Single gene reassortants identify a critical role for PB1, HA, and NA in the high virulence of the 1918 pandemic influenza virus

Sally Furniss · Feb 21, 2008

[SIZE=+2] Single gene reassortants identify a critical role for PB1, HA, and NA in the high virulence of the 1918 pandemic influenza virus[/SIZE] Claudia Pappas*,
$dagger.gif$
, Patricia V. Aguilar
$dagger.gif$
, Christopher F. Basler
$dagger.gif$
, Alicia Sol?rzano
$dagger.gif$
, Hui Zeng*, Lucy A. Perrone*, Peter Palese
$dagger.gif$
,
$Dagger.gif$
,
$sect.gif$
, Adolfo Garc?a-Sastre
$dagger.gif$
,
$Dagger.gif$
,?, Jacqueline M. Katz*, and Terrence M. Tumpey*,
$sect.gif$

*Influenza Division, Mailstop G-16, National Center for Immunization and Respiratory Diseases, Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifton Road Northeast, Atlanta, GA 30333; and

$dagger.gif$

Departments of Microbiology and

$Dagger.gif$

Medicine and ?Emerging Pathogens Institute, Mount Sinai School of Medicine, New York, NY 10029
Contributed by Peter Palese, December 17, 2007 (sent for review December 4, 2007)
[SIZE=+1]Abstract[/SIZE]

The 1918 influenza pandemic was exceptionally severe, resulting in the death of up to 50 million people worldwide. Here, we show which virus genes contributed to the replication and virulence of the 1918 influenza virus. Recombinant viruses, in which genes of the 1918 virus were replaced with genes from a contemporary human H1N1 influenza virus, A/Texas/36/91 (Tx/91), were generated. The exchange of most 1918 influenza virus genes with seasonal influenza H1N1 virus genes did not alter the virulence of the 1918 virus; however, substitution of the hemagglutinin (HA), neuraminidase (NA), or polymerase subunit PB1 genes significantly affected the ability of this virus to cause severe disease in mice. The 1918 virus virulence observed in mice correlated with the ability of 1918 recombinant viruses to replicate efficiently in human airway cells. In a second series of experiments, eight 1918 1:7 recombinants were generated, in which each Tx/91 virus gene was individually replaced by a corresponding gene from 1918 virus. Replication capacity of the individual 1:7 reassortant viruses was assessed in mouse lungs and human airway cells. Increased virus titers were observed among 1:7 viruses containing individual 1918 HA, NA, and PB1 genes. In addition, the 1918 PB1:Tx/91 (1:7) virus showed a distinctly larger plaque size phenotype than the small plaque phenotype of the 1918 PA:Tx/91 and 1918 PB2:Tx/91 1:7 reassortants. These results highlight the importance of the 1918 HA, NA, and PB1 genes for optimal virus replication and virulence of this pandemic strain.

http://www.pnas.org/cgi/content/abstract/0711815105v1?ct=ct

gsgs · Feb 21, 2008

Re: Single gene reassortants identify a critical role for PB1, HA, and NA in the high virulence of the 1918 pandemic influenza virus

would a 1918-virus or a reassortant with today's H1N1
likely cause seasonal infections of similar spreading as today's
H1N1, but increased virulence ?

did H1N1 decrease in virulence because of genetical changes
or because of gained human immunity ?

HA seems to be the main factor (also to lesser degree NA,PB1)
for virulence, so the frequent reassortments of H5N1
with H6N1,H9N2,... in China did not reduce the virulence very much.

So reassortments of H5N1 with human viruses which keep the HA
from H5N1 are probably very virulent.

Now, replace H1N1 with H5N1 and repeat the reassortment-tests
from 2006 of H5N1 variants and current human H3N2,H1N1
in mice or chickens ! That's a decisive experiment and should be repeated
and extended with several H5N1-variants.

And figure out which segments/genes are responsible for better
transmission in transmission experiments like those with the
Guinea-pigs in cages and horizontal airflow or such.

What would it cost ? What do you estimate did this study cost ?

HenryN · Feb 21, 2008

Re: Single gene reassortants identify a critical role for PB1, HA, and NA in the high virulence of the 1918 pandemic influenza virus

AnneZ said:
[SIZE=+2] Single gene reassortants identify a critical role for PB1, HA, and NA in the high virulence of the 1918 pandemic influenza virus[/SIZE] Claudia Pappas*,
$dagger.gif$
, Patricia V. Aguilar
$dagger.gif$
, Christopher F. Basler
$dagger.gif$
, Alicia Sol?rzano
$dagger.gif$
, Hui Zeng*, Lucy A. Perrone*, Peter Palese
$dagger.gif$
,
$Dagger.gif$
,
$sect.gif$
, Adolfo Garc?a-Sastre
$dagger.gif$
,
$Dagger.gif$
,?, Jacqueline M. Katz*, and Terrence M. Tumpey*,
$sect.gif$

*Influenza Division, Mailstop G-16, National Center for Immunization and Respiratory Diseases, Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifton Road Northeast, Atlanta, GA 30333; and 
$dagger.gif$
Departments of Microbiology and 
$Dagger.gif$
Medicine and ?Emerging Pathogens Institute, Mount Sinai School of Medicine, New York, NY 10029
Contributed by Peter Palese, December 17, 2007 (sent for review December 4, 2007)
[SIZE=+1]Abstract[/SIZE]

The 1918 influenza pandemic was exceptionally severe, resulting in the death of up to 50 million people worldwide. Here, we show which virus genes contributed to the replication and virulence of the 1918 influenza virus. Recombinant viruses, in which genes of the 1918 virus were replaced with genes from a contemporary human H1N1 influenza virus, A/Texas/36/91 (Tx/91), were generated. The exchange of most 1918 influenza virus genes with seasonal influenza H1N1 virus genes did not alter the virulence of the 1918 virus; however, substitution of the hemagglutinin (HA), neuraminidase (NA), or polymerase subunit PB1 genes significantly affected the ability of this virus to cause severe disease in mice. The 1918 virus virulence observed in mice correlated with the ability of 1918 recombinant viruses to replicate efficiently in human airway cells. In a second series of experiments, eight 1918 1:7 recombinants were generated, in which each Tx/91 virus gene was individually replaced by a corresponding gene from 1918 virus. Replication capacity of the individual 1:7 reassortant viruses was assessed in mouse lungs and human airway cells. Increased virus titers were observed among 1:7 viruses containing individual 1918 HA, NA, and PB1 genes. In addition, the 1918 PB1:Tx/91 (1:7) virus showed a distinctly larger plaque size phenotype than the small plaque phenotype of the 1918 PA:Tx/91 and 1918 PB2:Tx/91 1:7 reassortants. These results highlight the importance of the 1918 HA, NA, and PB1 genes for optimal virus replication and virulence of this pandemic strain.

http://www.pnas.org/cgi/content/abstract/0711815105v1?ct=ct

These experiments simply show which combinations of genetically distinct mammalian genes work together, and mimic data in swine, where swine flu isolates have a human PB1, or human HA and NA with human PB1.

Their use of the term "recombinant" to describe reassortants speaks volumes.

Single gene reassortants identify a critical role for PB1, HA, and NA in the high virulence of the 1918 pandemic influenza virus

Sally Furniss

Well-known member

gsgs

Registered User

HenryN

Retired