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.

[1]  S. Cartner,et al.  Gender Is a Major Factor in Determining the Severity of Mycoplasma Respiratory Disease in Mice , 2001, Infection and Immunity.

[2]  V. Morell.  Zeroing in on how hormones affect the immune system , 1995, Science.

[3]  G. Köhler,et al.  Both innate and acquired immunity to Listeria monocytogenes infection are increased in IL-10-deficient mice. , 1997, Journal of immunology.

[4]  E. Pamer,et al.  Quantitative studies of CD8+ T-cell responses during microbial infection. , 2003, Current opinion in immunology.

[5]  M. Salem,et al.  Estrogen, a double-edged sword: modulation of TH1- and TH2-mediated inflammations by differential regulation of TH1/TH2 cytokine production. , 2004, Current drug targets. Inflammation and allergy.

[6]  D. Sachs,et al.  Resistance to Listeria monocytogenes in mice: genetic control by genes that are not linked to the H-2 complex. , 1979, The Journal of infectious diseases.

[7]  E. Unanue,et al.  Lymphocyte apoptosis during early phase of Listeria infection in mice. , 1997, The American journal of pathology.

[8]  D. Wirth,et al.  Gender distribution in asymptomatic and invasive amebiasis , 2000, American Journal of Gastroenterology.

[9]  R. Mosher,et al.  Multigenic control of Listeria monocytogenes susceptibility in mice , 2001, Nature Genetics.

[10]  C. Roberts,et al.  Innate immunity to Toxoplasma gondii is influenced by gender and is associated with differences in interleukin-12 and gamma interferon production , 1997, Infection and immunity.

[11]  S. Huber,et al.  Differential Th1 and Th2 cell responses in male and female BALB/c mice infected with coxsackievirus group B type 3 , 1994, Journal of virology.

[12]  Werner Müller,et al.  Introducing the German Mouse Clinic: open access platform for standardized phenotyping , 2005, Nature Methods.

[13]  E. Unanue.  Studies in listeriosis show the strong symbiosis between the innate cellular system and the T‐cell response , 1997, Immunological reviews.

[14]  J. Cavaillon,et al.  Influence of gender and age on course of infection and cytokine responses in mice with disseminated Cryptococcus neoformans infection. , 2002, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[15]  B. Beutler,et al.  The evolution and genetics of innate immunity , 2001, Nature Reviews Genetics.

[16]  N. Schork,et al.  Serial backcross mapping of multiple loci associated with resistance to Leishmania major in mice. , 1997, Immunity.

[17]  R. Nishinakamura,et al.  The cytokine stew and innate resistance to L. monocytogenes , 1997, Immunological reviews.

[18]  D. Busch,et al.  Coordinate regulation of complex T cell populations responding to bacterial infection. , 1998, Immunity.

[19]  C. Czuprynski,et al.  Killing of Listeria monocytogenes by Inflammatory Neutrophils and Mononuclear Phagocytes From Immune and Nonimmune Mice , 1984, Journal of leukocyte biology.

[20]  J. F. Brown,et al.  Treatment with anti-interleukin-10 monoclonal antibody enhances early resistance to but impairs complete clearance of Listeria monocytogenes infection in mice , 1994, Infection and immunity.

[21]  D. Persing,et al.  Innate Resistance to Babesia Infection Is Influenced by Genetic Background and Gender , 2001, Infection and Immunity.

[22]  D. Busch,et al.  Processing of Listeria monocytogenes antigens and the in vivo T‐cell response to bacterial infection , 1999, Immunological reviews.

[23]  M. Bevan,et al.  Primary and secondary immune responses to Listeria monocytogenes. , 1996, Current opinion in immunology.

[24]  M. Barna,et al.  Sex differences in susceptibility to viral infection of the central nervous system , 1996, Journal of Neuroimmunology.

[25]  I. Gavilán,et al.  Consistent production of a higher TH1:TH2 cytokine ratio by stimulated T cells in men compared with women. , 2000, European journal of endocrinology.

[26]  J. Alexander.  Sex differences and cross-immunity in DBA/2 mice infected with L. mexicana and L. major , 1988, Parasitology.

[27]  E. Unanue,et al.  Listeriolysin O from Listeria monocytogenes Is a Lymphocyte Apoptogenic Molecule1 , 2004, The Journal of Immunology.

[28]  G. Ludlam,et al.  Age–sex distribution of various diseases with particular reference to toxoplasmic lymphadenopathy , 1976, Journal of Hygiene.

[29]  G. Mancuso,et al.  Role of IL-10 in a neonatal mouse listeriosis model. , 1999, Journal of immunology.

[30]  S. Scheu,et al.  The Lymphotoxin β Receptor Is Critically Involved in Controlling Infections with the Intracellular Pathogens Mycobacterium tuberculosis and Listeria monocytogenes1 , 2003, The Journal of Immunology.

[31]  C. Roberts,et al.  Sex-determined resistance to Toxoplasma gondii is associated with temporal differences in cytokine production , 1995, Infection and immunity.

[32]  T. Beery.  Sex differences in infection and sepsis. , 2003, Critical care nursing clinics of North America.

[33]  K. Rajewsky,et al.  Interleukin-10-deficient mice develop chronic enterocolitis , 1993, Cell.

[34]  K. Beagley,et al.  Regulation of innate and adaptive immunity by the female sex hormones oestradiol and progesterone. , 2003, FEMS immunology and medical microbiology.

[35]  S. Kaufmann,et al.  Neutrophilia in LFA-1-Deficient Mice Confers Resistance to Listeriosis: Possible Contribution of Granulocyte-Colony-Stimulating Factor and IL-171 , 2003, The Journal of Immunology.

[36]  R. Schreiber,et al.  Requirement of endogenous interferon-gamma production for resolution of Listeria monocytogenes infection. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[37]  S. Morrison,et al.  A Quantitative Difference in the Immune Response between Male and Female Mice∗ , 1968, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[38]  M. Giannini.  Sex‐influenced response in the pathogenesis of cutaneous leishmaniasis in mice , 1986, Parasite immunology (Print).

[39]  S. Segal,et al.  Sex-associated differences in the regulation of immune responses controlled by the MHC of the mouse. , 1984, Journal of immunology.

[40]  F. Gervais,et al.  Genetic control of resistance to Listeria monocytogenes: regulation of leukocyte inflammatory responses by the Hc locus. , 1984, Journal of immunology.

[41]  S. Sasaki,et al.  Dysregulation of interleukin-10 and interleukin-12 are involved in the reduced host resistance to Listeria monocytogenes infection in alymphoplastic aly mutant mice. , 2002, FEMS immunology and medical microbiology.

[42]  S. Ahmed,et al.  Effects of long-term estrogen treatment on IFN-gamma, IL-2 and IL-4 gene expression and protein synthesis in spleen and thymus of normal C57BL/6 mice. , 2001, Cytokine.

[43]  D. Radzioch,et al.  Influence of gender and interleukin‐10 deficiency on the inflammatory response during lung infection with Pseudomonas aeruginosa in mice , 2002, Immunology.

[44]  A. Lengeling,et al.  Genetic control of susceptibility to group A streptococcal infection in mice. , 2001, The Journal of infectious diseases.

[45]  C. Cheers,et al.  Resistance and susceptibility of mice to bacterial infection: genetics of listeriosis , 1978, Infection and immunity.

[46]  H. Offner,et al.  Estrogen Treatment Down-Regulates TNF-α Production and Reduces the Severity of Experimental Autoimmune Encephalomyelitis in Cytokine Knockout Mice1 , 2001, The Journal of Immunology.

[47]  S. Scheu,et al.  The lymphotoxin beta receptor is critically involved in controlling infections with the intracellular pathogens Mycobacterium tuberculosis and Listeria monocytogenes. , 2003, Journal of immunology.

[48]  A. Phillips,et al.  A sex comparison of rates of new AIDS‐defining disease and death in 2554 AIDS cases , 1994, AIDS.

[49]  J. W. Conlan,et al.  Neutrophil-mediated dissolution of infected host cells as a defense strategy against a facultative intracellular bacterium , 1991, The Journal of experimental medicine.

[50]  N. J. Bigley,et al.  Does the gender difference in interferon production seen in picornavirus-infected spleen cell cultures from ICR Swiss mice have any in vivo significance? , 1993, Journal of interferon research.

[51]  P. Lundberg,et al.  Gender Influences Herpes Simplex Virus Type 1 Infection in Normal and Gamma Interferon-Mutant Mice , 2001, Journal of Virology.

[52]  C. Caracta.  Gender differences in pulmonary disease. , 2003, The Mount Sinai journal of medicine, New York.