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ASC/PYCARD and Caspase-1 Regulate the IL-18/IFN- Axis during Anaplasma phagocytophilum Infection¹

Joao H. F. Pedra^*, Fayyaz S. Sutterwala^*,, Bindu Sukumaran^*, Yasunori Ogura, Feng Qian, Ruth R. Montgomery, Richard A. Flavell^, and Erol Fikrig^2,*

^* Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520; Section of Rheumatology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520; and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520

Anaplasma phagocytophilum is an obligate intracellular pathogen that resides within neutrophils and can cause fever, pancytopenia, or death. IFN- plays a critical role in the control of A. phagocytophilum; however, the mechanisms that regulate IFN- production remain unclear. In this study, we demonstrate that apoptotic specklike protein with a caspase-activating recruiting domain (ASC)/PYCARD, a central adaptor molecule in the Nod-like receptor (NLR) pathway, regulates the IL-18/IFN- axis during A. phagocytophilum infection through its effect on caspase-1. Caspase-1- and asc-null mice were more susceptible than control animals to A. phagocytophilum infection due to the absence of IL-18 secretion and reduced IFN- levels in the peripheral blood. Moreover, caspase-1 and ASC deficiency reduced CD4⁺ T cell-mediated IFN- after in vitro restimulation with A. phagocytophilum. The NLR family member IPAF/NLRC4, but not NALP3/NLRP3, was partially required for IFN- production in response to A. phagocytophilum. Taken together, our data demonstrate that ASC and caspase-1 are critical for IFN--mediated control of A. phagocytophilum infection.

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 Public Health Service Grant 5R01AI041440-08 (to E.F.) from the National Institute of Infectious Diseases and 5P30DK034989-22, Yale University Digestive Disease Research Core Center (to J.H.F.P.) from the National Institute of Digestive Diseases and Kidney and Ellison Foundation (to R.A.F.), and by the Northeast Biodefense Center-Lipkin (to E.F.). J.H.F.P. and F.S.S. are Brown-Coxe Fellow in Medical Sciences and Pfizer Fellow in Infectious Diseases, respectively. R.A.F. is an investigator with the Howard Hughes Medical Institute.

² Address correspondence and reprint requests to Dr. Erol Fikrig, Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520. E-mail address: erol.fikrig{at}yale.edu

³ Abbreviations used in this paper: NLR, Nod-like receptor; ASC, apoptotic specklike protein with a caspase-activating recruiting domain.

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