A paper in the Jan. 18, 2007, issue of Nature reports on the effects that the pandemic 1918 "Spanish flu" virus strain has in primates. Bottom line: For some reason, with the 1918 virus, the host immune system doesn't know when to quit.

The researchers infected macaque monkeys with either reconstructed 1918 virus, or milder, currently circulating forms of influenza virus that were isolated in 2001. Animals infected with the 2001 strains showed a robust initial response of the innate immune system, but as they cleared the virus, the immune response quieted down.

In contrast, co-author Michael Katze, professor of microbiology at the University of Washington in Seattle, told reporters at a press briefing that monkeys infected with the 1918 strain started out slow and showed "a slightly muted response early after infection."

But after five to six days, Katze said, with the 1918 strain "that response did not abate." Instead, the virus caused an uncontrolled innate inflammatory response. "Instead of protecting infected individuals, the immune response is actually contributing to the lethality of the virus," he added. The animals, they discovered, produced high levels of inflammatory cytokines and chemokines, which led to severe clinical symptoms including respiratory distress, pneumonia, tissue damage and hemorrhage.

Historically, the results might explain one puzzling aspect of the 1918 epidemic - why it did not kill mainly the very old and the very young, as most flu epidemics do. Instead, it afflicted those in their 20s and 30s who should be best protected by their robust immune systems.

Some practical applications also are obvious. For example, the fact that the innate immune response contributes to the symptoms after infection suggests that a combination therapy of immunomodulators and antivirals might be a promising approach. More generally, Katze said, "it's extremely important to develop animal models to study viruses at all levels of pathogenicity."

Most of the worries about influenza currently are focused on the avian strain H5N1, which is widespread in birds but has so far not mutated to become highly infectious to humans. To date, H5N1 only has infected a few hundred people, but it has been fatal in slightly more than half of confirmed infections. That suggests that if H5N1 does acquire the ability to be transmitted easily from person to person the resulting pandemic's death toll could be very high. However, some skeptics assert that this is due to the fact that only the most serious cases tend to come to the attention of public health officials in the first place. (See BioWorld Today, Jan 17, 2006.)

On Monday, the World Health Organization reported that a 22-year-old woman had died from the disease in Indonesia, while tests confirmed Tuesday that H5N1 has infected chickens in Japan, which had had no cases in the past three years.

How directly relevant to a future pandemic the experiments with 1918 strain are is not necessarily clear. While it is a fairly safe bet that another influenza pandemic will arrive sooner or later, it's impossible to predict whether that pandemic will be caused by a mutated H5N1, and whether it will be as serious as the 1918 pandemic or as mild as the long-forgotten 1957 and 1968 pandemics, which were caused by milder flu strains and were largely forgotten as soon as they were over.

"No one has a crystal ball," Katze cautioned.

But first author Darwyn Kobasa, a researcher at the Public Health Agency of Canada, said that despite some differences between the two, H5N1 appears to do its damage "in a way that is quite similar to the 1918 virus."

The fact that the host immune system plays a role in the seriousness of the 1918 flu strain suggests that the 1918 pandemic's severity was not just due to the fact that it came on the tail end of World War I and its ideal breeding ground in weakened individuals, or the cramped quarters of war, or a public health system that was in shambles in much of Europe, as some skeptics have suggested. As senior author Yoshihiro Kawaoka pointed out, "avian viruses don't change much." So "out in nature, we still have a precursor of the 1918 virus."

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