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Results: 4

1.
Figure 3

Figure 3. Altered leukocyte and cytokine response to influenza A infection in Ifitm3−/− mice. From: IFITM3 restricts the morbidity and mortality associated with influenza.

Cytometric analysis of proportional resident cell populations in the lungs of mice (a, +/+: black, −/−: white) showed evidence of lymphopenia in Ifitm3−/− mice six days post-infection. Systemic lymphopenia was confirmed through differential analysis of peripheral blood cell counts (b), which showed a significant depletion of lymphocytes on day two post-infection of Ifitm3−/− mice (monocytes: black, lymphocytes: grey, polymorphonuclear leukocytes: white). Levels of pro-inflammatory cytokines were also recorded as being elevated in Ifitm3−/− lungs over the course of infection (c, +/+: black, −/−: white). Results show means ± s.d., n=5. Statistical significance was assessed by Student’s t-test (*: P < 0.05, **: P < 0.01, ***: P < 0.001).

Aaron R. Everitt, et al. Nature. 2012 March 25;484(7395):519-523.
2.
Figure 2

Figure 2. Pathological examination of infected lungs. From: IFITM3 restricts the morbidity and mortality associated with influenza.

WT mice showed few visible signs of external damage on lung lobes at day six post-infection, whilst Ifitm3−/− mice showed multiple large lesions (a: left, ventral view of intact lungs, right, all lobes displayed) resulting from severe oedema and hemorrhagic pleural effusion (b), as well as a markedly higher infiltration of cells and proteinaceous debris into the alveoli and bronchioles. Localisation of virus within the lungs on day six (c) indicated virus penetrated deeper and more extensively into the lung tissue in the Ifitm3−/− mice, as determined by immunohistochemistry for total influenza protein and detection of virus nucleic acid (virus: red, cell nuclei: blue, A: alveolus, B: bronchiole). Original magnifications were 5x (b) and 20x (c).

Aaron R. Everitt, et al. Nature. 2012 March 25;484(7395):519-523.
3.
Figure 1

Figure 1. Influenza A virus replicates to higher levels in Ifitm3−/− mice. From: IFITM3 restricts the morbidity and mortality associated with influenza.

Change in body mass (a) and survival (b) of WT (•) and Ifitm3−/− (□) mice following intranasal inoculation with A/X-31 and pandemic H1N1/09 Eng/195 influenza (n>5). Absence of IFITM3 expression was verified in the Ifitm3−/− mice at all time points, but was seen to increase in WT mice (b). A/X-31 viral load in the lungs of mice (n>4) was calculated over the course of infection (c) by plaque assay. Ifitm3−/− murine embryonic fibroblasts (n=3 per condition) stably-expressing Ifitm3 (+), or the empty vector (−) were left untreated (blue), or incubated with IFN-α (red) or -γ (green), then challenged with either A/X-31 or PR/8 influenza. 12h after infection, the cells were assessed for either HA expression (PR/8), or NP expression (A/X-31) (d). Results show means ± s.d. Statistical significance was assessed by Student’s t-test (**: P < 0.01; ***: P < 0.001).

Aaron R. Everitt, et al. Nature. 2012 March 25;484(7395):519-523.
4.
Figure 4

Figure 4. Single nucleotide polymorphisms of the human IFITM3 gene. From: IFITM3 restricts the morbidity and mortality associated with influenza.

Multiple single nucleotide polymorphisms have been identified within the coding region of the human IFITM3 gene. One such SNP, rs12252 (red) (a), encodes a splice acceptor site altering T/C substitution mutation, which results in a truncated protein with an N-terminal 21 amino acid deletion. Therefore two transcripts are predicted to be expressed from the IFITM3 gene. Positive selection analysis using a haplotype-based test (∣XP-EHH-max∣, b) where data points above 2.7 in the YRI (red), 3.9 in the CEU (blue) and 5.0 in the CHB+JPT (green) are in the top 1% of values and using a combination of three allele frequency spectrum-based test statistics (c), namely Tajima’s D, Fay and Wu’s H and Nielsen et al.’s CLR on 10 kb windows along chromosome 11 encompassing the IFITM3 locus. Evidence for positive selection is seen only in the YRI. Mutations recorded through sequencing of patients hospitalised with influenza virus during the H1N1/09 pandemic showed an overrepresentation of individuals with the C allele at SNP rs12252 (d), relative to matched Europeans. A549 cells transduced to express either full-length (IFITM3) or truncated (NΔ21) IFITM3 (e) (cell nuclei: blue, virus: green, 4× magnification), show a reduction in viral restriction when IFITM3’s N-terminal 21 amino acids are removed, relative to vector controls (Vector). Alignment of the N-termini of full length (IFITM3, top) and truncated IFITM3 (NΔ21, bottom). Values represent the mean of the percent infected cells ± s.d. (n=3).

Aaron R. Everitt, et al. Nature. 2012 March 25;484(7395):519-523.

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