The DBA.2 Mouse Is Susceptible to Disease following Infection with a Broad, but Limited, Range of Influenza A and B Viruses

Abstract

We assessed the relative susceptibilities to disease of the DBA.2 and C57BL/6 mouse models upon infection with a range of influenza A and B viruses. DBA.2 mice were more susceptible to disease upon inoculation with human H1N1 influenza A virus strains, several swine influenza viruses, and influenza B viruses but were not overtly susceptible to infection with human seasonal H3N2 strains. Hemagglutination inhibition and immunoglobulin isotype profiling indicated that DBA.2 and C57BL/6 mice generate comparable humoral responses upon equivalent 50% mouse lethal dose (MLD 50 ) challenges with influenza virus. Our data demonstrate the utility of DBA.2 mice for the elucidation of influenza virus pathogenicity determinants and the testing of influenza vaccines.Seasonal influenza constitutes a significant public health problem, causing an estimated 200,000 hospitalizations (25) and an average of 25,000 to 35,000 excess deaths yearly in the United States (6,7,26). Additionally, infrequent influenza pandemics cause considerable disease, with associated mortality ranging from approximately 50 million deaths during the 1918 pandemic (11) to 1 to 4 million deaths in 1957 and approximately 1 million deaths in 1968 (5). In 2009, a novel H1N1 virus emerged and spread rapidly in humans (17, 21), causing severe disease in susceptible populations, as well as an unusually high number of hospitalizations of young people (8).The most practical model for the study of influenza virus pathogenicity is the mouse; nevertheless, commonly utilized mouse strains such as C57BL/6 and BALB/c carry a significant drawback in that there is typically an absence or relative lack of disease generated by human seasonal and animal influenza viruses (4). For this reason, pathogenicity studies are conducted predominantly using highly pathogenic or mouse-adapted strains of influenza virus (14,23,27).The low virulence of primary influenza virus isolates in mouse models further limits the number of challenge viruses that can be used in the development of influenza vaccines and therapeutics. Efforts to circumvent this problem by adapting influenza virus strains to mice can lead to mutations in the viral genome which are not reflective of human influenza viruses and which may alter the susceptibility of the virus to vaccines or therapeutics, as has been shown to be the case for eggadaptive changes (15).Recent reports indicate that DBA.2 mice are highly susceptible to H5N1 influenza viruses (2) as well as the mouseadapted strain A/Puerto Rico/8/1934 (H1N1) (PR8) (23). Furthermore, a majority of avian viruses with low pathogenicity in natural hosts are pathogenic in this model and are more pathogenic than in C57BL/6 mice (3). For these reasons, use of the DBA.2 model in influenza virus research has increased recently (1,9,10,12,22). Despite the rising popularity of this model, the breadth of susceptibility of DBA.2 mice to influenza viruses isolated from mammalian hosts is as yet unclear. Herein we addressed this knowledge gap in the field. Specifically, we demo...

Influenza A and B Virus Intertypic Reassortment through Compatible Viral Packaging Signals

“…In contrast, PR8 BNA at the same dose was fatal to mice, with a calculated MLD 50 of 50 PFU (Fig. 7B), which is only twice that of rWT PR8 (MLD 50 , ϳ25 PFU) (68) and suggests that PR8 HA is a major pathogenicity factor in mice, similar to the results found for the pandemic 1918 Spanish influenza virus (69).…”

Fecal Influenza in Mammals: Selection of Novel Variants

“…We could not compare the fecal isolate of md/MN/07a to its corresponding wildtype virus or lung isolate, because virus could not be recovered from the feces of DBA/2J mice infected with wild-type md/MN/ 07a. In general, we could not assess the differences in pathogenicity of fecal and lung isolates in DBA/2J mice because the animals were so highly sensitive to influenza A virus infections (21,(39)(40)(41).…”

A broadly neutralizing human monoclonal antibody is effective against H7N9

“…A variety of influenza viruses, including H5N1 and influenza B viruses, have been shown to be lethal to DBA mice without prior adaptation (7,8). We reasoned that to complement the cytokine measurements in BALB/c mice, a lethal DBA mouse model could be used to examine the effect of VIS410 on mortality, thereby providing an appropriate model of the significant morbidity and mortality associated with H7N9 infection in humans.…”