Dey, A. A. | Search bioRxiv

bioRxiv2024

Decoding non-human mammalian adaptive signatures of 2.3.4.4b H5N1 to assess its human adaptive potential

The recent panzootic 2.3.4.4b clade H5N1 infected diverse non-human mammalian species globally, showed mammal-to-mammal transmission among them and caused sporadic human infections. However, whether 2.3.4.4b H5N1 circulating in non-human mammals can establish human infections and spread among humans is unclear. Gain-of-function research restrictions preclude assessing human adapting mutations of 2.3.4.4b H5N1. Here, we tracked the evolution of 2.3.4.4b H5N1 that infected non-human mammals and evaluated their ability to gain human adaptations. The non-human mammal 2.3.4.4b H5N1 partly acquired classical human adapting mutations, which are identical to the residues of H1N1pdm09 and seasonal human H3N2 infections while showing a few species-specific adaptations that might be potential barriers for successful human adaptations. Despite minimal changes in Hemagglutinin (HA), A160T and T199I mutations near the receptor binding site of HA in dairy cattle viruses indicate the rapid HA glycan surface evolution affecting virus entry and immune evasion. The quantitative assessment indicated that 2.3.4.4b H5N1 circulating in bears, cattle, dolphins, and foxes show higher human adaptive potential than other hosts. Also, H5N1 infections in mammals across time showed a unique set of adaptations in the 2.3.4.4b clade compared to previously circulating strains, especially the acquisition of Q591 adaptation in PB2 that enables human adaptation. Thus, 2.3.4.4b H5N1 acquires human adaptations due to natural selection pressure in non-human mammals. Overall, our study delineates human adaptation and infection risk of specific non-human mammalian circulating HPAI 2.3.4.4b H5N1 strains. O_FIG O_LINKSMALLFIG WIDTH=164 HEIGHT=200 SRC="FIGDIR/small/609722v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@2dde4borg.highwire.dtl.DTLVardef@15d4983org.highwire.dtl.DTLVardef@1857093org.highwire.dtl.DTLVardef@1a1eec2_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGRAPHICAL ABSTRACTC_FLOATNO C_FIG

microbiology↗

bioRxiv2023

SARS-CoV-2 Nsp13 is a viral RHIM protein promoting cell death linked to Z-RNA sensing and ZBP1-RIPK3 signaling

RHIM is a protein motif in cell death proteins that assembles higher-order signaling complexes and triggers regulated cell death, which in itself limits virus spread and additionally triggers inflammation for mounting immune responses. A few DNA viruses employ viral RHIMs mimicking host RHIMs. However, these viral RHIMs counteract host cell death by interacting with host RHIM proteins and blocking complex formation to alleviate antiviral defenses. Whether RNA viruses operate such viral RHIMs remains unknown. RHIM-protein signaling promotes lung damage and cytokine storm in respiratory RNA virus infections, arguing the presence of viral RHIMs. Here, we report the novel viral RHIMs in Nsp13 and Nsp14 of SARS-CoV-2 and other bat RNA viruses, providing the basis for bats as the hosts for their evolution. Nsp13 promoted cell death in bat and human cells, however, viral RHIM of Nsp13 is more critical for human cell death than bat cells, suggesting species-specific regulation. The conformation of RNA-binding channel in Nsp13 is critical for cell death in bat and human cells. Nsp13 showed RHIM-dependent interactions with ZBP1 and RIPK3 and promoted the formation of large insoluble complexes of ZBP1 and RIPK3. Also, Nsp13 promoted ZBP1-RIPK3 signaling-mediated cell death dependent on intracellular RNA ligands. Intriguingly, the SARS-CoV-2 genome consists of bona fide Z-RNA-forming segments. These SARS-CoV-2 Z-RNA segments promoted Nsp13-dependent cell death, further revealing Nsp13s association with Z-RNA sensing and ZBP1-RIPK3 signaling. Our findings reveal the functional viral RHIMs of bat-originated RNA viruses regulating host cell death associated with Z-RNA sensing and ZBP1-RIPK3 signaling activation. These observations allow the understanding of mechanisms of cellular damage and cytokine storm in SARS-CoV-2 and other bat-originated RNA virus infections. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=144 SRC="FIGDIR/small/554434v2_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@f71c5aorg.highwire.dtl.DTLVardef@1666aa5org.highwire.dtl.DTLVardef@e37d82org.highwire.dtl.DTLVardef@145020f_HPS_FORMAT_FIGEXP M_FIG C_FIG One-sentence summaryBat-associated RNA viruses employ viral RHIMs and regulate host cell death.

immunology↗