Cyclic GMP-AMP Synthase Is the Cytosolic Sensor of Plasmodium falciparum Genomic DNA and Activates Type I IFN in Malaria
Department of Medicine, Program in Innate Immunity; Department of Medicine, Division of Infectious Diseases and Immunology; Proteomics and Mass Spectrometry Facility; Department of Biochemistry and Molecular Pharmacology
Immunity | Immunology of Infectious Disease | Parasitic Diseases
Innate immune receptors have a key role in the sensing of malaria and initiating immune responses. As a consequence of infection, systemic inflammation emerges and is directly related to signs and symptoms during acute disease. We have previously reported that plasmodial DNA is the primary driver of systemic inflammation in malaria, both within the phagolysosome and in the cytosol of effector cells. In this article, we demonstrate that Plasmodium falciparum genomic DNA delivered to the cytosol of human monocytes binds and activates cyclic GMP-AMP synthase (cGAS). Activated cGAS synthesizes 2'3'-cGAMP, which we subsequently can detect using liquid chromatography-tandem mass spectrometry. 2'3'-cGAMP acts as a second messenger for STING activation and triggers TBK1/IRF3 activation, resulting in type I IFN production in human cells. This induction of type I IFN was independent of IFI16. Access of DNA to the cytosolic compartment is mediated by hemozoin, because incubation of purified malaria pigment with DNase abrogated IFN-beta induction. Collectively, these observations implicate cGAS as an important cytosolic sensor of P. falciparum genomic DNA and reveal the role of the cGAS/STING pathway in the induction of type I IFN in response to malaria parasites.
DOI of Published Version
Gallego-Marin C, Schrum JE, Andrade WA, Shaffer SA, Giraldo LF, Lasso AM, Kurt-Jones EA, Fitzgerald KA, Golenbock DT. Cyclic GMP-AMP Synthase Is the Cytosolic Sensor of Plasmodium falciparum Genomic DNA and Activates Type I IFN in Malaria. J Immunol. 2018 Jan 15;200(2):768-774. doi: 10.4049/jimmunol.1701048. Epub 2017 Dec 6. PMID: 29212905; PMCID: PMC5912257. Link to article on publisher's site
Journal of immunology (Baltimore, Md. : 1950)
Gallego-Marin C, Schrum JE, Andrade WA, Shaffer SA, Giraldo LF, Lasso AM, Kurt-Jones EA, Fitzgerald KA, Golenbock DT. (2018). Cyclic GMP-AMP Synthase Is the Cytosolic Sensor of Plasmodium falciparum Genomic DNA and Activates Type I IFN in Malaria. Infectious Diseases and Immunology Publications. https://doi.org/10.4049/jimmunol.1701048. Retrieved from https://escholarship.umassmed.edu/infdis_pp/432