Conservation and similarity of bacterial and eukaryotic innate immunity

Ledvina, Hannah E.; Whiteley, Aaron T.

doi:10.1038/s41579-024-01017-1

Cited by 16 publications

(6 citation statements)

References 176 publications

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“…For example, the Thoeris system uses TIR domain-containing proteins to produce the cADPR isomer v-cADPR which triggers cell death leading to abortive phage infections in bacteria [ 82 ]. Other non-Thoeris TIR domain-containing proteins have also been implicated in a cGAS-like pathway in bacteria termed the “CBASS” pathway which also blocks phage replication [ 83 ]. Thus, our finding that HopAM1 can break virus restriction in insect cells suggests that TIR domain-containing proteins may be critical regulators of ancient antiviral defense systems used by diverse organisms.…”

Section: Discussionmentioning

confidence: 99%

Exploiting bacterial effector proteins to uncover evolutionarily conserved antiviral host machinery

Embry,

Baggett,

Heisler

et al. 2024

PLoS Pathog

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Arboviruses are a diverse group of insect-transmitted pathogens that pose global public health challenges. Identifying evolutionarily conserved host factors that combat arbovirus replication in disparate eukaryotic hosts is important as they may tip the balance between productive and abortive viral replication, and thus determine virus host range. Here, we exploit naturally abortive arbovirus infections that we identified in lepidopteran cells and use bacterial effector proteins to uncover host factors restricting arbovirus replication. Bacterial effectors are proteins secreted by pathogenic bacteria into eukaryotic hosts cells that can inhibit antimicrobial defenses. Since bacteria and viruses can encounter common host defenses, we hypothesized that some bacterial effectors may inhibit host factors that restrict arbovirus replication in lepidopteran cells. Thus, we used bacterial effectors as molecular tools to identify host factors that restrict four distinct arboviruses in lepidopteran cells. By screening 210 effectors encoded by seven different bacterial pathogens, we identify several effectors that individually rescue the replication of all four arboviruses. We show that these effectors encode diverse enzymatic activities that are required to break arbovirus restriction. We further characterize Shigella flexneri-encoded IpaH4 as an E3 ubiquitin ligase that directly ubiquitinates two evolutionarily conserved proteins, SHOC2 and PSMC1, promoting their degradation in insect and human cells. We show that depletion of either SHOC2 or PSMC1 in insect or human cells promotes arbovirus replication, indicating that these are ancient virus restriction factors conserved across invertebrate and vertebrate hosts. Collectively, our study reveals a novel pathogen-guided approach to identify conserved antimicrobial machinery, new effector functions, and conserved roles for SHOC2 and PSMC1 in virus restriction.

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Section: Discussionmentioning

confidence: 99%

Exploiting bacterial effector proteins to uncover evolutionarily conserved antiviral host machinery

Embry,

Baggett,

Heisler

et al. 2024

PLoS Pathog

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“…Two dominant mechanisms innate immune pathways use to sense invading pathogens are to detect either (1) pathogen-derived molecules or (2) pathogen-specific activities 2 , 40 , 41 . In the first mechanism, pathogen-associated molecular patterns (PAMPs) are directly sensed by pattern recognition receptors (PRRs).…”

Section: Discussionmentioning

confidence: 99%

“…CP is not a conventional pathogen effector; however, it still impacts a core host process that bNACHT25 monitors as a proxy for infection. Across bacteria, bNACHT25 joins retrons 46 , 47 and ToxIN 48 in a growing list antiphage systems that indirectly survey the cell for signs of infection 1 , 2 .…”

Section: Discussionmentioning

confidence: 99%

“…Antiphage systems are distributed in the pangenome for each bacterial species and any one bacterial strain has a subset of these systems, which tend to colocalize and move between bacteria on mobile genetic elements [3][4][5] . The collection of antiphage systems within a given bacterium is referred to as the bacterial immune system 1,2 . Bacterial antiphage systems, like all immune pathways, can be categorized as adaptive or innate.…”

Section: Introductionmentioning

confidence: 99%

“…The coevolution of bacteria and their viruses, bacteriophages (phages), has led bacteria to evolve diverse antiphage systems that halt infection. These systems can be a single gene or an operon of genes whose products cooperate to sense phage, amplify that signal, and activate an effector response that is antiviral 1 , 2 . Antiphage systems are distributed in the pangenome for each bacterial species and any one bacterial strain has a subset of these systems, which tend to colocalize and move between bacteria on mobile genetic elements 3 – 5 .…”

Section: Introductionmentioning

confidence: 99%

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Phage detection by a bacterial NLR-related protein is mediated by DnaJ

Conte,

Ruchel,

Ridgeway

et al. 2024

Preprint

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Bacteria encode a wide range of antiphage systems and a subset of these proteins are homologous to components of the human innate immune system. Mammalian nucleotide-binding and leucine-rich repeat containing proteins (NLRs) and bacterial NLR-related proteins use a central NACHT domain to link infection detection with initiation of an antimicrobial response. Bacterial NACHT proteins provide defense against both DNA and RNA phages. Here we determine the mechanism of RNA phage detection by the bacterial NLR-related protein bNACHT25 inE. coli. bNACHT25 was specifically activated byEmesvirusssRNA phages and analysis of MS2 phage suppressor mutants that evaded detection revealed Coat Protein (CP) was sufficient for activation. bNACHT25 and CP did not physically interact. Instead, we found bNACHT25 requires the host chaperone DnaJ to detect CP. Our data suggest that bNACHT25 detects a wide range of phages by guarding a host cell process rather than binding a specific phage-derived molecule.

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