The C5a anaphylatoxin receptor (C5aR1) protects against Listeria monocytogenes infection by inhibiting type 1 IFN expression

J Immunol. 2014 Nov 15;193(10):5099-107. doi: 10.4049/jimmunol.1401750. Epub 2014 Oct 8.

Abstract

Listeria monocytogenes is a major cause of mortality resulting from food poisoning in the United States. In mice, C5 has been genetically linked to host resistance to listeriosis. Despite this genetic association, it remains poorly understood how C5 and its activation products, C5a and C5b, confer host protection to this Gram-positive intracellular bacterium. In this article, we show in a systemic infection model that the major receptor for C5a, C5aR1, is required for a normal robust host immune response against L. monocytogenes. In comparison with wild-type mice, C5aR1(-/-) mice had reduced survival and increased bacterial burden in their livers and spleens. Infected C5aR1(-/-) mice exhibited a dramatic reduction in all major subsets of splenocytes, which was associated with elevated caspase-3 activity and increased TUNEL staining. Because type 1 IFN has been reported to impede the host response to L. monocytogenes through the promotion of splenocyte death, we examined the effect of C5aR1 on type 1 IFN expression in vivo. Indeed, serum levels of IFN-α and IFN-β were significantly elevated in L. monocytogenes-infected C5aR1(-/-) mice. Similarly, the expression of TRAIL, a type 1 IFN target gene and a proapoptotic factor, was elevated in NK cells isolated from infected C5aR1(-/-) mice. Treatment of C5aR1(-/-) mice with a type 1 IFNR blocking Ab resulted in near-complete rescue of L. monocytogenes-induced mortality. Thus, these findings reveal a critical role for C5aR1 in host defense against L. monocytogenes through the suppression of type 1 IFN expression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaphylatoxins / immunology
  • Animals
  • Antibodies / pharmacology
  • Apoptosis
  • Bacterial Load
  • Caspase 3 / genetics
  • Caspase 3 / immunology
  • Complement C5a / genetics
  • Complement C5a / immunology
  • Complement C5b / genetics
  • Complement C5b / immunology
  • Gene Expression
  • Interferon-alpha / genetics*
  • Interferon-alpha / immunology
  • Interferon-beta / genetics*
  • Interferon-beta / immunology
  • Listeria monocytogenes / immunology*
  • Listeriosis / drug therapy
  • Listeriosis / immunology*
  • Listeriosis / microbiology
  • Listeriosis / mortality
  • Liver / immunology
  • Liver / microbiology
  • Liver / pathology
  • Lymphocytes / immunology
  • Lymphocytes / microbiology
  • Lymphocytes / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Receptor, Anaphylatoxin C5a / genetics
  • Receptor, Anaphylatoxin C5a / immunology
  • Receptors, Interferon / antagonists & inhibitors
  • Receptors, Interferon / genetics
  • Receptors, Interferon / immunology
  • Spleen / immunology*
  • Spleen / microbiology
  • Spleen / pathology
  • Survival Analysis
  • TNF-Related Apoptosis-Inducing Ligand / genetics
  • TNF-Related Apoptosis-Inducing Ligand / immunology

Substances

  • Anaphylatoxins
  • Antibodies
  • C5AR1 protein, human
  • Interferon-alpha
  • Receptor, Anaphylatoxin C5a
  • Receptors, Interferon
  • TNF-Related Apoptosis-Inducing Ligand
  • Tnfsf10 protein, mouse
  • Interferon-beta
  • Complement C5a
  • Complement C5b
  • Casp3 protein, mouse
  • Caspase 3