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Multiple Nod-Like Receptors Activate Caspase 1 during Listeria monocytogenes Infection^1,2

Sarah E. Warren^*,, Dat P. Mao, April E. Rodriguez, Edward A. Miao^3, and Alan Aderem^3,4,*,

^* Department of Immunology, University of Washington, Seattle WA 98195; and Institute for Systems Biology, Seattle WA 98103

Listeria monocytogenes escapes from the phagosome of macrophages and replicates within the cytosolic compartment. The macrophage responds to L. monocytogenes through detection pathways located on the cell surface (TLRs) and within the cytosol (Nod-like receptors) to promote inflammatory processes aimed at clearing the pathogen. Cytosolic L. monocytogenes activates caspase 1, resulting in post-translational processing of the cytokines IL-1β and IL-18 as well as caspase 1-dependent cell death (pyroptosis). We demonstrate that the presence of L. monocytogenes within the cytosolic compartment induces caspase 1 activation through multiple Nod-like receptors, including Ipaf and Nalp3. Flagellin expression by cytosolic L. monocytogenes was detected through Ipaf in a dose-dependent manner. Concordantly, detection of flagellin promoted bacterial clearance in a murine infection model. Finally, we provide evidence that suggests cytosolic L. monocytogenes activates caspase 1 through a third pathway, which signals through the adaptor protein ASC. Thus, L. monocytogenes activates caspase 1 in macrophages via multiple pathways, all of which detect the presence of bacteria within the cytosol.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants AI065878, AI052286, AI032972, and AI025032, Howard Hughes Grant 56005710, and Grant T32CA009537 from the National Cancer Institute.

² The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.

³ E.A.M. and A.A. are co-last authors.

⁴ Address correspondence and reprint requests to Dr. Alan Aderem, Institute for Systems Biology 1441 North 34th Street, Seattle WA 98103. E-mail address: aderem{at}systemsbiology.org

⁵ Abbreviations used in this paper: PRR, pattern recognition receptor; PAMP, pathogen-associated molecular pattern; NLR, Nod-like receptor; LLO, listeriolysin O; CARD, caspase activation and recruitment domain; BMM, bone marrow-derived macrophages; WT, wild type; MOI, multiplicity of infection.