Sex-Dependent Susceptibility toListeria monocytogenesInfection 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.Infectious diseases are a major cause of morbidity and mortality worldwide (52). It is well established that the sex of a host can significantly affect susceptibility to infection. A number of reports have shown that patients of one sex are more likely to get an infectious disease, and gender is often referred to as a risk factor for the severity and outcome of an illness; wellknown examples from human pathology include tuberculosis (13), sepsis (7), invasive amebiasis (1), toxoplasmosis-related entities (8, 42), and listeriosis (21). The underlying molecular mechanisms of this predisposition are largely unknown.Mice have been extensively used to study immune responses during infection, and it is not surprising that sex differences in susceptibility have also been observed in mouse models, further confirming clinical observations that female and male individuals handle infections differently. Most experimental settings examining a variety of different infectious agents have revealed a rather redundant susceptibility pattern, suggesting that female mice are in general more resistant to bacterial or viral diseases than males (4,17,27,30,35,36,53). In all these experimental models, increased resistance was associated with more vigorous and better-sustained immune responses in females (36,41,47,51), which have been attributed to hormoneregulated dissimilarities in immune cell function and cytokine production (5, 44). Nevertheless, the intricate mechanisms of sex differences in infection susceptibility have remained obscure.Listeria monocytogenes is an intracellular gram-positive bacterium that causes disease in immunocompromised individuals and pregnant women, often with deleterious consequences for the fetus (21). It is also one of the most widely used pathogens in exp...

The Aryl Hydrocarbon Receptor Is Required for Optimal Resistance to Listeria monocytogenes Infection in Mice

“…In contrast, IL-10 is generally considered to be antiinflammatory and an inhibitor of Th1 cellular immunity, as reflected in IL-10 Ϫ/Ϫ mice being more resistant to listeriosis (48,49). Female mice also produce more IL-10, which correlates with their greater susceptibility to listeriosis than male mice (50). We were surprised to find no difference in serum levels of IFN-␥ and TNF-␣ between L. monocytogenes-infected AhR ϩ/Ϫ and AhR Ϫ/Ϫ mice.…”

Gender differences in expression of the human caspase-12 long variant determines susceptibility to Listeria monocytogenes infection

“…The increased susceptibility of female mice to L. monocytogenes has been linked to enhanced production of the immunosuppressive cytokine IL-10 and downregulation of the protective cytokine IFN␥ by estrogen (ref. 20 and references therein). To examine the effects of Csp-12L on the production of these cytokines, we quantified their levels in the serum of infected mice.…”

“…Epidemiological clinical data and animal models of various human illnesses including sepsis (18) and listeriosis (19,20) reveal that males and females handle infections differently.…”

Nocardia brasiliensis Induces an Immunosuppressive Microenvironment That Favors Chronic Infection in BALB/c Mice

“…These data suggest that IL-10 detected during the following days could have been produced by macrophages and dendritic cells in the lesion site. IL-10 has been associated with the susceptibility with several intracellular infections, such as M. tuberculosis (41), Listeria monocytogenes (27), and Salmonella (28). It is known that IL-10 suppresses the mycobactericide mechanisms, and IL-10-deficient mice showed an increased protection against M. tuberculosis infection (30,36).…”