Biology subjects

Levin, T. C.

Publications and source records attributed to Levin, T. C..

4 recordsLinked to original sources

bioRxiv2026

Eukaryotic domestication of a bacterial immune protein following horizontal transfer

Many components of eukaryotic innate immunity originated from bacterial immune systems. However, it is unclear how eukaryotes acquire these genes and how the components are domesticated into eukaryotic physiology. Here, we discovered a recent instance of bacteria-eukaryote horizontal transfer and used it to characterize the genetic and biochemical changes that accompanied eukaryotic acquisition. We focus on Toll/interleukin-1 receptor (TIR) domains, which are widespread yet potentially costly immune modules associated with inflammation and/or cell death. By generating an atlas of TIR diversity across the tree of life, we phylogenetically categorized the domains and uncovered highly diverged, eukaryotic TIR families. This analysis revealed a horizontal transfer event that created the TirBCD protein family of Dictyostelium amoebae, which is closely related to the bacterial immune protein TIR-STING. While the TIR domain was transferred into amoebae, the genomic locus did not contain known regulatory domains nor other components of a bacterial operon. Nevertheless, TirC retained biochemical and physiological similarities to TIR-STING. TirC is a highly potent NADase, capable of oligomerizing into large complexes and depleting NAD+ even at very low protein concentrations. When expressed in heterologous systems, TirC was spontaneously active and highly toxic. In contrast, the natural amoeba host tolerated expression of full length TirC, showing that the cells can typically regulate its activity and avoid autoimmunity. However, a truncated form of TirC induced rapid rounding and cell lysis. These results suggest that amoebae have used TirC to retool a form of bacterial cell death for use in eukaryotic cells. Overall, this study uncovers recent eukaryotic TIR evolution that captures features of both bacterial and eukaryotic immunity. We also expect that the TIR domain atlas will be useful to researchers across model systems as they explore the vast diversity of TIR molecular and cellular functions.

microbiology↗

bioRxiv2025

Evolutionary dynamics of the tgr gene family in Dictyostelium allows escape from Crozier's Paradox

Croziers Paradox states that genetic kin recognition will select for its own demise, and theoretical analyses over the past decades have supported this conclusion. Here we examine the molecular evolution of two kin recognition genes in the social amoeba Dictyostelium discoideum, tgrB1 and tgrC1, which enable cells to recognize and reject unrelated cells during cooperative multicellular development. Our results reveal extraordinary polymorphism in these genes, placing them amongst the most rapidly evolving genes in the genome. Co-occurring amoebae, isolated from just a few grams of soil, show highly diverged recognition alleles, indicating plentiful sequence variation that can impact social decision-making on a micro-scale. Analyses of closely related gene duplicates show dynamic evolution of the gene family as a whole, suggesting a mechanism for replenishing genetic variation lost through Croziers Paradox. Our results provide evidence that kin recognition loci can retain sufficient genetic variation in real-world settings and suggest that large gene families may be crucial to retaining genetic variation necessary to evade Croziers paradox.

evolutionary biology↗

bioRxiv2023

Eukaryotic antiviral immune proteins arose via convergence, horizontal transfer, and ancient inheritance

Animals use a variety of cell-autonomous innate immune proteins to detect viral infections and prevent replication. Recent studies have discovered that a subset of mammalian antiviral proteins have homology to anti-phage defense proteins in bacteria, implying that there are aspects of innate immunity that are shared across the Tree of Life. While the majority of these studies have focused on characterizing the diversity and biochemical functions of the bacterial proteins, the evolutionary relationships between animal and bacterial proteins are less clear. This ambiguity is partly due to the long evolutionary distances separating animal and bacterial proteins, which obscures their relationships. Here, we tackle this problem for three innate immune families (CD-NTases [including cGAS], STINGs, and Viperins) by deeply sampling protein diversity across eukaryotes. We find that Viperins and OAS family CD-NTases are truly ancient immune proteins, likely inherited since the last eukaryotic common ancestor and possibly longer. In contrast, we find other immune proteins that arose via at least four independent events of horizontal gene transfer (HGT) from bacteria. Two of these events allowed algae to acquire new bacterial viperins, while two more HGT events gave rise to distinct superfamilies of eukaryotic CD-NTases: the Mab21 superfamily (containing cGAS) which has diversified via a series of animal-specific duplications, and a previously undefined eSMODS superfamily, which more closely resembles bacterial CD-NTases. Finally, we found that cGAS and STING proteins have substantially different histories, with STINGs arising via convergent domain shuffling in bacteria and eukaryotes. Overall, our findings paint a picture of eukaryotic innate immunity as highly dynamic, where eukaryotes build upon their ancient antiviral repertoires through the reuse of protein domains and by repeatedly sampling a rich reservoir of bacterial anti-phage genes.

microbiology↗

bioRxiv2018

L. pneumophila deploys a self-active inhibitor for inter-Legionella competition

To persist in the extracellular state, the bacterial pathogen Legionella pneumophila must withstand competition from neighboring bacteria. Here, we find that L. pneumophila can antagonize the growth of neighboring Legionella species using a secreted inhibitor: HGA (homogentisic acid), the unstable, redox-active precursor molecule to L. pneumophilas brown-black pigment. Unexpectedly, we find that L. pneumophila can itself be inhibited by HGA secreted from neighboring, isogenic strains. Our genetic approaches further identify lpg1681 as a gene that modulates L. pneumophila susceptibility to HGA. We find that L. pneumophila sensitivity to HGA is density-dependent and cell intrinsic. This resistance is not mediated by the stringent response nor the previously described Legionella quorum-sensing pathway. Instead, we find that L. pneumophila cells secrete HGA only when they are conditionally HGA-resistant, which allows these bacteria to produce a potentially self-toxic molecule while restricting the opportunity for self-harm. We speculate that established Legionella communities may deploy molecules such as HGA as an unusual public good that can protect against invasion by low-density competitors.

microbiology↗