Biological sex influences susceptibility to Acinetobacter baumannii pneumonia in mice
Sílvia Pires, Adeline Peignier, Jeremy Seto, Davida S. Smyth, Dane Parker
Sílvia Pires, Adeline Peignier, Jeremy Seto, Davida S. Smyth, Dane Parker
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Research Article Immunology Infectious disease

Biological sex influences susceptibility to Acinetobacter baumannii pneumonia in mice

Abstract

Acinetobacter baumannii (A. baumannii) is an extremely versatile multidrug-resistant pathogen with a very high mortality rate; therefore, it has become crucial to understand the host response during its infection. Given the importance of mice for modeling infection and their role in preclinical drug development, equal emphasis should be placed on the use of both sexes. Through our studies using a murine model of acute pneumonia with A. baumannii, we observed that female mice were more susceptible to infection. Likewise, treatment of male mice with estradiol increased their susceptibility to infection. Analysis of the airway compartment revealed enhanced inflammation and reduced neutrophil and alveolar macrophage numbers compared with male mice. Depletion of either neutrophils or alveolar macrophages was important for bacterial clearance; however, depletion of alveolar macrophages further exacerbated female susceptibility because of severe alterations in metabolic homeostasis. Our data highlight the importance of using both sexes when assessing host immune pathways.

Authors

Sílvia Pires, Adeline Peignier, Jeremy Seto, Davida S. Smyth, Dane Parker

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Figure 2

Female mice have exacerbated inflammation and reduced immune cell numbers in the airway in response to A. baumannii.

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Female mice have exacerbated inflammation and reduced immune cell number...
(A) Flow cytometry analysis of neutrophils and alveolar macrophages present in the airway of female and male weight-matched mice before and 24 hours after intranasal infection with A. baumannii. Infected mice: n = 8 female, 10 male; n = 2 uninfected. (B) Cytokine levels in BALF (infected mice: n = 8 female, 10 male). Heatmap is log10 scale of cytokines in pg/mL, with female/male ratio and statistical significance. Select cytokines are shown individually. (C) Bacterial numbers were assessed 4 hours after infection of purified alveolar macrophages from both sexes of mice with A. baumannii (n = 14). (D) Bacterial numbers were assessed 1 hour after infection of bone marrow–derived neutrophils from female and male mice with A. baumannii (n = 12). (E) WT C57BL/6J mice were infected with 107 CFU of A. baumannii for 24 hours, and neutrophils were treated with CellRox reagent to assess ROS production and cell death. n = 8 males, and n = 7 females. (F) Immortalized bone marrow macrophages (iBMMs) and (G) RAW macrophages were incubated with β-estradiol or vehicle overnight before incubating with A. baumannii and assessing killing 2 hours later. iBMM control n = 4, β-estradiol n = 6; RAW control n = 6, β-estradiol n = 5. Graphs show means with SEM. Data are from at least 2 independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. A nonparametric Mann-Whitney test U was used to assess differences between groups.