Year: 2019
Type: preprint
Abstract: Resisting or tolerating microbes are alternative strategies to survive infection, but little is known about the evolutionary mechanisms controlling this balance. Here, genomic analyses of anatomically modern humans, extinct Denisovan hominins, and mice revealed a series of missense variants in the immune response inhibitor A20 (encoded by TNFAIP3 ), substituting non-catalytic residues of the ubiquitin protease domain to diminish IκB-dependent phosphorylation and activation of A20. Two A20 variants with partial phosphorylation deficits appeared beneficial: one originating in Denisovans and introgressed in modern humans throughout Oceania, and another in a mouse strain resistant to Coxsackievirus. By contrast, a variant with 95% loss of phosphorylation caused spontaneous inflammatory disease in humans and mice. Analysis of the partial phosphorylation variant in mice revealed diminished tolerance of bacterial lipopolysaccharide or to poxvirus inoculation as trade-offs for enhanced immunity. One Sentence Summary Modern and ancient variants reveal a genetically tunable element for balancing immunity and microbial tolerance.
DOI: 10.1101/589507
Authors: Nathan W. Zammit, Owen M. Siggs, Paul Gray, Keisuke Horikawa, Stephen R. Daley, David B. Langley, Daniele Cultrone, Elisabeth K. Malle, Stacey N. Walters, Jeanette E. Villanueva, Joanna Warren, Amanda Russell, Mark J. Cowley, Velimir Gayevskiy, Marcel E. Dinger, Claudia Loetsch, Cecile King, Robert Brink, David Zahra, Geeta Chaudhri, Gunasegaran Karupiah, Belinda Whittle, Carla Roots, Edward Bertram, Michiko Yamada, Yogesh Jeelall, Anselm Enders, Benjamin E. Clifton, Peter D. Mabbitt, Colin J. Jackson, Susan R. Watson, Craig N. Jenne, Lewis L. Lanier, Tim Wiltshire, Matthew H. Spitzer, Garry P. Nolan, Frank Schmitz, Alan Aderem, Benjamin T. Porebski, Ashley M. Buckle, Derek W. Abbott, John B. Ziegler, Maria E. Craig, Paul Benitez-Aguirre, Juliana Teo, Melanie Wong, Murray P. Cox, Wilson Phung, Ingrid E. Wertz, Daniel Christ, Christopher C. Goodnow, Shane T. Grey
Institutions: Garvan Institute of Medical Research, Flinders University, UNSW Sydney, Sydney Children's Hospital, Australian National University, University of California, San Francisco, Parker Institute for Cancer Immunotherapy, University of North Carolina at Chapel Hill, Stanford University, Center for Infectious Disease Research, Monash University, Case Western Reserve University, The University of Sydney, Children's Hospital at Westmead, Massey University, Genentech
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Awards: Research Fellowship, Immunological diseases: understanding their cause and improving their treatment by human genome sequencing, Uncovering the basis of inflammatory and immunodeficiency diseases, G606335999, Genetic control of islet inflammation in diabetes, Australia Fellowship, G8397376588, Pancreatic islet inflammation and its role in diabetes and islet transplantation
OpenAlex ID: W2923859637