Increased virulence of a mouse-adapted variant of influenza A/FM/1/47 virus is controlled by mutations in genome segments 4, 5, 7, and 8

Abstract

To cause disease, influenza virus must possess several genetically determined abilities that mediate stages in pathogenesis. The virulent mouse-adapted variant A/FM/1/47-MA (FM-MA), derived from the avirulent A/FM/1/47 (FM) strain, had acquired mutations in genes that control virulence. The purpose of this study was to identify those genes that had mutated to result in increased virulence and to obtain viruses that differed in virulence because of differences in individual genome segments. The genes that had mutated to increase virulence were initially identified by genetic analysis of reassortants obtained by crossing FM-MA with the avirulent strain A/HK/1/68 (HK). FM-MA genome segments 4, 5, 7, and 8 were significantly associated with virulence, as determined by using the Wilcoxon ranked sum analysis. The role of FM-MA segments 4, 7, and 8 was confirmed by reintroduction of these genes into the parental strain, which also provided virus strains that differed in virulence because of mutations in individual genome segments. Segments 4, 7, and 8 were responsible for a 103 6-fold increase in virulence that was proportioned 102-2_, 100-7-. and 10°8-fold, respectively. The role of segment 5 could not be confirmed on transfer back into the parental strain because of reversion during preparation of such reassortants. The incidence of reversion was shown to be significantly associated with culturing of FM-MA in chicken embryo cells but was not associated with growth in MDCK cells. The genetic analysis of FM-MA suggests that adaptation to increased virulence is an incremental process that involves the acquisition of mutations in multiple genes, each of which plays an individual role in pathogenesis. The structural and functional properties of segments 4, 7, and 8 that control the virulence of FM-MA can now be determined by using viruses that differ in virulence because of mutations in these individual genome segments.

A Mouse-Adapted SARS-Coronavirus Causes Disease and Mortality in BALB/c Mice

“…Reports of adaptation of an influenza A virus for increased virulence in mice indicate that multiple gene products may interact or contribute independently to virulence. In one adaptation of influenza A/FM/1/47 (FM-MA), findings indicated that four viral gene segments contributed to increased virulence [4], but additional analyses indicated that mutations occurring in at least two and likely three gene products acted synergistically to account for the increased virulence [10][11][12]. Recombinant icSARS-CoV produced mild pneumonia identified by X-ray changes in macaques, similar to the clinical disease noted with wild-type SARS-CoV (Urbani) [13].…”

“…Adaptation of SARS-CoV (Urbani) was achieved by serial passage through lungs of BALB/c mice as previously described for influenza A and influenza B viruses [4,5]. Lightly anesthetized mice were inoculated intranasally with 10 5 50% tissue culture infectious dose (TCID 50 ) per mouse of SARS-CoV (Urbani).…”

Episodic evolution mediates interspecies transfer of a murine coronavirus

“…Among influenza A viruses, host range discrimination was polygenic and primarily involved genetic determinants within the nucleoprotein that affected the replication of the virus in various hosts (22,51). Other influenza virus genes, including the hemagglutinin and polymerase genes, also encoded important determinants affecting host range specificity (6,56,58). Canine parvovirus type 2 emerged in 1978 as a variant of feline panleukopenia virus or some other closely related parvovirus infecting carnivores (46).…”

Cigarette Smoke Silences Innate Lymphoid Cell Function and Facilitates an Exacerbated Type I Interleukin-33-Dependent Response to Infection

“…Because IL-33 is found to be upregulated in COPD and plays a role in viralinduced AHR (Byers et al, 2013;Kim et al, 2012), we examined whether there was a role for IL-33 in a model of exacerbation. Therefore, we exposed Il1rl1 À/À (encoding ST2; Townsend et al, 2000), Il33 À/À ( Figure S1A), or BALB/c mice to cigarette smoke or room air and later infected them with influenza A virus ( Figure S1C; Bauer et al, 2010;Brown, 1990). In viral infection alone (i.e., mice exposed to room air), we found that absence of IL-33 or ST2 had minimal impact on the observed weight loss and inflammatory response to infection ( Figures 1A-1C, data shown for Il1rl1 À/À mice only).…”