Topics overview: Targeting FimH with M4284 can reduce intestinal colonization of genetically diverse UPEC isolates; Insights into the generalizable, underlying features of epitope-specific repertoires and adaptive immune recognition; The function of H3K9me2 and H3K9me3; The association of Parkinson’s disease with alleles of the major histocompatibility complex; Analytical tools to identify which host species are likely to harbour the next human virus.
1. Selective depletion of uropathogenic E. coli from the gut by a FimH antagonist.
Urinary tract infections (UTIs) caused by uropathogenic Escherichia coli (UPEC) affect 150 million people annually. Despite effective antibiotic therapy, 30–50% of patients experience recurrent UTIs. In addition, the growing prevalence of UPEC that are resistant to last-line antibiotic treatments, and more recently to carbapenems and colistin, make UTI a prime example of the antibiotic-resistance crisis and emphasize the need for new approaches to treat and prevent bacterial infections. UPEC strains establish reservoirs in the gut from which they are shed in the faeces, and can colonize the periurethral area or vagina and subsequently ascend through the urethra to the urinary tract, where they cause UTIs. UPEC isolates encode up to 16 distinct chaperone-usher pathway pili, and each pilus type may enable colonization of a habitat in the host or environment. For example, the type 1 pilus adhesin FimH binds mannose on the bladder surface, and mediates colonization of the bladder. However, little is known about the mechanisms underlying UPEC persistence in the gut. Here, using a mouse model, Caitlin N. Spaulding at Washington University in Missouri, USA and his colleagues show that F17-like and type 1 pili promote intestinal colonization and show distinct binding to epithelial cells distributed along colonic crypts. Phylogenomic and structural analyses reveal that F17-like pili are closely related to pilus types carried by intestinal pathogens, but are restricted to extra-intestinal pathogenic E. coli. Moreover, they show that targeting FimH with M4284, a high-affinity inhibitory mannoside, reduces intestinal colonization of genetically diverse UPEC isolates, while simultaneously treating UTI, without notably disrupting the structural configuration of the gut microbiota. By selectively depleting intestinal UPEC reservoirs, mannosides could markedly reduce the rate of UTIs and recurrent UTIs.
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2. Quantifiable predictive features define epitope-specific T cell receptor repertoires.
T cells are defined by a heterodimeric surface receptor, the T cell receptor (TCR), that mediates recognition of pathogen-associated epitopes through interactions with peptide and major histocompatibility complexes (pMHCs). TCRs are generated by genomic rearrangement of the germline TCR locus, a process termed V(D)J recombination, that has the potential to generate marked diversity of TCRs (estimated to range from 1015to as high as 1061 possible receptors). Despite this potential diversity, TCRs from T cells that recognize the same pMHC epitope often share conserved sequence features, suggesting that it may be possible to predictively model epitope specificity. Here Pradyot Dash at St Jude Children’s Research Hospital in Tennessee, USA and his colleagues report the in-depth characterization of ten epitope-specific TCR repertoires of CD8+ T cells from mice and humans, representing over 4,600 in-frame single-cell-derived TCRαβ sequence pairs from 110 subjects. They developed analytical tools to characterize these epitope-specific repertoires: a distance measure on the space of TCRs that permits clustering and visualization, a robust repertoire diversity metric that accommodates the low number of paired public receptors observed when compared to single-chain analyses, and a distance-based classifier that can assign previously unobserved TCRs to characterized repertoires with robust sensitivity and specificity. Their analyses demonstrate that each epitope-specific repertoire contains a clustered group of receptors that share core sequence similarities, together with a dispersed set of diverse ‘outlier’ sequences. By identifying shared motifs in core sequences, they were able to highlight key conserved residues driving essential elements of TCR recognition. These analyses provide insights into the generalizable, underlying features of epitope-specific repertoires and adaptive immune recognition.
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3. Unique roles for histone H3K9me states in RNAi and heritable silencing of transcription.
Heterochromatic DNA domains play important roles in regulation of gene expression and maintenance of genome stability by silencing repetitive DNA elements and transposons. From fission yeast to mammals, heterochromatin assembly at DNA repeats involves the activity of small noncoding RNAs (sRNAs) associated with the RNA interference (RNAi) pathway. Typically, sRNAs, originating from long noncoding RNAs, guide Argonaute-containing effector complexes to complementary nascent RNAs to initiate histone H3 lysine 9 di- and tri-methylation (H3K9me2 and H3K9me3, respectively) and heterochromatin formation. H3K9me is in turn required for recruitment of RNAi to chromatin to promote sRNA amplification. Yet, how heterochromatin formation, which silences transcription, can proceed by a co-transcriptional mechanism that also promotes sRNA generation remains paradoxical. Here, using Clr4, the fission yeast S. pombe homolog of mammalian SUV39H H3K9 methyltransferases, Gloria Jih at Harvard Medical School in Massachusetts, USA and her colleagues designed active site mutations that block H3K9me3, but allow H3K9me2 catalysis. They show that H3K9me2 defines a functionally distinct heterochromatin state that is sufficient for RNAi-dependent co-transcriptional gene silencing (CTGS) at pericentromeric DNA repeats. Unlike H3K9me3 domains, which are transcriptionally silent, H3K9me2 domains are transcriptionally active, contain modifications associated with euchromatic transcription, and couple RNAi-mediated transcript degradation to the establishment of H3K9me domains. The two H3K9me states recruit reader proteins with different efficiencies, explaining their different downstream silencing functions. Furthermore, transition from H3K9me2 to H3K9me3 is required for RNAi-independent epigenetic inheritance of H3K9me domains. Their findings demonstrate that H3K9me2 and H3K9me3 define functionally distinct chromatin states and uncover a mechanism for formation of transcriptionally permissive heterochromatin that is compatible with its broadly conserved role in sRNA-mediated genome defense.
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4. T cells from patients with Parkinson’s disease recognize α-synuclein peptides.
Genetic studies have shown the association of Parkinson’s disease with alleles of the major histocompatibility complex. Here David Sulzer at Columbia University in New York, USA and his colleagues show that a defined set of peptides that are derived from α-synuclein, a protein aggregated in Parkinson’s disease, act as antigenic epitopes displayed by these alleles and drive helper and cytotoxic T cell responses in patients with Parkinson’s disease. These responses may explain the association of Parkinson’s disease with specific major histocompatibility complex alleles.
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5. Host and viral traits predict zoonotic spillover from mammals.
The majority of human emerging infectious diseases are zoonotic, with viruses that originate in wild mammals of particular concern (for example, HIV, Ebola and SARS). Understanding patterns of viral diversity in wildlife and determinants of successful cross-species transmission, or spillover, are therefore key goals for pandemic surveillance programs. However, few analytical tools exist to identify which host species are likely to harbour the next human virus, or which viruses can cross species boundaries. Here Kevin J. Olival at EcoHealth Alliance in New York, USA and his colleagues conduct a comprehensive analysis of mammalian host–virus relationships and show that both the total number of viruses that infect a given species and the proportion likely to be zoonotic are predictable. After controlling for research effort, the proportion of zoonotic viruses per species is predicted by phylogenetic relatedness to humans, host taxonomy and human population within a species range—which may reflect human–wildlife contact. They demonstrate that bats harbour a significantly higher proportion of zoonotic viruses than all other mammalian orders. They also identify the taxa and geographic regions with the largest estimated number of ‘missing viruses’ and ‘missing zoonoses’ and therefore of highest value for future surveillance. They then show that phylogenetic host breadth and other viral traits are significant predictors of zoonotic potential, providing a novel framework to assess if a newly discovered mammalian virus could infect people.
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