destruction of Type II pneumocytes may limit the lung’s ability to repair damage, which could explain the increased severity of disease seen in monkeys and humans infected with D222G variant viruses. This study is now in press at the Journal of Virology.