Date Published: October 11, 2018
Publisher: Public Library of Science
Author(s): Connor G. G. Bamford, Elihu Aranday-Cortes, Ines Cordeiro Filipe, Swathi Sukumar, Daniel Mair, Ana da Silva Filipe, Juan L. Mendoza, K. Christopher Garcia, Shaohua Fan, Sarah A. Tishkoff, John McLauchlan, Glenn Randall.
As antimicrobial signalling molecules, type III or lambda interferons (IFNλs) are critical for defence against infection by diverse pathogens, including bacteria, fungi and viruses. Counter-intuitively, expression of one member of the family, IFNλ4, is associated with decreased clearance of hepatitis C virus (HCV) in the human population; by contrast, a natural frameshift mutation that abrogates IFNλ4 production improves HCV clearance. To further understand how genetic variation between and within species affects IFNλ4 function, we screened a panel of all known extant coding variants of human IFNλ4 for their antiviral potential and identify three that substantially affect activity: P70S, L79F and K154E. The most notable variant was K154E, which was found in African Congo rainforest ‘Pygmy’ hunter-gatherers. K154E greatly enhanced in vitro activity in a range of antiviral (HCV, Zika virus, influenza virus and encephalomyocarditis virus) and gene expression assays. Remarkably, E154 is the ancestral residue in mammalian IFNλ4s and is extremely well conserved, yet K154 has been fixed throughout evolution of the hominid genus Homo, including Neanderthals. Compared to chimpanzee IFNλ4, the human orthologue had reduced activity due to amino acid K154. Comparison of published gene expression data from humans and chimpanzees showed that this difference in activity between K154 and E154 in IFNλ4 correlates with differences in antiviral gene expression in vivo during HCV infection. Mechanistically, our data show that the human-specific K154 negatively affects IFNλ4 activity through a novel means by reducing its secretion and potency. We thus demonstrate that attenuated activity of IFNλ4 is conserved among humans and postulate that differences in IFNλ4 activity between species contribute to distinct host-specific responses to—and outcomes of—infection, such as HCV infection. The driver of reduced IFNλ4 antiviral activity in humans remains unknown but likely arose between 6 million and 360,000 years ago in Africa.
Vertebrates have evolved the capacity to coordinate their antiviral defences through the action of proteins called interferons (IFNs) , which are small secreted signalling proteins produced by cells after sensing viral infection. IFNs bind to cell surface receptors, commencing autocrine and paracrine signalling via the ‘JAK-STAT’ pathway. Through this mechanism, IFNs induce expression of hundreds of ‘interferon-stimulated genes’ (ISGs) that establish a cell-intrinsic ‘antiviral state’ and regulate cellular immunity and inflammation [2,3]. Thus, IFNs are pleiotropic in activity and modulate aspects of protective immunity and pathogenesis .
In this study we have identified further functional variants of human and non-human IFNλ4 that expand the spectrum of its activity. By comparing IFNλ4 from different species we demonstrate that the genus Homo evolved an IFNλ4 gene with attenuated activity (prior to the TT allele), and that the vast majority of extant humans carry an IFNλ4 variant with lower antiviral potential due to a mutation of a single highly-conserved amino acid residue (E154K). Human African hunter-gatherer Pygmies and chimpanzees encode a more active IFNλ4 (E154). We speculate that position 154 in IFNλ4 plays a key role in intramolecular interactions that may facilitate stabilisation of the protein thereby influencing its secretability and antiviral activity (S12 Fig)