TY - JOUR
T1 - AIM2 sensors mediate immunity to Plasmodium infection in hepatocytes
AU - Marques-Da-Silva, Camila
AU - Poudel, Barun
AU - Baptista, Rodrigo P.
AU - Peissig, Kristen
AU - Hancox, Lisa S.
AU - Shiau, Justine C.
AU - Pewe, Lecia L.
AU - Shears, Melanie J.
AU - Kanneganti, Thirumala Devi
AU - Sinnis, Photini
AU - Kyle, Dennis E.
AU - Gurung, Prajwal
AU - Harty, John T.
AU - Kurup, Samarchith P.
N1 - Funding Information:
We thank Dr. Rick Tarleton for comments, Gibran Nasir for preparing humanized mice for analyses, Dr. Magdy Alabady for assistance with scRNAseq, Dr. Teneema Kuriakose for helpful discussions, Carson Bowers for help with the mouse colonies, and Dr. Fayyaz Sutterwala for providing valuable knock-out mice. We also express our gratitude to the UGA CTEGD Flow Cytometry Core, UI Central Microscopy Research facility, UGA CTEGD Sporocore, UGA Georgia Genomics and Bioinformatics Core, Iowa Institute of Human Genetics, UGA and UIowa animal research facility staff and the NYU and Johns Hopkins Malaria Institute Insectary Cores. Support for these studies was provided by NIH (AI168307 to S.P.K., AI85515, AI95178, AI100527 to J.T.H., AI132359 to P.S. and K22AI127836 to P.G.) and the UGA Research Foundation (Startup funding to S.P.K.).
Funding Information:
knock-out mice.We also express our gratitude to the UGACTEGD Flow Cytometry Core, UI Central Microscopy Research facility, UGA CTEGD Sporocore, UGA Georgia Genomics and Bioinformatics Core, Iowa Institute of Human Genetics, UGA and UIowa animal research facility staff and the NYU and Johns Hopkins Malaria Institute Insectary Cores. Support for these studies was provided by NIH (AI168307 to S.P.K., AI85515, AI95178, AI100527 to J.T.H., AI132359 to P.S. and K22AI127836 to P.G.) and the UGA Research Foundation (Startup funding to S.P.K.).
Publisher Copyright:
Copyright © 2023 the Author(s).
PY - 2023/1/10
Y1 - 2023/1/10
N2 - Malaria, caused by Plasmodium parasites is a severe disease affecting millions of people around the world. Plasmodium undergoes obligatory development and replication in the hepatocytes, before initiating the life-threatening blood-stage of malaria. Although the natural immune responses impeding Plasmodium infection and development in the liver are key to controlling clinical malaria and transmission, those remain relatively unknown. Here we demonstrate that the DNA of Plasmodium parasites is sensed by cytosolic AIM2 (absent in melanoma 2) receptors in the infected hepatocytes, resulting in Caspase-1 activation. Remarkably, Caspase-1 was observed to undergo unconventional proteolytic processing in hepatocytes, resulting in the activation of the membrane pore-forming protein, Gasdermin D, but not inflammasome-associated proinflammatory cytokines. Nevertheless, this resulted in the elimination of Plasmodium-infected hepatocytes and the control of malaria infection in the liver. Our study uncovers a pathway of natural immunity critical for the control of malaria in the liver.
AB - Malaria, caused by Plasmodium parasites is a severe disease affecting millions of people around the world. Plasmodium undergoes obligatory development and replication in the hepatocytes, before initiating the life-threatening blood-stage of malaria. Although the natural immune responses impeding Plasmodium infection and development in the liver are key to controlling clinical malaria and transmission, those remain relatively unknown. Here we demonstrate that the DNA of Plasmodium parasites is sensed by cytosolic AIM2 (absent in melanoma 2) receptors in the infected hepatocytes, resulting in Caspase-1 activation. Remarkably, Caspase-1 was observed to undergo unconventional proteolytic processing in hepatocytes, resulting in the activation of the membrane pore-forming protein, Gasdermin D, but not inflammasome-associated proinflammatory cytokines. Nevertheless, this resulted in the elimination of Plasmodium-infected hepatocytes and the control of malaria infection in the liver. Our study uncovers a pathway of natural immunity critical for the control of malaria in the liver.
KW - Caspase-1
KW - Malaria
KW - innate immunity
KW - liver
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U2 - 10.1073/pnas.2210181120
DO - 10.1073/pnas.2210181120
M3 - Article
C2 - 36595704
AN - SCOPUS:85145431061
SN - 0027-8424
VL - 120
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 2
M1 - e2210181120
ER -