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Innate immunity is considered the first line of defense against microbial invasion, and its dysregulation can increase the susceptibility of hosts to infections by invading pathogens. Host cells rely on pattern recognition receptors (PRRs) to recognize invading pathogens and initiate protective innate immune responses. Toll-like receptor 2 (TLR2) is believed to be among the most important Toll-like receptors for defense against mycobacterial infection. TLR2 has been reported to have very broad functions in infectious diseases and also in other diseases, such as chronic and acute inflammatory diseases, cancers, and even metabolic disorders. However, TLR2 has an unclear dual role in both the activation and suppression of innate immune responses. Moreover, in some studies, the function of TLR2 was shown to be controversial, and therefore its role in several diseases is still inconclusive. Therefore, although TLR2 has been shown to have an important function in innate immunity, its usefulness as a therapeutic target in clinical application is still uncertain. In this literature review, we summarize the knowledge of the functions of TLR2 in host–mycobacterial interactions, discuss controversial results, and suggest possibilities for future research.

The genus Mycobacteria comprises a multitude of species known to cause serious disease in humans, including Mycobacterium tuberculosis and M. leprae, the responsible agents for tuberculosis and leprosy, respectively. In addition, there is a worldwide spike in the number of infections caused by a mixed group of species such as the M. avium, M. abscessus and M. ulcerans complexes, collectively called nontuberculous mycobacteria (NTMs). The situation is forecasted to worsen because, like tuberculosis, NTMs either naturally possess or are developing high resistance against conventional antibiotics. It is, therefore, important to implement and develop models that allow us to effectively examine the fundamental questions of NTM virulence, as well as to apply them for the discovery of new and improved therapies. This literature review will focus on the known molecular mechanisms behind drug resistance in NTM and the current models that may be used to test new effective antimicrobial therapies.

Lungfishes belong to lobe-fined fish (Sarcopterygii) that, in the Devonian period, ‘conquered’ the land and ultimately gave rise to all land vertebrates, including humans 1 – 3 . Here we determine the chromosome-quality genome of the Australian lungfish ( Neoceratodus forsteri ), which is known to have the largest genome of any animal. The vast size of this genome, which is about 14× larger than that of humans, is attributable mostly to huge intergenic regions and introns with high repeat content (around 90%), the components of which resemble those of tetrapods (comprising mainly long interspersed nuclear elements) more than they do those of ray-finned fish. The lungfish genome continues to expand independently (its transposable elements are still active), through mechanisms different to those of the enormous genomes of salamanders. The 17 fully assembled lungfish macrochromosomes maintain synteny to other vertebrate chromosomes, and all microchromosomes maintain conserved ancient homology with the ancestral vertebrate karyotype. Our phylogenomic analyses confirm previous reports that lungfish occupy a key evolutionary position as the closest living relatives to tetrapods 4 , 5 , underscoring the importance of lungfish for understanding innovations associated with terrestrialization. Lungfish preadaptations to living on land include the gain of limb-like expression in developmental genes such as hoxc13 and sall1 in their lobed fins. Increased rates of evolution and the duplication of genes associated with obligate air-breathing, such as lung surfactants and the expansion of odorant receptor gene families (which encode proteins involved in detecting airborne odours), contribute to the tetrapod-like biology of lungfishes. These findings advance our understanding of this major transition during vertebrate evolution. A chromosome-quality genome of the lungfish Neoceratodus fosteri sheds light on the development of obligate air-breathing and the gain of limb-like gene expression in lobed fins, providing insights into the water-to-land transition in vertebrate evolution.

Host pathways mediating changes in immune states elicited by intestinal microbial colonization are incompletely characterized. Here we describe alterations of the host immune state induced by colonization of germ-free zebrafish larvae with an intestinal microbial community or single bacterial species. We show that microbiota-induced changes in intestinal leukocyte subsets and whole-body host gene expression are dependent on the innate immune adaptor gene myd88 . Similar patterns of gene expression are elicited by colonization with conventional microbiome, as well as mono-colonization with two different zebrafish commensal bacterial strains. By studying loss-of-function myd88 mutants, we find that colonization suppresses Myd88 at the mRNA level. Tlr2 is essential for microbiota-induced effects on myd88 transcription and intestinal immune cell composition. It remains unclear how microbial sensing during early-life colonization results in immune homeostasis rather than acute inflammation. Here the authors show that zebrafish larvae colonization suppresses intestinal MyD88, accounting for a considerable proportion of microbiota-induced alterations in immune setpoint.

Inactivation of p53 contributes significantly to the dismal prognosis of breast tumors, most notably triple-negative breast cancers (TNBCs). How the relief from p53 tumor suppressive functions results in tumor cell aggressive behavior is only partially elucidated. In an attempt to shed light on the implication of microRNAs in this context, we discovered a new signaling axis involving p53, miR-30a and ZEB2. By an in silico approach we identified miR-30a as a putative p53 target and observed that in breast tumors reduced miR-30a expression correlated with p53 inactivation, lymph node positivity and poor prognosis. We demonstrate that p53 binds the MIR30A promoter and induces the transcription of both miRNA strands 5p and 3p. Both miR-30a-5p and -3p showed the capacity of targeting ZEB2, a transcription factor involved in epithelial–mesenchymal transition (EMT), tumor cell migration and drug resistance. Intriguingly, we found that p53 does restrain ZEB2 expression via miR-30a. Finally, we provide evidence that the new p53/miR-30a/ZEB2 axis controls tumor cell invasion and distal spreading and impinges upon miR-200c expression. Overall, this study highlights the existence of a novel axis linking p53 to EMT via miR-30a, and adds support to the notion that miRNAs represent key elements of the complex network whereby p53 inactivation affects TNBC clinical behavior.

Studying macrophage biology in the context of a whole living organism provides unique possibilities to understand the contribution of this extremely dynamic cell subset in the reaction to infections, and has revealed the relevance of cellular and molecular processes that are fundamental to the cell-mediated innate immune response. In particular, various recently established zebrafish infectious disease models are contributing substantially to our understanding of the mechanisms by which different pathogens interact with macrophages and evade host innate immunity. Transgenic zebrafish lines with fluorescently labeled macrophages and other leukocyte populations enable non-invasive imaging at the optically transparent early life stages. Furthermore, there is a continuously expanding availability of vital reporters for subcellular compartments and for probing activation of immune defense mechanisms. These are powerful tools to visualize the activity of phagocytic cells in real time and shed light on the intriguing paradoxical roles of these cells in both limiting infection and supporting the dissemination of intracellular pathogens. This Review will discuss how several bacterial and fungal infection models in zebrafish embryos have led to new insights into the dynamic molecular and cellular mechanisms at play when pathogens encounter host macrophages. We also describe how these insights are inspiring novel therapeutic strategies for infectious disease treatment.

Bacteria have an extensive adaptive ability to live in close association with eukaryotic hosts, exhibiting detrimental, neutral or beneficial effects on host growth and health. However, the genes involved in niche adaptation are mostly unknown and their functions poorly characterized. Here, we present bacLIFE ( https://github.com/Carrion-lab/bacLIFE ) a streamlined computational workflow for genome annotation, large-scale comparative genomics, and prediction of lifestyle-associated genes (LAGs). As a proof of concept, we analyzed 16,846 genomes from the Burkholderia / Paraburkholderia and Pseudomonas genera, which led to the identification of hundreds of genes potentially associated with a plant pathogenic lifestyle. Site-directed mutagenesis of 14 of these predicted LAGs of unknown function, followed by plant bioassays, showed that 6 predicted LAGs are indeed involved in the phytopathogenic lifestyle of Burkholderia plantarii and Pseudomonas syringae pv. phaseolicola. These 6 LAGs encompassed a glycosyltransferase, extracellular binding proteins, homoserine dehydrogenases and hypothetical proteins. Collectively, our results highlight bacLIFE as an effective computational tool for prediction of LAGs and the generation of hypotheses for a better understanding of bacteria-host interactions. Many bacteria live in close association with eukaryotic hosts, exhibiting detrimental, neutral or beneficial effects on host growth and health. Here, the authors present a streamlined computational workflow for bacterial genome annotation, large-scale comparative genomics, and prediction of genes potentially involved in niche adaptation.

Background Toll-like receptor 2 (TLR2) plays a pivotal role in innate immunity and has recently emerged as a critical regulator of host-microbiome interactions. However, how TLR2 influences host transcriptional responses to colonized microbiome and microbial community dynamics remains largely unclear. A comparison between germ free (GF) and conventionalized zebrafish ( Danio rerio ) larvae provides a valuable system to investigate how the microbiome influences host transcriptomic responses in a tlr2 mutant versus wild-type control. Vice versa, to understand the role of Tlr2 in regulating the microbiome, we have analyzed microbial community composition in both tlr2 mutant and wild-type zebrafish at larval and adult stages. Results RNAseq analysis revealed that approximately 2.6% of the zebrafish genome (827 genes) exhibited transcriptomic alterations in tlr2 mutant larvae compared to the wild type under microbiome-colonized conditions, whereas around 2% of the genome (639 genes) showed differential expression under GF conditions. KEGG enrichment analyses show that under both microbiome-colonized and GF conditions major differences between the tlr2 mutant and wild type are related to metabolism. Furthermore, there is a striking difference in endoplasmic reticulum stress responses, including well-known markers for inflammatory bowel disease which are all downregulated in the mutant under the microbiome-colonized condition. Microbiome colonization elicited a broader transcriptional response in tlr2 wild-type larvae than in the mutant, with specifically the ferroptosis, apoptosis and inflammation related pathways differently regulated. In terms of how Tlr2 influences microbial composition, 16 S rRNA gene sequencing showed large differences in beta diversity between the tlr2 mutant and wild type. The tlr2 mutant exhibited higher microbial alpha diversity during early development, whereas alpha diversity was higher in wild-type adults. For larvae at the genus level, tlr2 mutant larvae showed increased Chryseobacterium and Flectobacillus but reduced Gracilibacteria abundance relative to wild-type controls. For adult gut samples, the relative abundance of Cetobacterium was higher in the tlr2 mutants, indicating a developmental stage-specific restructuring of the microbiome. Conclusions TLR2 not only modulates host transcriptional responses to microbial colonization, but also shapes gut microbial diversity, composition, and metabolic potential. Our findings highlight the critical role of TLR2 in orchestrating immune-metabolic homeostasis and provide new insights into its broader function in maintaining host-microbiota symbiosis across developmental stages.

Investigating regulation and function of the Hox genes, key regulators of positional identity in the embryo, opened a new vista in developmental biology. One of their most striking features is collinearity: the temporal and spatial orders of expression of these clustered genes each match their 3' to 5' order on the chromosome. Despite recent progress, the mechanisms underlying collinearity are not understood. Here we show that ectopic expression of 4 different single Hox genes predictably induces and represses expression of others, leading to development of different predictable specific sections of the body axis. We use ectopic expression in wild-type and noggin-dorsalised (Hox-free) Xenopus embryos, to show that two Hox-Hox interactions are important. Posterior induction (induction of posterior Hox genes by anterior ones: PI), drives Hox temporal collinearity (Hox timer), which itself drives anteroposterior (A-P) patterning. Posterior prevalence (repression of anterior Hox genes by posterior ones: PP) is important in translating temporal to spatial collinearity. We thus demonstrate for the first time that two collinear Hox interactions are important for vertebrate axial patterning. These findings considerably extend and clarify earlier work suggesting the existence and importance of PP and PI, and provide a major new insight into genesis of the body axis.

Macrophages are phagocytic cells from the innate immune system, which forms the first line of host defense against invading pathogens. These highly dynamic immune cells can adopt specific functional phenotypes, with the pro-inflammatory M1 and anti-inflammatory M2 polarization states as the two extremes. Recently, the process of macrophage polarization during inflammation has been visualized by real time imaging in larvae of the zebrafish. This model organism has also become widely used to study macrophage responses to microbial pathogens. To support the increasing use of zebrafish in macrophage biology, we set out to determine the complete transcriptome of zebrafish larval macrophages. We studied the specificity of the macrophage signature compared with other larval immune cells and the macrophage-specific expression changes upon infection. We made use of the well-established , and fluorescent reporter lines to sort and sequence the transcriptome of larval macrophages, neutrophils, and lymphoid progenitor cells, respectively. Our results provide a complete dataset of genes expressed in these different immune cell types and highlight their similarities and differences. Major differences between the macrophage and neutrophil signatures were found within the families of proteinases. Furthermore, expression of genes involved in antigen presentation and processing was specifically detected in macrophages, while lymphoid progenitors showed expression of genes involved in macrophage activation. Comparison with datasets of polarized human macrophages revealed that zebrafish macrophages express a strongly homologous gene set, comprising both M1 and M2 markers. Furthermore, transcriptome analysis of low numbers of macrophages infected by the intracellular pathogen revealed that infected macrophages change their transcriptomic response by downregulation of M2-associated genes and overexpression of specific M1-associated genes. Among the infection-induced genes, a homolog of the human chemokine gene, , stood out as the most strongly overexpressed M1 marker. Upregulation of in -infected macrophages was found to require the function of Myd88, a critical adaptor molecule in the Toll-like and interleukin 1 receptor pathways that are central to pathogen recognition and activation of the innate immune response. Altogether, our data provide a valuable data mining resource to support infection and inflammation research in the zebrafish model.