- 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
- 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
- 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."
- Patricia A. Doyle DVM, PhD
- Bus Admin, Tropical Agricultural Economics
- Univ of West Indies
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