Host Genetic Background Strongly Influences the Response to Influenza A Virus Infections

[mixin]

7 strains of mice were infected with H1N1 and H7N7

* DBA/2J mice are highly susceptible to both infections compared to C57BL/6J mice
* Male and female mice of DBA/2J and C57BL/6J mice show similar weight loss and survival
* Higher viral load is detected in DBA/2J mice compared to C57BL/6J mice
* DBA/2J mice exhibit a stronger inflammatory response than C57BL/6J mice
* Severe damage of bronchial epithelia occurs in DBA/2J compared to C57BL/6J mice
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(comments of interest)

Since both DBA/2J and C57BL/6J mice are deficient for Mx1, yet DBA/2J is highly susceptible, we hypothesize that the high susceptibility of the DBA/2J mice to influenza virus may be due to differences in pathways that are not downstream of the interferon response.

F1 hybrids from a cross between DBA/2J and C57BL/6J exhibited an intermediate weight loss phenotype and were resistant at a dose of 2?103. We thus speculate that the susceptibility to influenza infection is a polygenic trait.

In infected DBA/2J mice, we observed higher virus replication at early time points after infection and a much stronger immune response than in C57BL/6J infected mice. Histological analyses showed that at day 4 after infection, the damage of the bronchial epithelium was being repaired in C57BL/6J mice but DBA/2J mice still showed the same severe lung phenotype as on day 2.

Alternatively, receptors for virus entry into epithelial cells may be more densely distributed or exhibit a more favorable structure in DBA/2J mice.
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The full version has good discussion plus 9 graphs

Abstract:
The genetic make-up of the host has a major influence on its response to combat pathogens. For influenza A virus, several single gene mutations have been described which contribute to survival, the immune response and clearance of the pathogen by the host organism. Here, we have studied the influence of the genetic background to influenza A H1N1 (PR8) and H7N7 (SC35M) viruses. The seven inbred laboratory strains of mice analyzed exhibited different weight loss kinetics and survival rates after infection with PR8.

Two strains in particular, DBA/2J and A/J, showed very high susceptibility to viral infections compared to all other strains. The LD50 to the influenza virus PR8 in DBA/2J mice was more than 1000-fold lower than in C57BL/6J mice. High susceptibility in DBA/2J mice was also observed after infection with influenza strain SC35M. In addition, infected DBA/2J mice showed a higher viral load in their lungs, elevated expression of cytokines and chemokines, and a more severe and extended lung pathology compared to infected C57BL/6J mice.

These findings indicate a major contribution of the genetic background of the host to influenza A virus infections. The overall response in highly susceptible DBA/2J mice resembled the pathology described for infections with the highly virulent influenza H1N1-1918 and newly emerged H5N1 viruses.

http://www.plosone.org/article/info:doi/10.1371/journal.pone.0004857#pone.0004857-Tate1

 

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Re: Host Genetic Background Strongly Influences the Response to Influenza A Virus Infections

"strongly" = ~redoubles ?

 

[Shiloh]

Re: Host Genetic Background Strongly Influences the Response to Influenza A Virus Infections

Source: http://cordis.europa.eu/fetch?CALLER=EN_NEWS&ACTION=D&SESSION=&RCN=30627

Researchers uncover link between host gene and influenza response
[Date: 2009-03-27]

Humans in recent history have succumbed to a number of severe pandemics triggered by the influenza virus. Intensive research has focused on the virulence and evolution of the virus, but information about how specific genes or genetic profiles in humans contribute to their susceptibility or resistance to the resulting illness is limited. Enter a group of researchers from the Helmholtz Centre for Infection Research in Germany, which has found that in mice, an excessive immune response is responsible for a fatal outcome of the disease. According to the scientists, the immune response has a genetic basis.

In the early 20th century, some 50 million people died from influenza worldwide. Every year, different subtypes of the virus cause seasonal epidemics, and around 1 million people die on a global scale.

In this latest study, the researchers studied how mice respond to infection with influenza. Their findings are published in the journal PLoS ONE.

Seven different inbred mouse strains were injected with the same quantity of type-A Influenza viruses, the researchers said, adding that the animals were genetically identical within one mouse strain.

The team was able to piece together the puzzle by determining that strong differences existed in the progression of the disease between the seven strains. They recorded mild illness in five of the seven strains; these mice lost weight, but were back to normal health within eight days.

In the remaining two strains, DBA/2J and A/J, the researchers recorded quick weight loss in the mice. These mice either succumbed to the illness within the first seven days after infection, or were sacrificed because their weight loss exceeded 25%.

The researchers explored the reaction of the animals' immune system to the virus. 'The mice die from their own immune defences, which are actually supposed to protect them against the virus,' explained Professor Klaus Schughart, head of the Experimental Mouse Genetics Department at the Helmholtz Centre for Infection Research, and co-author of the study.

'The immune system produces too many messengers, which have a strong activating effect on the immune cells. These cells then kill tissue cells in the lungs that are infected with the virus.'

Another sour point is that the cells working in overdrive are effectively killing healthy lung tissue. Virus levels in the mice that died were 100 times higher than in the mice that pulled through. An interesting discovery was that the infected DBA/2J mice showed a higher viral load in their lungs, elevated expression of cytokines and chemokines, as well as a more severe and extended lung pathology compared with C57BL/6J infected mice (C57BL/6J is a more resistant strain).

The factor of sex was also compared for both these strains, but was found not to affect susceptibility to influenza infections. Male and female mice from each strain were observed, and based on the results, both sexes from the DBA/2J strain showed similar patterns of weight loss and were highly susceptible, while both sexes from the C57BL/6J strain were resistant.

'It appears that the animals have specific receptors on their cells that make them more receptive to a severe viral infection,' Professor Schughart said. Genetic factors could also influence the progression of influenza in humans. 'It is only now that we are beginning to understand the role played by the genetic factors of the host and what increased receptiveness means in the case of influenza,' he remarked.

Germany reports between 10,000 and 30,000 deaths from influenza each year. Data show that most die from the Influenza type-A virus. H1N1 and H3N2 are the most widely distributed flu strains amongst humans, experts say. A new sub-type, H5N1, recently surfaced and is highly pathogenic in birds. Humans can be infected if they come into close contact with the birds, and a fatal outcome results in 50% of cases.

For more information, please visit:

PLoS ONE:
http://www.plosone.org/home.action

Helmholtz Centre for Infection Research:
http://www.helmholtz-hzi.de/en/

Related stories: 29706, 30432

Category: Miscellaneous
Data Source Provider: PLoS ONE journal; Helmholtz Centre for Infection Research
Document Reference: Srivastava, B. et al. (2009) Host Genetic Background Strongly Influences the Response to Influenza A Virus Infections. PLoS ONE 4(3): e4857. doi:10.1371/journal.pone.0004857
Subject Index: Coordination, Cooperation; Life Sciences; Medicine, Health; Scientific Research

RCN: 30627