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.
Highlights
Influenza A virus infections have caused multiple severe pandemics in recent human history
The weight loss in C57BL/6J mice was significantly different to the BALB/c mouse strain on days 2–4 but not at later time points
Several single gene mutations are known which confer resistance or susceptibility to an infection with influenza A virus, very few studies have addressed the influence of multiple complex genetic interactions in mouse genetic reference populations [29,41]
Summary
Influenza A virus infections have caused multiple severe pandemics in recent human history. Seasonal yearly epidemics are caused by variants of the subtypes H1N1 and H3N2 and kill about 1 million people per year world-wide [4]. A new subtype, H5N1, appeared which is highly pathogenic in birds and can be transmitted to humans that are in close contact with infected birds. Very little is known about the influence of specific genes or genetic backgrounds in humans that contribute to the susceptibility or resistance to influenza infections. It is important to note that it is very difficult to perform studies on host susceptibility to acute infections in humans due to the complexity of genetic variants and largely different environmental influences, such as nutrition, life style, medication, exposure to other pathogens, etc. A much better way to understand the principle mechanisms underlying susceptibility or resistance to infectious diseases is to use experimental animal model systems
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