INFLUENZA (11): SITE 222 MUTATIONS AND OUTCOMES
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A ProMED-mail post
ProMED-mail is a program of the
International Society for Infectious Diseases
Date: Thu 28 Oct 2010
Source: Eurosurveillance, Volume 15, Issue 43 [abbreviated & edited]
Molecular surveillance of pandemic influenza A(H1N1) viruses
circulating in Italy from May 2009 to February 2010: association
between haemagglutinin mutations and clinical outcome
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By: S Puzelli1, M Facchini1, M A De Marco1, A Palmieri1, D Spagnolo1,
S Boros1, F Corcioli2, D Trotta3, P Bagnarelli3, A Azzi2, A Cassone1,
G Rezza1, M G Pompa4, F Oleari4, I Donatelli1, the Influnet
Surveillance Group for Pandemic A(H1N1) 2009 Influenza Virus in Italy5
At:
(1) Department of Infectious, Parasitic and Immune-mediated Diseases,
National Institute of Health (Istituto Superiore di Sanita - ISS), Rome, Italy
(2) Department of Public Health, University of Florence, Italy
(3) Unit of Virology, Department of Biomedical Sciences, Universita
Politecnica delle Marche, Ancona, Italy
(4) Ministry of Health, Rome, Italy
Summary:
Haemagglutinin sequences of pandemic influenza A(H1N1) viruses
circulating in Italy were examined, focusing on amino acid changes at
position 222 because of its suggested pathogenic relevance. Among 169
patients, the D222G substitution was detected in 3 of 52 (5.8
percent) severe cases and in one of 117 (0.9 percent) mild cases,
whereas the D222E mutation was more frequent and evenly distributed
in mild (31.6 percent) and severe cases (38.4 percent). A cluster of
D222E viruses among school children confirms reported human-to-human
transmission of viruses mutated at amino acid position 222.
[Readers should access the original text to view the data, figures
and literature references. What follows are extracts from the
authors' discussion of their conclusions. - Mod.CP]
Discussion and conclusions:
We have previously described the only documented transmission event
of a D222G mutant pandemic influenza A(H1N1) virus; to the best of
our knowledge, this mutation appears to be hardly ever transmitted.
Less is known about the human-to-human transmissibility of D222E
virus mutants. In the present study, we found that this mutation is
much more frequent than the D222G mutation and equally distributed
between severe and mild cases. In particular, we describe a cluster
of close contacts carrying the D222E substitution in a group of high
school students with mild disease returning from England, suggesting
inter-human transmission of D222E pandemic influenza A(H1N1) mutant
viruses. However, the clinical significance of the D222E substitution
remains uncertain.
It is of note that the D222G mutation was detected more commonly
among viruses isolated from severe cases, which were about 7 times
more likely to have this genetic change than those isolated from mild
cases; however, the difference did not reach statistical
significance, probably due to limited study power.
The D222G variants were detected among adults (18-64 age group).
Whether this was due to the fact that this age group had the highest
number of cases (including severe ones) or to unidentified biological
factors remains undefined. In particular, due to the relatively
limited number of cases with the D222G variant, definitive
conclusions about possible age differences cannot be drawn.
Studies conducted in other countries, e.g. Norway and Scotland, also
found D222G to be more common among severe than mild cases. Although
these results indicate that the 222G variant may be more virulent,
this association must be interpreted with caution as the same
mutation was detected in mild cases, and mixed D222D and D222G virus
populations were found in original samples and isolates from patients
with severe disease.
In vitro studies show conflicting results. Studies conducted in the
United States found the 222G mutation only in isolated viruses but
not in the original clinical samples. On the other hand, preliminary
results from in vitro studies suggest that D222G substitution might
enhance binding of HA to alpha2-3 sialic acid (avian-like) cell
receptors, thus increasing virus ability to infect human lung cells.
Moreover, studies from Liu et al. [9] and Chutinimitkul et al. [See
ProMED-mail report: Influenza (10): D222G & severity 20101026.3881.]
suggest an increased receptor affinity of the 222G variant for
ciliated bronchial epithelial cells, which may explain enhanced
disease in humans. Increased binding to macrophages and pneumocytes
of the respiratory tract may indeed have an impact on disease
severity, since those cells are major producers of inflammatory
cytokines upon viral antigen stimulation.
Finally, our data suggest that the D222G substitution is overall
rather infrequent, even among severe cases. However, we confirm that
it occurs with a higher frequency in severe cases. Whether this
association is indicative of higher virulence or is the consequence
of receptor-specific adaptive mutation needs to be further investigated.
--
Communicated by;
ProMED-mail
[These data further document the mutability of the 222 site in the
influenza virus haemagglutinin and demonstrate an association of the
D222G substitution with a severe disease outcome in a subset of
Italian patients, in addition to those previously reported in
patients in Norway, Scotland and elsewhere. However, evidence for
transmissibility of the D222G mutation is lacking. In contrast, a
cluster of isolates from school children with D222E substitutions
confirms human-to-human transmission of viruses mutated at amino acid
position 222. Whether this association of the D222G substitution with
severe disease outcomes is indicative of higher virulence or is the
consequence of receptor-specific adaptive mutation is an open question.
WHO Collaborating Centre for Reference and Research on Influenza in
Atlanta found the D222G substitution in 14 virus isolates, but not in
viruses in the original clinical specimens, indicating the D222G
substitution in these 14 virus isolates occurred after growth in the
laboratory
[see also:
Influenza (10): D222G & severity 20101026.3881
Influenza pandemic (H1N1) (31): UK (Scotland) D222G mut'n 20100422.1310
Influenza pandemic (H1N1) (28): Hong Kong SAR, Norway, D222G mutation
20100409.1147
Influenza pandemic (H1N1) (21): Norway, D222G mutation 20100305.0729]
..........................................................cp/msp/dk
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