Interesting Science

In a study of nonhuman primates infected with the influenza virus that killed 50 million people in 1918, an international team of scientists has found a critical clue to how the virus killed so quickly and efficiently.

Writing this week (January 18) in the journal Nature (see below), a team led by University of Wisconsin-Madison virologist Yoshihiro Kawaoka reveals how the 1918 virus - modern history's most savage influenza strain - unleashes an immune response that destroys the lungs in a matter of days, leading to death.

The finding is important because it provides insight into how the virus that swept the world in the closing days of World War I was so efficiently deadly, claiming many of its victims in the prime of life. The work suggests that it may be possible in future outbreaks of highly pathogenic flu to stem the tide of death through early intervention.

The study "proves the 1918 virus was indeed different from all of the other flu viruses we know of," says Kawaoka, a professor in the UW-Madison School of Veterinary Medicine and at the University of Tokyo.

The new study, conducted at the Public Health Agency of Canada's National Microbiology Laboratory in Winnipeg, Manitoba, utilized the 1918 flu virus, which has been reconstructed by researchers using genes obtained from the tissues of victims of the great pandemic in a reverse genetics process that enables scientists to make fully functioning viruses.

"In 1918, the existence of viruses had barely been recognized. In fact, the influenza virus wasn't identified until 1933. Thanks to recent technological advancements, we are now able to study this virus and how it wreaked havoc around the globe," explains Darwyn Kobasa, research scientist with the Public Health Agency of Canada and lead author of the new study. "This research provides an important piece in the puzzle of the 1918 virus, helping us to better understand influenza viruses and their potential to cause pandemics."

By infecting monkeys with the virus, the team was able to show that the 1918 virus prompted a deadly respiratory infection that echoed historical accounts of how the disease claimed its victims.

Importantly, the new work shows that infection with the virus prompted an immune response that seems to derail the body's typical reaction to viral infection and instead unleashes an attack by the immune system on the lungs. As immune cells attack the respiratory system, the lungs fill with fluid and victims, in essence, drown.

The mechanisms that contribute to the lethality of the virus were uncovered by University of Washington researchers using functional genomics, a technique in which researchers analyze the gene functions and interactions. Learning more about the virulence mechanisms of the 1918 flu virus may help researchers understand how to keep the virus from causing such a severe immune response.

"This study in macaques, combined with our earlier research showing the host response in mice infected with the 1918 flu, suggests that the host immune response is out of control in animals infected with the virus," says Michael G. Katze*, professor of microbiology at the University of Washington in Seattle, who led the functional genomics portion of the new study and led the previous mouse-based study. "Our analysis revealed potential mechanisms of virulence, which we hope will help us develop novel antiviral strategies to both outwit the virus and moderate the host immune response."

The same excessive immune reaction is characteristic of the deadly complications of H5N1 avian influenza, the strain of bird flu present in Asia and which has claimed nearly 150 human lives, but has not yet shown a capacity to spread easily among people.

"What we see with the 1918 virus in infected monkeys is also what we see with H5N1 viruses," Kawaoka says, suggesting that the ability to modulate immune response may be a shared feature of the most virulent influenza viruses.

In the new study, conducted in a high-level biosafety laboratory (BSL 4) at the Public Health Agency of Canada's National Microbiology Laboratory, seven primates were infected with the reconstructed 1918 virus. Clinical signs of disease were apparent within 24 hours of infection, and within eight days, euthanization was necessary. The rapid course of the disease mirrors how quickly the disease ran its course in its human victims in 1918.

Upon infection, the virus grew rapidly in the infected animals, suggesting the agent somehow sets the stage for virulent infection. "Somehow, early in infection, this virus does something to the host that allows it to grow really well," says Kawaoka. "But we don't know what that is."

Knowing that the virus does something early in infection to trigger such a devastating immune response may provide biomedical researchers with clues about how to intervene and stop or mitigate the virus' potentially lethal effects, Kawaoka says.

"Things may be happening at an early time point (in infection), but we may be able to step in and stop that reaction."

[Source: University of Wisconsin-Madison (adapted)]

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Based on the Letter to Nature:

Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus

Kobasa D et al.

Nature 2007 Jan 18; 445:319-23.

Opening Paragraph

The 1918 influenza pandemic was unusually severe, resulting in about 50 million deaths worldwide. The 1918 virus is also highly pathogenic in mice, and studies have identified a multigenic origin of this virulent phenotype in mice. However, these initial characterizations of the 1918 virus did not address the question of its pathogenic potential in primates. Here we demonstrate that the 1918 virus caused a highly pathogenic respiratory infection in a cynomolgus macaque model that culminated in acute respiratory distress and a fatal outcome. Furthermore, infected animals mounted an immune response, characterized by dysregulation of the antiviral response, that was insufficient for protection, indicating that atypical host innate immune responses may contribute to lethality. The ability of influenza viruses to modulate host immune responses, such as that demonstrated for the avian H5N1 influenza viruses, may be a feature shared by the virulent influenza viruses.

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*Michael G. Katze is co-author of the following 2006 paper from the Journal of Virology:

An Integrated Molecular Signature of Disease: Analysis of Influenza Virus-Infected Macaques through Functional Genomics and Proteomics

T Baas et al.

J. Virol. doi:10.1128/JVI.00851-06

Abstract

Recent outbreaks of avian influenza in humans have stressed the need for an improved non-human primate model of influenza pathogenesis. In order to further develop a macaque model, we expanded our previous in vivo genomics experiments in influenza virus infected macaques by focusing on the innate immune response at day 2 post-inoculation and on gene expression in affected lung tissue with viral genetic material present. Finally, we sought to identify signature genes for early infection in whole blood. For these purposes, we infected six pigtailed macaques (Macaca nemestrina) with reconstructed influenza A/Texas/36/91 virus and three control animals with a sham inoculate. We sacrificed one control and two experimental animals at days 2, 4, and 7 post infection (PI). Lung tissue was harvested for pathology, gene expression profiling, and proteomics. Blood was collected for genomics every other day from each animal until experimental endpoint. Gross and microscopic pathology, immunohistochemistry, viral gene expression by arrays and/or quantitative real-time RT-PCR confirmed successful yet mild infection in all experimental animals. Genomic experiments were performed using macaque-specific oligonucleotide arrays and high-throughput proteomics revealed the host response to infection at the mRNA and protein levels. Our data showed dramatic differences in gene expression within regions in influenza virus-induced lesions based on the presence or absence of viral mRNA. We also identified genes tightly co-regulated in peripheral white blood cells and in lung tissue at day 2 post-inoculation. This latter finding opens the possibility of using gene expression arrays on whole blood to detect infection after exposure but prior to onset of symptoms or shedding.

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Related post: "Molecular Anatomy of Influenza Virus Detailed"

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