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Pathogenesis and Immunity

A Mouse Model for the Evaluation of Pathogenesis and Immunity to Influenza A (H5N1) Viruses Isolated from Humans

Xiuhua Lu, Terrence M. Tumpey, Timothy Morken, Sherif R. Zaki, Nancy J. Cox, Jacqueline M. Katz
Xiuhua Lu
Influenza Branch and
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Terrence M. Tumpey
Influenza Branch and
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Timothy Morken
Infectious Disease Pathology Activity,Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333
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Sherif R. Zaki
Infectious Disease Pathology Activity,Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333
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Nancy J. Cox
Influenza Branch and
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Jacqueline M. Katz
Influenza Branch and
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DOI: 10.1128/JVI.73.7.5903-5911.1999
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  • Fig. 1.
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    Fig. 1.

    Comparison of lethality of human H5N1 influenza viruses for BALB/c mice. Groups of 10 mice were infected i.n. with 104 (A), 103 (B), or 102 (C) MID50 of HK/483 (●), HK/485 (○), HK/156 (▾), or HK/486 (▿) virus and examined daily for 14 days.

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    Fig. 2.

    Replication of influenza A (H5N1) viruses in mice. Mice were infected with 100 MID50 of each virus; tissues and blood were collected on days 4 (■) and 6 (□) p.i., and titrated in eggs. The mean virus titers from three mice per group are shown. The limit of virus detection was 101.2 EID50/ml for lungs and 100.8 EID50/ml for blood and other tissues. ∗ and †, P < 0.01 and P < 0.05, respectively, versus groups infected with HK/156 or HK/486 virus.

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    Fig. 3.

    Immunostaining of viral antigens in lung and brain from mice infected with 1,000 MID50 of HK/483 virus. (A) Immunostaining in bronchial epithelium and subepithelial tissue from a mouse that succumbed to infection on day 7 p.i. (B) Higher magnification of a bronchus showing mainly nuclear, and to a less extent cytoplasmic, staining of bronchial epithelial cells. Note immunostaining in association with necrotic detached epithelial cells in bronchial lumen. (C) Brain collected on day 6 p.i. showing a focus of antigen-positive cells. (D) High-power magnification showing nuclear and cytoplasmic immunostaining of glial cells and neurons (naphthol-fast red with hematoxylin counterstain; original magnifications, ×50 [A], ×158 [B], ×50 [C], and ×158 [D]).

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    Fig. 4.

    Serum HI antibody responses following one or two doses of dk/Sing vaccine. Mice were vaccinated i.m. with alum alone (A), 10 μg of dk/Sing vaccine alone (B), or vaccine with alum (C). Sera from 17 to 20 mice per group were collected 3 weeks after the first and second vaccinations and tested individually for HI antibody against HK/156 virus. HI titers are expressed as a log2 value of the reciprocal of the highest dilution of serum inhibiting agglutination of 0.5% of turkey erythrocytes at 4 HA units of virus. Antibody responses shown in panel C were significantly greater than the corresponding responses shown in panel B (P < 0.001). A log2 value of ≥5.3 represents an HI titer of ≥40. Solid bars represent the GMT.

Tables

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  • Table 1.

    Characteristics of influenza A H5N1 viruses

    VirusGroupaCase descriptionPassage no.Infectivity titer (log10/ml)bMID50cLD50d
    Age (yr)/genderOutcomeMDCKEggsTCID50EID50
    HK/483B13/femaleFatal138.59.02.22.4
    HK/485B24/femaleSevere/recovered228.58.71.12.9
    HK/156A3/maleFatal037.710.03.25.9
    HD/486A5/femaleMild/recovered248.79.01.2>7
    X-31 (H3N2)NAe NA0>107.38.50.7>5.2
    • ↵a Antigenic/genetic group of H5N1 viruses isolated from humans (3).

    • ↵b Calculated by the method of Reed and Muench (24) from the results of serial titrations of viruses in MDCK cells and embryonated eggs.

    • ↵c Expressed as the EID50 required to give 1 MID50.

    • ↵d Expressed as the EID50 required to give 1 LD50.

    • ↵e NA, not applicable.

  • Table 2.

    HI reactivity of serum samples from vaccinated mice for influenza A H5 viruses

    SerumHI antibody titer
    dk/Sing (H5N3)H5N1 group AH5N1 group B
    HK/156HK/486HK/516HK/538HK/483HK/485HK/491HK/514
    Vaccinated micea
     dk/Sing808040404040408040
     dk/Sing + alum32032016032064016080320160
     Alum101010101010101010
    Infected ferretsb
     dk/Sing1601608016016040408080
     HK/15616016016016016020208080
     HK/48316016080160160160408080
    • ↵a Serum samples from groups of 17 to 22 mice immunized with dk/Sing vaccine with or without alum or alum alone were collected 3 weeks after the second vaccination and were pooled for HI assay against H5N1 group A and group B viruses.

    • ↵b Serum samples from single ferrets infected with dk/Sing, HK/483, or HK/156 virus were concentrated fourfold. The ferret infected with HK/156 virus was also inoculated i.n. with A/Turkey/Wisconsin/68 virus (H5N9).

  • Table 3.

    Protective efficacy of dk/Sing (H5N3) vaccine against lethal infection with HK/483 virus

    Vaccine groupPrechallenge antibody titera against:Mean virus titer (log10 EID50/ml) ± SDbNo. protected/total no.c
    HK/156HK/483
    HINeutralizationHINeutralizationLungBrainInfectionDeath
    dk/Singd 80400401002.6 ± 0.6e ≤0.8e 7/10f 12/12e
    dk/Sing + alum1,2808,0003201,600≤1.2e ≤0.8e 8/8e 12/12e
    Alum102510256.3 ± 0.92.5 ± 1.00/70/10
    • ↵a Serum samples pooled from 10 mice per group were used.

    • ↵b Mean virus titers and protection from infection were determined on day 6 p.i. Titers represent means ± SD of 7 to 10 mice per group.

    • ↵c Mice were monitored for 14 days after challenge. Mice in the alum-vaccinated group died on day 6 or 7.

    • ↵d Mice were vaccinated with two doses of 10 μg of formalin-inactivated dk/Sing vaccine and challenged 4 months later with 50 LD50 of HK/483 virus.

    • ↵e P < 0.001 compared with alum-vaccinated group.

    • ↵f P < 0.01 compared with alum-vaccinated group.

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A Mouse Model for the Evaluation of Pathogenesis and Immunity to Influenza A (H5N1) Viruses Isolated from Humans
Xiuhua Lu, Terrence M. Tumpey, Timothy Morken, Sherif R. Zaki, Nancy J. Cox, Jacqueline M. Katz
Journal of Virology Jul 1999, 73 (7) 5903-5911; DOI: 10.1128/JVI.73.7.5903-5911.1999

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A Mouse Model for the Evaluation of Pathogenesis and Immunity to Influenza A (H5N1) Viruses Isolated from Humans
Xiuhua Lu, Terrence M. Tumpey, Timothy Morken, Sherif R. Zaki, Nancy J. Cox, Jacqueline M. Katz
Journal of Virology Jul 1999, 73 (7) 5903-5911; DOI: 10.1128/JVI.73.7.5903-5911.1999
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KEYWORDS

Influenza A Virus, H5N1 Subtype
influenza A virus
Influenza, Human

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