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Updated: Feb 23, 2026
Influenza A Virus Studies in a Mouse Model of Infection
Published on: September 7, 2017
Childhood tolerance of severe influenza: a mortality analysis in mice
Freeman Suber1, Lester Kobzik2
1Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
Insights
Puberty increases influenza mortality in mice, driven by estrogen. Blocking estrogen or puberty improved survival, explaining why children fared better during the 1918 pandemic.
Area of Science:
- Immunology
- Endocrinology
- Virology
Background:
- Children had lower mortality during the 1918 influenza pandemic, but the reasons remain unclear.
- It is unknown if this was due to better resistance or tolerance to infection.
Purpose of the Study:
- To investigate the role of puberty and sex hormones in influenza mortality.
- To explain the lower mortality observed in children during the 1918 H1N1 influenza pandemic.
Main Methods:
- Used prepubertal and pubertal mice infected with H1N1 influenza virus.
- Analyzed lung tissue transcriptome, utilized gonadectomy, hormone treatments, and receptor blockade (fulvestrant).
- Investigated the role of interleukin-1 beta (IL-1β) by neutralizing its activity.
Main Results:
- Prepubertal mice showed higher survival than pubertal mice despite similar virus loads.
- Estrogen was identified as a key regulator of susceptibility, increasing mortality in both sexes.
- Blocking puberty or estrogen receptor improved survival, while estrogen/testosterone restored susceptibility.
Conclusions:
- Increased estrogen during puberty in both sexes is linked to higher influenza mortality.
- This hormonal effect explains the reduced mortality in children during the 1918 pandemic.
- Findings may also apply to childhood tolerance of other infectious diseases.
Abstract:
During the 1918 influenza pandemic, children experienced substantially lower mortality than adults, a striking but unexplained finding. Whether this was due to enhanced resistance (reduced virus load) or better tolerance (reduced impact of infection) has not been defined. We found that prepubertal mice infected with H1N1 influenza virus also showed greater survival than infected pubertal mice, despite similar virus loads. Transcriptome profiling of infected lungs identified estrogen as a regulator of susceptibility in both sexes and also linked better survival to late expression of IL-1β. Blocking puberty with gonadectomy or a gonadotropin-releasing hormone antagonist improved survival. Estrogen or testosterone (which can be converted to estrogen) restored susceptibility of gonadectomized pubertal mice to influenza mortality, but dihydrotestosterone (which cannot be converted to estrogen) did not. Estrogen receptor blockade with fulvestrant in both male and female pubertal mice resulted in improved survival, even when given 3 days after infection. Moreover, late, but not early, IL-1β neutralization after infection was also protective. These findings indicate that pubertal increases in estrogen in both sexes are associated with increased mortality during influenza. This helps explain the reduced mortality of children seen with influenza in 1918 and might also be relevant to childhood tolerance to many other infectious diseases.
