Editor’s summary
Birds operate at body temperatures several degrees higher than those of mammals, and, like mammals, birds are infected by influenza viruses. Influenza viruses can move between animal hosts, often reassorting their gene segments as they transition. Knowing that the body temperature of humans often elevates when sick, Turnbull et al. investigated whether virus gene segments originating from hot-blooded birds may give the virus an advantage in feverish mammals. They found that a viral polymerase containing an avian origin PB1 subunit indeed allowed the virus to replicate at higher temperatures in vitro and in a hyperthermic mouse model. —Caroline Ash
Structured Abstract
INTRODUCTION
Influenza A viruses circulate in diverse species of birds and periodically spill over to cause severe or fatal infections in humans. Avian influenza A viruses are adapted to replicate in the gastrointestinal tract of birds at ~40° to 42°C. By contrast, human-adapted seasonal influenza A viruses tend to cause mild symptoms and thrive in the cool upper respiratory tract at ~33°C but struggle to replicate in cells cultured at 40°C. Notably, the normal body temperature of avian hosts exceeds that of a typical human fever.
Elevating core body temperature in response to infection is an evolutionarily ancient antipathogen strategy, which in humans (and other endotherms) is the hallmark of a febrile response. However, whether elevated temperature itself is directly antiviral or acts indirectly, such as through thermally stimulated immune processes, can be difficult to untangle because pyrogens and antipyretics have pro- and anti-inflammatory properties as well as affecting body temperature.
RATIONALE
We sought to harness the strain-specific temperature sensitivity of influenza viruses to assess the antiviral potential of febrile temperature in vivo. We hypothesized that elevated temperature can inhibit the replication of human-origin influenza A viruses, whereas avian viruses, adapted to higher temperatures in birds, may be able to resist this defense.
RESULTS
To avoid false comparison, we wanted to engineer viruses that were identical apart from their ability to replicate at different temperatures. Taking advantage of the segmented viral genome, we found that avian-origin PB1 proteins (a component of the viral polymerase) enabled viral replication at higher temperatures. Notably, the 1918, 1957, and 1968 pandemic influenza viruses all acquired an avian-origin PB1 that enabled temperature-resistant replication, and they were associated with more-severe disease compared with their seasonal descendants.
We used a human-origin laboratory-adapted virus (PR8) that is avirulent in humans for our in vivo experiments. PR8 causes severe disease in mice but, like seasonal influenza A viruses, it replicates poorly at 40°C. We made a series of chimeric PB1 proteins and mapped two amino acid substitutions that conferred avian-like temperature resistance to PR8. This allowed us to generate two similar viruses for comparative experiments: one that replicated poorly at 40°C and one “avianized” mutant that replicated effectively at this temperature.
In mice housed under standard conditions, the parental virus and the avianized mutant both caused severe disease. However, when we simulated a fever in mice by elevating the ambient temperature to increase core body temperature, the mice were protected against the parental virus and experienced relatively mild symptoms. By contrast, the avianized temperature-resistant virus caused severe disease in mice, despite their higher body temperature.
CONCLUSION
Because the avianized mutant that replicates effectively at 40°C in vitro was the only virus that caused severe disease in the presence of a simulated fever, we conclude that elevated temperature itself can be a potent antiviral defense in vivo. The ~2°C increase in body temperature, which is similar to an everyday febrile response, transformed a normally severe or lethal challenge into mild disease. And because the avian-like virus resisted the elevated temperature defense, fever-resistant replication could help explain why avian spillover viruses and pandemic influenza viruses with an avian-origin PB1 cause more-severe disease in humans.
Abstract
Host body temperature can define a virus’s replicative profile—influenza A viruses (IAVs) adapted to 40° to 42°C in birds are less temperature sensitive in vitro compared with human isolates adapted to 33° to 37°C. In this work, we show that avian-origin PB1 polymerase subunits enable IAV replication at elevated temperatures, including avian-origin PB1s from the 1918, 1957, and 1968 pandemic viruses. Using a model system to ensure biosafety, we show that a small increase in body temperature protects against severe disease in mice and that this protection is overcome by a febrile temperature–resistant PB1. These findings indicate that although elevated temperature itself can be a potent antiviral defense, it may not be effective against all influenza strains. These data inform both the clinical use of antipyretics and IAV surveillance efforts.
Source:
Link: https://www.science.org/doi/10.1126/science.adq4691
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