Destabilized adaptive influenza variants critical for innate immune system escape are potentiated by host chaperones

• Published in: PLoS biology Vol. 16; no. 9; p. e3000008
• Main Authors: Phillips, Angela M, Ponomarenko, Anna I, Chen, Kenny, Ashenberg, Orr, Miao, Jiayuan, McHugh, Sean M, Butty, Vincent L, Whittaker, Charles A, Moore, Christopher L, Bloom, Jesse D, Lin, Yu-Shan, Shoulders, Matthew D
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 17.09.2018; Public Library of Science (PLoS)
• Subjects: Adaptation, Physiological; Amino Acid Sequence; Animals; Biology and Life Sciences; Biophysical Phenomena; DNA Mutational Analysis; Dogs; Host-Pathogen Interactions; Host-virus relationships; Humans; Immune Evasion; Immune system; Immune System - virology; Immunity, Innate; Influenza viruses; Madin Darby Canine Kidney Cells; Medicine and Health Sciences; Microbiological research; Models, Biological; Molecular chaperones; Molecular Chaperones - metabolism; Myxovirus Resistance Proteins - metabolism; Nucleoproteins - chemistry; Orthomyxoviridae - immunology; Physical Sciences; Physiological aspects; Protein Structure, Secondary; Temperature; Viral Proteins - chemistry
• DOI: 10.1371/journal.pbio.3000008
• ISSN: 1545-7885; 1544-9173

The threat of viral pandemics demands a comprehensive understanding of evolution at the host-pathogen interface. Here, we show that the accessibility of adaptive mutations in influenza nucleoprotein at fever-like temperatures is mediated by host chaperones. Particularly noteworthy, we observe that the Pro283 nucleoprotein variant, which (1) is conserved across human influenza strains, (2) confers resistance to the Myxovirus resistance protein A (MxA) restriction factor, and (3) critically contributed to adaptation to humans in the 1918 pandemic influenza strain, is rendered unfit by heat shock factor 1 inhibition-mediated host chaperone depletion at febrile temperatures. This fitness loss is due to biophysical defects that chaperones are unavailable to address when heat shock factor 1 is inhibited. Thus, influenza subverts host chaperones to uncouple the biophysically deleterious consequences of viral protein variants from the benefits of immune escape. In summary, host proteostasis plays a central role in shaping influenza adaptation, with implications for the evolution of other viruses, for viral host switching, and for antiviral drug development.