How Avian Flu Triggers
Human Immune 'Storm'

From Patricia Doyle, PhD
By Helen Branswell
Canadian Press

Some avian influenza viruses, and particularly the dangerous H5N1 subtype, appear to prompt the human immune system to over-produce important pathogen-fighting chemicals called chemokines, triggering an exaggerated response that creates more damage than it fixes, a new study suggests. The study shows that at least with older versions of the H5N1 virus, this response -- referred to as a cytokine storm -- was significantly more acute in adults than children. The findings could help to explain why the 1997 outbreak of H5N1 was far more deadly for adults than children and why the infamous 1918 Spanish flu -- caused by the H1N1 subtype -- wreaked its greatest havoc on young adults.
They could also offer clues to help in the design of therapies to treat infections caused by these viruses, by pinpointing the response that needs to be moderated to avoid this immune response tidal wave and the damage it inflicts.
"I think this is starting to provide us with a framework to better understand why H5N1 does what it does," said Dr. Michael Osterholm, director of the Center for Infectious Disease Research and Policy at the University of Minnesota. "And I think also it's a reason to be more concerned about similarities between 1918 H1N1 and 2006 H5N1."
The work, by scientists at the University of Hong Kong, is reported in the July issue of the Journal of Infectious Diseases and was financed by Hong Kong's Research Grants Council. The research is part of a series of studies done by this group of scientists that is looking at the way human cells respond to H5N1 and related avian influenza viruses. Group leader Dr. Malik Peiris, a leading influenza expert, said the study was inspired by the mortality pattern observed during the first recorded outbreak of human disease with the H5N1 virus in Hong Kong in 1997. Of the 18 recorded cases, 5 of 9 who were over 12 years of age died. Only one patient under that age succumbed to the virus. "It made us wonder if there was some host factor associated with age," Peiris said in an interview from Hong Kong.
But the current wave of human infections with H5N1, which began in late 2003, includes many cases under 12, many of whom have died. Peiris acknowledged that host response -- in other words, the immune system reaction -- obviously isn't the only factor involved in determining the severity of disease caused by H5N1 viruses. He suggested the route of infection, or the dose of virus to which an individual is exposed, may also play a role. Peiris's team tested their age hypothesis using blood from healthy adult blood donors and donated umbilical cord blood from healthy, full-term babies.
The scientists tested the response to 3 influenza viruses: a human H1N1 virus from 1998, an H5N1 virus from 1997, and a 1997 H9N2 virus. The last is considered an ancestor of the H5N1 virus, because while the 2 wear different hemagglutinins (the H in a flu virus's name) and neuraminidases (the N) on their outer shell, their 6 internal genes are very closely related. The blood samples were used to isolate macrophages -- immune system warriors which are drawn to the site of infection by signalling chemicals such as chemokines. Once at the site of infection, macrophages engulf and destroy invading pathogens. In this experiment, the flu viruses were added to cultures of macrophages to see what responses were provoked. Interestingly, the flu viruses all replicated at about the same rate, in both the adult and infant cells. "So these differences weren't due to differences in the extent of virus growth that they could discern, but rather something intrinsic to the viruses themselves which were causing the different (chemokine) expression levels that they reported," said Dr. Frederick Hayden, a scientist with the World Health Organization's global influenza program.
But while the viruses generated the same amount of infection, the immune response to the infection varied greatly, both between the human and avian viruses and between the adult and infant cells. In particular the avian viruses triggered the production of significantly higher levels of a chemokine called CCL3 in the adult cells. The authors noted elevated levels of CCL3 have also been found in the blood of patients who have died from H5N1 infection as compared to those who were infected but survived. "The higher CCL3 response in adult (macrophages) may be one of the important factors responsible for the age-related severity of avian influenza virus infection in 1997," they wrote.
Peiris also noted that in fatal human cases of H5N1 infection it has been observed that macrophages have virtually swarmed the lungs. Chemokines like CCL3 draw macrophages, he noted, saying the pattern of actual disease and the experiments done by his team "do fit." Chemicals like these play a crucial role in the body's response to invading pathogens. But overproduction can create a cascading hyper-response that actually exacerbates the damage already done by the virus.
The authors noted that mice infected with the newly reconstituted 1918 H1N1 Spanish flu virus produced high levels of the same immune system signalling chemicals as were seen to be over-produced by the H5N1 and H9N2 viruses. Since these more contemporary avian flu viruses carry a number of the same mutations on their internal genes as the 1918 virus did, they argued, further analysis of the role of these mutations is needed to determine what role they play in the disease process.
For Osterholm, the work provides further supporting evidence that the cytokine-storm phenomenon was at work during the deadly 2nd wave of the Spanish flu. It also supports the concern he and others share about the similarities between the type of human disease H5N1 causes and reports of what patients suffered during the 1918 pandemic, which claimed an estimated 50 million lives worldwide. "We'll never be able to go back to 1918 and demonstrate that the cytokine storm was the key feature of those early and dramatic deaths in patients," Osterholm said. "But clinically those patients were so similar and [from a] patho-physiologic standpoint it makes so much sense that that's what was happening that I've got to believe that there are important parallels here."
The paper referred to above is published in The Journal of Infectious Diseases, Volume 194, Number 1, 1 Jul 2006, and entited: Differential Expression of Chemokines and Their Receptors in Adult and Neonatal Macrophages Infected with Human or Avian Influenza Viruses. The authors are: Jianfang Zhou,1,3 Helen K. W. Law,1,3 Chung YanCheung,2,3 Iris H. Y. Ng,2,3 J. S. Malik Peiris,2,3 and Yu Lung Lau1,3, at the Departments of 1Paediatrics and Adolescent Medicine and 2Microbiology, Hong Kong Jockey Club Clinical Research Centre, Faculty of Medicine, and 3Research Centre of Infection and Immunology, University of Hong Kong, Pokfulam, Hong Kong SAR, China.
The abstract reads as follows: "In 1997, avian influenza virus H5N1 was transmitted directly from chicken to human and resulted in a severe disease that had a higher mortality rate in adults than in children. The characteristic mononuclear leukocyte infiltration in the lung and the high inflammatory response in H5N1 infection prompted us to compare the chemokine responses between influenza virus-infected adult and neonatal monocyte-derived macrophages (MDMs).
The effects of avian influenza virus A/Hong Kong/483/97 (H5N1) (H5N1/97), its precursor A/Quail/Hong Kong/G1/97 (H9N2) (H9N2/G1), and human influenza virus A/Hong Kong/54/98 (H1N1) (H1N1/98) were compared. Significantly higher expression of CCL2, CCL3, CCL5, and CXCL10 was induced by avian influenza viruses than by human influenza virus. Moreover, the increase in CCL3 expression in H5N1/97-infected adult MDMs was significantly higher than that in neonatal MDMs. Enhanced expression of CCR1 and CCR5 was found in avian virus-infected adult MDMs. The strong induction of chemokines and their receptors by avian influenza viruses, particularly in adult MDMs, may account for the severity of H5N1 disease." - Mod.CP
Patricia A. Doyle DVM, PhD
Bus Admin, Tropical Agricultural Economics
Univ of West Indies
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