Sex-dependent susceptibility to Listeria monocytogenes infection is mediated by differential interleukin-10 production

Abstract

It is well documented that sex-dependent factors affect susceptibility to infection, with most mouse models demonstrating higher resistance in females. We made the unexpected observation that infection with the intracellular bacterium Listeria monocytogenes showed an opposite pattern in several commonly used inbred mouse strains: female C57BL/6J, BALB/c, C3H/HeN, and CBA/J mice were significantly more susceptible to Listeria infection. The pronounced sensitivity of females to Listeria, which was revealed by significantly higher lethality rates, correlated also with increased bacterial numbers in organ tissues (spleen and liver) and several immunological changes in peripheral blood samples. Surprisingly, increased severity of infection in females was associated with elevated interleukin-10 (IL-10) levels in plasma. Experiments using Il10 knockout mice, for which no differences between the susceptibilities of males and females to Listeria infection could be detected, confirmed the important role of this immunosuppressive cytokine for the outcome of disease. Our findings are likely to have clinical relevance, since similar sex differences with regard to infection with Listeria monocytogenes and other intracellular pathogens have been reported for humans.

FIG. 1.

Infection of BALB/c mice with L. monocytogenes reveals increased lethality in females. Kaplan-Meier survival curves for male (•) and female (▵) mice after infection with L. monocytogenes (right) or S. pyogenes (left) are shown. Seven mice per group were monitored for a period of 14 days. Representative data from one out of three independent experiments are shown.

FIG. 2.

Increased severity of L. monocytogenes infection in female mice is not dependent on the genetic background. Kaplan-Meier survival curves for L. monocytogenes-infected BALB/c (upper left), C57BL/6J (upper right), C3H/HeN (lower right), and CBA/J (lower left) male (•) and female (▵) mice are shown. Seven mice per group were monitored for 14 days. Representative data from one out of three independent experiments are shown.

FIG.3.

Female mice show higher bacterial loads, more-pronounced lymphopenia, lower IFN-γ and higher IL-10 plasma concentrations than males on day 3 after L. monocytogenes infection. (A) CFU numbers in the spleen were calculated for male (closed symbols) and female (open symbols) BALB/c, C57BL/6J, CBA/J, and C3H/HeN mice. For each group, the mean CFU (horizontal lines) and standard error of the mean are indicated. (B though D) Relative proportions of CD4⁺ T cells (B) and plasma concentrations of IFN-γ (C) and IL-10 (D) were determined in peripheral blood samples from infected (black bars) and control (white bars) mice. In control groups, IFN-γ and IL-10 levels were below the detection limits of the assay. Means of results obtained from three to seven mice per group (± standard errors of the means) are shown. Significant differences are indicated as follows: *, P < 0.05; **, P < 0.01.

FIG. 4.

Female mice show increased bacterial loads after L. monocytogenes infection with a sublethal dose. CFU numbers in the spleen were calculated for male (closed symbols) and female (open symbols) BALB/c, C57BL/6J, and C3H/HeN mice. Mean CFU (horizontal lines) calculated for 9 or 10 mice per group and standard errors of the means are indicated. Significant differences are indicated as follows: *, P < 0.05; **, P < 0.01.

FIG. 5.

Absence of sex-specific susceptibility patterns in Il10 knockout mice after L. monocytogenes infection. (A) Kaplan-Meier survival curves for L. monocytogenes-infected (1.5 × 10⁴ CFU) male (•) and female (▵) control (left) and Il10 knockout (Il10^−/−) (right) mice. Seven mice per group were monitored for a period of 14 days. Representative data from one out of two independent experiments are shown. (B) Kaplan-Meier survival curves for L. monocytogenes-infected (2 × 10⁶ CFU) male (•) and female (▵) Il10 knockout mice. The experimental setup was the same as that for panel A. Representative data from one out of three independent experiments are shown. (C) Female Il10 knockout mice show IFN-γ levels comparable to concentrations found in wild-type males after L. monocytogenes infection. Seven mice per group were sampled on day 3 postinfection. The level of significance is indicated as follows: *, P < 0.05; n.s., not significant.