Scientists have discovered that avian influenza viruses have a gene that makes them incredibly resistant to heat, rendering our body's natural defense system – fever – powerless in fighting infection. In fact, higher temperatures actually help the viruses replicate.
Reserchers from the University of Cambridge and University of Glasgow have furthered our understanding of why bird flu is particularly dangerous when it infects humans, compared to seasonal influenza A viruses. And it comes down to one gene that appears to protect it from heat, known as BP1.
Fever is one of the oldest immune defenses found in mammals, raising core body temperature just enough to slow the replication of many pathogens, such as influenza A. Human-adapted seasonal influenza strains are finely tuned to the cooler environment of the upper airway, thriving at around 33 °C (91 °F) and losing steam rapidly as temperatures approach 40 °C (104 °F). Birds, on the other hand, run far hotter. Their normal body temperature sits between 40 °C and 42 °C (104 °F and 108 °F), and avian influenza viruses – including the highly pathogenic strains that occasionally spill over into humans – have evolved to replicate efficiently in that heat.
The researchers set out to test whether this explains the severity of avian influenza infections when the virus finds a human host. They created near-identical viruses that differed only in PB1 – the pathogen's engine it needs to be running to replicate. In one version, the PB1 came from a human-adapted strain, which falters when it encounters fever-like temperatures. The other housed a PB1 from avian influenza, including variants found in the 1957 and 1968 pandemic viruses.
This seemingly small genetic change transformed the virus’s behavior, which was demonstrated first in cell cultures and then a mouse model. When housed at normal temperatures, both viruses caused serious illness in the rodents. To make up for a biological difference – mice don't often get fevers in response to influenza – the scientists increased the temperature of the animals' environment, which raised their core temperature 2 °C (3.6 °F).
The human-adapted virus, struggling with the warmer environment, couldn't function properly or replicate – resulting in only a mild illness. However, the avian-PB1 virus had no such issue, replicating and causing the same kind of severe illness seen in the mice that hadn't had their body heat turned up.
"This elegant study builds on the very simple observation that different animals have different body temperatures, and shows how this may impact the way that viruses replicate in new hosts as they cross species barriers," said Professor Wendy Barclay, Chair of the Medical Research Council (MRC) Infections and Immunity Board. "The authors show that replication of human-adapted influenza virus is attenuated when temperatures are increased, such as in a fever. But avian influenza viruses, whose natural hosts have higher body temperatures, are not controlled by the fever response when they cross into mammals."
As mentioned, our deadliest influenza outbreaks last century involved strains of the virus that had PB1 of avian origins, uncovered through extensive genetic sequencing. Influenza A has eight separate gene segments, so when two flu strains infect the same cell, they can shuffle these segments (reassortment), and PB1 is a segment prone to moving between human and bird viruses during this process.
"The ability of viruses to swap genes is a continued source of threat for emerging flu viruses," said first author Dr. Matt Turnbull, from the Medical Research Council Centre for Virus Research at the University of Glasgow. "We’ve seen it happen before during previous pandemics, such as in 1957 and 1968, where a human virus swapped its PB1 gene with that from an avian strain. This may help explain why these pandemics caused serious illness in people."
These new findings suggest that this tiny gene may have allowed those viruses to sneak past the human body's temperature defenses and then cause such devastating infections in those pandemics. And could again spell trouble for us if a bird flu virus successfully spills over into human populations.
"It’s crucial that we monitor bird flu strains to help us prepare for potential outbreaks," said Turnbull. "Testing potential spillover viruses for how resistant they are likely to be to fever may help us identify more virulent strains."
Last month, a Washington resident died due to complications after contracting a novel strain of avian influenza that hadn't been seen in humans before. However, bird flu viruses are yet to master the art of transmission, so we're still seeing isolated cases in humans – these cases, though, have generally caused severe illness.
"Thankfully, humans don’t tend to get infected by bird flu viruses very frequently, but we still see dozens of human cases a year," said senior author Professor Sam Wilson, from the Cambridge Institute of Therapeutic Immunology and Infectious Disease at the University of Cambridge. "Bird flu fatality rates in humans have traditionally been worryingly high, such as in historic H5N1 infections that caused more than 40% mortality."
"Understanding what makes bird flu viruses cause serious illness in humans is crucial for surveillance and pandemic preparedness efforts," Wilson added. "This is especially important because of the pandemic threat posed by avian H5N1 viruses."
The study was published in the journal Science.
Source: University of Cambridge
