Sex-Based Differences in Susceptibility to Severe Acute Respiratory Syndrome Coronavirus Infection

Rudragouda Channappanavar, Craig Fett, Matthias Mack, Patrick P. Ten Eyck, David K. Meyerholz and Stanley Perlman
J Immunol May 15, 2017, 198 (10) 4046-4053; DOI: https://doi.org/10.4049/jimmunol.1601896

Article Figures & Data

Figures

  • FIGURE 1.
    FIGURE 1.

    Male mice are more susceptible to MA15 infection than female mice. (A) Nine-month-old male and female mice were infected with 1250, 5000, or 104 PFU MA15, and survival was monitored for 12 d. (B) Two- and nine-month-old B6 male and female mice were infected with 5000 PFU MA15, and 18–20-mo-old B6 mice were challenged with 1000 PFU MA15. Survival was monitored for 12 dpi. (A and B) Data are derived from two independent experiments with four or five mice per group per experiment. (C) Two-month-old BALB/c mice and 5- and 9-mo-old BALB/c mice were infected with 104 and 50 PFU MA15, respectively, and were monitored for morbidity and mortality. Data are derived from two or three independent experiments with three to five mice per group per experiment (left and middle panels) and from one experiment with four or five mice per group (right panel). **p < 0.01, ***p < 0.001, ****p < 0.0001, log-rank test with 95% CI.

  • FIGURE 2.
    FIGURE 2.

    Virus titers and lung pathology in MA15-infected mice. Nine-month-old male and female mice were infected with 5000 PFU MA15, and lungs were analyzed for titer (A), viral Ag staining in the lungs at different times p.i. (original magnification ×10) (B), gross pathology and vascular leakage in lungs of naive and MA15-infected male and female mice on day 4 p.i. (C), and histology in naive and MA15-infected male and female mice on day 4 p.i. (D). (E) Lung inflammation and edema scores were determined at day 4 p.i. These data are derived from four or five mice per group. (A) Data are representative of two independent experiments. Statistical significance was determined as described in Materials and Methods. *p < 0.05.

  • FIGURE 3.
    FIGURE 3.

    Increased IMM accumulation in the lungs of MA15-infected male mice. Mice were infected with 5000 PFU MA15 and analyzed for IMMs (A–C) or neutrophils (D–F) in the lungs on days 0, 1, and 3 p.i. Representative FACS plots show the percentage of IMMs (A) and neutrophils (D) in the lings. Bar graphs show the percentage and total number of IMMs (B and C) and neutrophils (E and F) at different time p.i. Data are representative of two independent experiments with four mice per group per experiment. Statistical significance was determined as described in Materials and Methods. **p < 0.01, ***p < 0.001.

  • FIGURE 4.
    FIGURE 4.

    Enhanced proinflammatory cytokines/chemokines in the lungs of MA15-challenged male mice. Eight- to nine-month-old male and female mice were infected with 5000 PFU MA15. (A) mRNA levels of antiviral and proinflammatory cytokines/chemokines in the lungs were measured at different times p.i. Data were obtained from four or five mice per group. FACS plots (B) and bar graphs (C) show the percentage and number of cytokine-producing IMMs in the lungs of male and female mice on day 3 p.i. following a 7-h ex vivo incubation in the presence of brefeldin A. (D) Nine-month-old female and male mice were treated with control Ig or MC21 Ab (anti-CCR2, depletes IMMs) at −6 h and day 1. These mice were infected with 4000 PFU MA15, and survival was recorded. (B–D) Data represent two independent experiments with four or five mice per group per experiment. Statistical significance was determined as described in Materials and Methods. *p < 0.05, **p < 0.01, ***p < 0.001. ns, not significant.

  • FIGURE 5.
    FIGURE 5.

    Enhanced susceptibility of male mice to MA15 infection is independent of T and B cell response. Seven-to eight-month-old male and female RAG1−/− mice were challenged with 1750 PFU MA15 and monitored for morbidity and mortality for 14 d. Data are derived from seven or eight mice per group. **p < 0.01, log-rank test with 95% CI.

  • FIGURE 6.
    FIGURE 6.

    Estrogen receptor signaling protects female mice from lethal MA15 infection. Nine- to ten-month-old male and female and their gonadectomized counterparts were infected with 5000 PFU MA15. Nine-month old gonadectomized (n = 8) or nongonadectomized (n = 8) (A) and control (n = 6) or flutamide-treated (n = 7) (B) male mice were monitored for disease severity. (C) Percentage of initial weight and survival among control (n = 12) or ovariectomized female (n = 12) mice. (D) Female mice treated with vehicle (corn oil; n = 9), tamoxifen (1 mg per mouse; n = 9–10), or ICI 182, 780 (1 mg per mouse; n = 10) in 100 μl of corn oil were infected with 5000 PFU MA15 and monitored for morbidity and mortality. Data are derived from two or three independent experiments with three to five mice per group per experiment. *p < 0.05, **p < 0.01, log-rank test with 95% CI.

  • FIGURE 7.
    FIGURE 7.

    Virus titer and IMM accumulation in ovariectomized female mice. Nine-month old control or ovariectomized mice were infected with 5000 PFU MA15, and virus titers and inflammatory cell accumulation were analyzed. (A) Lung virus titers in 9-mo-old male and female mice at days 2 and 4 p.i. (B and C) IMM and neutrophil accumulation in the lungs at day 2 p.i. Data are derived from two independent experiments with three or four mice per group per experiment (A) or are representative of two independent experiments with three or four mice per group per experiment (B and C). Statistical significance was determined as described in Materials and Methods. **p < 0.01, ***p < 0.001. ns, not significant.

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