Abrego N, Furneaux B, Hardwick B
… +111 more, Somervuo P, Palorinne I, Aguilar-Trigueros CA, Andrew NR, Babiy UV, Bao T, Bazzano G, Bondarchuk SN, Bonebrake TC, Brennan GL, Bret-Harte S, Bässler C, Cagnolo L, Cameron EK, Chapurlat E, Creer S, D'Acqui LP, de Vere N, Desprez-Loustau ML, Dongmo MAK, Jacobsen IBD, Fisher BL, Flores de Jesus M, Gilbert GS, Griffith GW, Gritsuk AA, Gross A, Grudd H, Halme P, Hanna R, Hansen J, Hansen LH, Hegbe ADMT, Hill S, Hogg ID, Hultman J, Hyde KD, Hynson NA, Ivanova N, Karisto P, Kerdraon D, Knorre A, Krisai-Greilhuber I, Kurhinen J, Kuzmina M, Lecomte N, Lecomte E, Loaiza V, Lundin E, Meire A, Mešić A, Miettinen O, Monkhouse N, Mortimer P, Müller J, Nilsson RH, Nonti PYC, Nordén J, Nordén B, Norros V, Paz C, Pellikka P, Pereira D, Petch G, Pitkänen JM, Popa F, Potter C, Purhonen J, Pätsi S, Rafiq A, Raharinjanahary D, Rakos N, Rathnayaka AR, Raundrup K, Rebriev YA, Rikkinen J, Rogers HMK, Rogovsky A, Rozhkov Y, Runnel K, Saarto A, Savchenko A, Schlegel M, Schmidt NM, Seibold S, Skjøth C, Stengel E, Sutyrina SV, Syvänperä I, Tedersoo L, Timm J, Tipton L, Toju H, Uscka-Perzanowska M, van der Bank M, van der Bank FH, Vandenbrink B, Ventura S, Vignisson SR, Wang X, Weisser WW, Wijesinghe SN, Wright SJ, Yang C, Yorou NS, Young A, Yu DW, Zakharov EV, Hebert PDN, Roslin T, Ovaskainen O
Fungi are among the most diverse and ecologically important kingdoms in life. However, the distributional ranges of fungi remain largely unknown as do the ecological mechanisms that shape their distributions. To provide...Fungi are among the most diverse and ecologically important kingdoms in life. However, the distributional ranges of fungi remain largely unknown as do the ecological mechanisms that shape their distributions. To provide an integrated view of the spatial and seasonal dynamics of fungi, we implemented a globally distributed standardized aerial sampling of fungal spores. The vast majority of operational taxonomic units were detected within only one climatic zone, and the spatiotemporal patterns of species richness and community composition were mostly explained by annual mean air temperature. Tropical regions hosted the highest fungal diversity except for lichenized, ericoid mycorrhizal and ectomycorrhizal fungi, which reached their peak diversity in temperate regions. The sensitivity in climatic responses was associated with phylogenetic relatedness, suggesting that large-scale distributions of some fungal groups are partially constrained by their ancestral niche. There was a strong phylogenetic signal in seasonal sensitivity, suggesting that some groups of fungi have retained their ancestral trait of sporulating for only a short period. Overall, our results show that the hyperdiverse kingdom of fungi follows globally highly predictable spatial and temporal dynamics, with seasonality in both species richness and community composition increasing with latitude. Our study reports patterns resembling those described for other major groups of organisms, thus making a major contribution to the long-standing debate on whether organisms with a microbial lifestyle follow the global biodiversity paradigms known for macroorganisms.
In the period between 5,300 and 4,900 calibrated years before present (cal. BP), populations across large parts of Europe underwent a period of demographic decline. However, the cause of this so-called Neolithic decline...In the period between 5,300 and 4,900 calibrated years before present (cal. BP), populations across large parts of Europe underwent a period of demographic decline. However, the cause of this so-called Neolithic decline is still debated. Some argue for an agricultural crisis resulting in the decline, others for the spread of an early form of plague. Here we use population-scale ancient genomics to infer ancestry, social structure and pathogen infection in 108 Scandinavian Neolithic individuals from eight megalithic graves and a stone cist. We find that the Neolithic plague was widespread, detected in at least 17% of the sampled population and across large geographical distances. We demonstrate that the disease spread within the Neolithic community in three distinct infection events within a period of around 120 years. Variant graph-based pan-genomics shows that the Neolithic plague genomes retained ancestral genomic variation present in Yersinia pseudotuberculosis, including virulence factors associated with disease outcomes. In addition, we reconstruct four multigeneration pedigrees, the largest of which consists of 38 individuals spanning six generations, showing a patrilineal social organization. Lastly, we document direct genomic evidence for Neolithic female exogamy in a woman buried in a different megalithic tomb than her brothers. Taken together, our findings provide a detailed reconstruction of plague spread within a large patrilineal kinship group and identify multiple plague infections in a population dated to the beginning of the Neolithic decline.
Systemic lupus erythematosus (SLE) is prototypical autoimmune disease driven by pathological T cell-B cell interactions. Expansion of T follicular helper (T) and T peripheral helper (T) cells, two T cell populations that...Systemic lupus erythematosus (SLE) is prototypical autoimmune disease driven by pathological T cell-B cell interactions. Expansion of T follicular helper (T) and T peripheral helper (T) cells, two T cell populations that provide help to B cells, is a prominent feature of SLE. Human T and T cells characteristically produce high levels of the B cell chemoattractant CXCL13 (refs. ), yet regulation of T cell CXCL13 production and the relationship between CXCL13 T cells and other T cell states remains unclear. Here, we identify an imbalance in CD4 T cell phenotypes in patients with SLE, with expansion of PD-1/ICOS CXCL13 T cells and reduction of CD96 IL-22 T cells. Using CRISPR screens, we identify the aryl hydrocarbon receptor (AHR) as a potent negative regulator of CXCL13 production by human CD4 T cells. Transcriptomic, epigenetic and functional studies demonstrate that AHR coordinates with AP-1 family member JUN to prevent CXCL13 T/T cell differentiation and promote an IL-22 phenotype. Type I interferon, a pathogenic driver of SLE, opposes AHR and JUN to promote T cell production of CXCL13. These results place CXCL13 T/T cells on a polarization axis opposite from T helper 22 (T22) cells and reveal AHR, JUN and interferon as key regulators of these divergent T cell states.
Innate immune pattern recognition receptors, such as the Toll-like receptors (TLRs), are key mediators of the immune response to infection and central to our understanding of health and disease. After microbial detection...Innate immune pattern recognition receptors, such as the Toll-like receptors (TLRs), are key mediators of the immune response to infection and central to our understanding of health and disease. After microbial detection, these receptors activate inflammatory signal transduction pathways that involve IκB kinases, mitogen-activated protein kinases, ubiquitin ligases and other adaptor proteins. The mechanisms that connect the proteins in the TLR pathways are poorly defined. To delineate TLR pathway activities, we engineered macrophages to enable microscopy and proteomic analysis of the endogenous myddosome constituent MyD88. We found that myddosomes form transient contacts with activated TLRs and that TLR-free myddosomes are dynamic in size, number and composition over the course of 24 h. Analysis using super-resolution microscopy revealed that, within most myddosomes, MyD88 forms barrel-like structures that function as scaffolds for effector protein recruitment. Proteomic analysis demonstrated that myddosomes contain proteins that act at all stages and regulate all effector responses of the TLR pathways, and genetic analysis defined the epistatic relationship between these effector modules. Myddosome assembly was evident in cells infected with Listeria monocytogenes, but these bacteria evaded myddosome assembly and TLR signalling during cell-to-cell spread. On the basis of these findings, we propose that the entire TLR signalling pathway is executed from within the myddosome.
Xia H, Zhang D, Wang J
… +17 more, Fagernäs Z, Li T, Li Y, Yao J, Lin D, Troché G, Smith GM, Chen X, Cheng T, Shen X, Han Y, Olsen JV, Shen Z, Pei Z, Hublin JJ, Chen F, Welker F
Genetic and fragmented palaeoanthropological data suggest that Denisovans were once widely distributed across eastern Eurasia. Despite limited archaeological evidence, this indicates that Denisovans were capable of adapt...Genetic and fragmented palaeoanthropological data suggest that Denisovans were once widely distributed across eastern Eurasia. Despite limited archaeological evidence, this indicates that Denisovans were capable of adapting to a highly diverse range of environments. Here we integrate zooarchaeological and proteomic analyses of the late Middle to Late Pleistocene faunal assemblage from Baishiya Karst Cave on the Tibetan Plateau, where a Denisovan mandible and Denisovan sedimentary mitochondrial DNA were found. Using zooarchaeology by mass spectrometry, we identify a new hominin rib specimen that dates to approximately 48-32 thousand years ago (layer 3). Shotgun proteomic analysis taxonomically assigns this specimen to the Denisovan lineage, extending their presence at Baishiya Karst Cave well into the Late Pleistocene. Throughout the stratigraphic sequence, the faunal assemblage is dominated by Caprinae, together with megaherbivores, carnivores, small mammals and birds. The high proportion of anthropogenic modifications on the bone surfaces suggests that Denisovans were the primary agent of faunal accumulation. The chaîne opératoire of carcass processing indicates that animal taxa were exploited for their meat, marrow and hides, while bone was also used as raw material for the production of tools. Our results shed light on the behaviour of Denisovans and their adaptations to the diverse and fluctuating environments of the late Middle and Late Pleistocene of eastern Eurasia.
Mehrotra P, Maschalidi S, Boeckaerts L
… +17 more, Maueröder C, Tixeira R, Pinney J, Burgoa Cardás J, Sukhov V, Incik Y, Anderson CJ, Hu B, Keçeli BN, Goncalves A, Vande Walle L, Van Opdenbosch N, Sergushichev A, Hoste E, Jain U, Lamkanfi M, Ravichandran KS
Pyroptosis is a lytic cell death mode that helps limit the spread of infections and is also linked to pathology in sterile inflammatory diseases and autoimmune diseases. During pyroptosis, inflammasome activation and the...Pyroptosis is a lytic cell death mode that helps limit the spread of infections and is also linked to pathology in sterile inflammatory diseases and autoimmune diseases. During pyroptosis, inflammasome activation and the engagement of caspase-1 lead to cell death, along with the maturation and secretion of the inflammatory cytokine interleukin-1β (IL-1β). The dominant effect of IL-1β in promoting tissue inflammation has clouded the potential influence of other factors released from pyroptotic cells. Here, using a system in which macrophages are induced to undergo pyroptosis without IL-1β or IL-1α release (denoted Pyro), we identify unexpected beneficial effects of the Pyro secretome. First, we noted that the Pyro supernatants upregulated gene signatures linked to migration, cellular proliferation and wound healing. Consistent with this gene signature, Pyro supernatants boosted migration of primary fibroblasts and macrophages, and promoted faster wound closure in vitro and improved tissue repair in vivo. In mechanistic studies, lipidomics and metabolomics of the Pyro supernatants identified the presence of both oxylipins and metabolites, linking them to pro-wound-healing effects. Focusing specifically on the oxylipin prostaglandin E (PGE), we find that its synthesis is induced de novo during pyroptosis, downstream of caspase-1 activation and cyclooxygenase-2 activity; further, PGE synthesis occurs late in pyroptosis, with its release dependent on gasdermin D pores opened during pyroptosis. As for the pyroptotic metabolites, they link to immune cell infiltration into the wounds, and polarization to CD301 macrophages. Collectively, these data advance the concept that the pyroptotic secretome possesses oxylipins and metabolites with tissue repair properties that may be harnessed therapeutically.
The COVID-19 pandemic is an ongoing global health threat, yet our understanding of the dynamics of early cellular responses to this disease remains limited. Here in our SARS-CoV-2 human challenge study, we used single-ce...The COVID-19 pandemic is an ongoing global health threat, yet our understanding of the dynamics of early cellular responses to this disease remains limited. Here in our SARS-CoV-2 human challenge study, we used single-cell multi-omics profiling of nasopharyngeal swabs and blood to temporally resolve abortive, transient and sustained infections in seronegative individuals challenged with pre-Alpha SARS-CoV-2. Our analyses revealed rapid changes in cell-type proportions and dozens of highly dynamic cellular response states in epithelial and immune cells associated with specific time points and infection status. We observed that the interferon response in blood preceded the nasopharyngeal response. Moreover, nasopharyngeal immune infiltration occurred early in samples from individuals with only transient infection and later in samples from individuals with sustained infection. High expression of HLA-DQA2 before inoculation was associated with preventing sustained infection. Ciliated cells showed multiple immune responses and were most permissive for viral replication, whereas nasopharyngeal T cells and macrophages were infected non-productively. We resolved 54 T cell states, including acutely activated T cells that clonally expanded while carrying convergent SARS-CoV-2 motifs. Our new computational pipeline Cell2TCR identifies activated antigen-responding T cells based on a gene expression signature and clusters these into clonotype groups and motifs. Overall, our detailed time series data can serve as a Rosetta stone for epithelial and immune cell responses and reveals early dynamic responses associated with protection against infection.
Amazonia contains the most extensive tropical forests on Earth, but Amazon carbon sinks of atmospheric CO are declining, as deforestation and climate-change-associated droughts threaten to push these forests past a tippi...Amazonia contains the most extensive tropical forests on Earth, but Amazon carbon sinks of atmospheric CO are declining, as deforestation and climate-change-associated droughts threaten to push these forests past a tipping point towards collapse. Forests exhibit complex drought responses, indicating both resilience (photosynthetic greening) and vulnerability (browning and tree mortality), that are difficult to explain by climate variation alone. Here we combine remotely sensed photosynthetic indices with ground-measured tree demography to identify mechanisms underlying drought resilience/vulnerability in different intact forest ecotopes (defined by water-table depth, soil fertility and texture, and vegetation characteristics). In higher-fertility southern Amazonia, drought response was structured by water-table depth, with resilient greening in shallow-water-table forests (where greater water availability heightened response to excess sunlight), contrasting with vulnerability (browning and excess tree mortality) over deeper water tables. Notably, the resilience of shallow-water-table forest weakened as drought lengthened. By contrast, lower-fertility northern Amazonia, with slower-growing but hardier trees (or, alternatively, tall forests, with deep-rooted water access), supported more-drought-resilient forests independent of water-table depth. This functional biogeography of drought response provides a framework for conservation decisions and improved predictions of heterogeneous forest responses to future climate changes, warning that Amazonia's most productive forests are also at greatest risk, and that longer/more frequent droughts are undermining multiple ecohydrological strategies and capacities for Amazon forest resilience.
The vast majority of glycosidases characterized to date follow one of the variations of the 'Koshland' mechanisms to hydrolyse glycosidic bonds through substitution reactions. Here we describe a large-scale screen of a h...The vast majority of glycosidases characterized to date follow one of the variations of the 'Koshland' mechanisms to hydrolyse glycosidic bonds through substitution reactions. Here we describe a large-scale screen of a human gut microbiome metagenomic library using an assay that selectively identifies non-Koshland glycosidase activities. Using this, we identify a cluster of enzymes with extremely broad substrate specificities and thoroughly characterize these, mechanistically and structurally. These enzymes not only break glycosidic linkages of both α and β stereochemistry and multiple connectivities, but also cleave substrates that are not hydrolysed by standard glycosidases. These include thioglycosides, such as the glucosinolates from plants, and pseudoglycosidic bonds of pharmaceuticals such as acarbose. This is achieved through a distinct mechanism of hydrolysis that involves oxidation/reduction and elimination/hydration steps, each catalysed by enzyme modules that are in many cases interchangeable between organisms and substrate classes. Homologues of these enzymes occur in both Gram-positive and Gram-negative bacteria associated with the gut microbiome and other body parts, as well as other environments, such as soil and sea. Such alternative step-wise mechanisms appear to constitute largely unrecognized but abundant pathways for glycan degradation as part of the metabolism of carbohydrates in bacteria.
Skinnider MA, Gautier M, Teo AYY
… +14 more, Kathe C, Hutson TH, Laskaratos A, de Coucy A, Regazzi N, Aureli V, James ND, Schneider B, Sofroniew MV, Barraud Q, Bloch J, Anderson MA, Squair JW, Courtine G
Here, we introduce the Tabulae Paralytica-a compilation of four atlases of spinal cord injury (SCI) comprising a single-nucleus transcriptome atlas of half a million cells, a multiome atlas pairing transcriptomic and epi...Here, we introduce the Tabulae Paralytica-a compilation of four atlases of spinal cord injury (SCI) comprising a single-nucleus transcriptome atlas of half a million cells, a multiome atlas pairing transcriptomic and epigenomic measurements within the same nuclei, and two spatial transcriptomic atlases of the injured spinal cord spanning four spatial and temporal dimensions. We integrated these atlases into a common framework to dissect the molecular logic that governs the responses to injury within the spinal cord. The Tabulae Paralytica uncovered new biological principles that dictate the consequences of SCI, including conserved and divergent neuronal responses to injury; the priming of specific neuronal subpopulations to upregulate circuit-reorganizing programs after injury; an inverse relationship between neuronal stress responses and the activation of circuit reorganization programs; the necessity of re-establishing a tripartite neuroprotective barrier between immune-privileged and extra-neural environments after SCI and a failure to form this barrier in old mice. We leveraged the Tabulae Paralytica to develop a rejuvenative gene therapy that re-established this tripartite barrier, and restored the natural recovery of walking after paralysis in old mice. The Tabulae Paralytica provides a window into the pathobiology of SCI, while establishing a framework for integrating multimodal, genome-scale measurements in four dimensions to study biology and medicine.
Overbey EG, Kim J, Tierney BT
… +106 more, Park J, Houerbi N, Lucaci AG, Garcia Medina S, Damle N, Najjar D, Grigorev K, Afshin EE, Ryon KA, Sienkiewicz K, Patras L, Klotz R, Ortiz V, MacKay M, Schweickart A, Chin CR, Sierra MA, Valenzuela MF, Dantas E, Nelson TM, Cekanaviciute E, Deards G, Foox J, Narayanan SA, Schmidt CM, Schmidt MA, Schmidt JC, Mullane S, Tigchelaar SS, Levitte S, Westover C, Bhattacharya C, Lucotti S, Wain Hirschberg J, Proszynski J, Burke M, Kleinman AS, Butler DJ, Loy C, Mzava O, Lenz J, Paul D, Mozsary C, Sanders LM, Taylor LE, Patel CO, Khan SA, Suhail Mohamad M, Byhaqui SGA, Aslam B, Gajadhar AS, Williamson L, Tandel P, Yang Q, Chu J, Benz RW, Siddiqui A, Hornburg D, Blease K, Moreno J, Boddicker A, Zhao J, Lajoie B, Scott RT, Gilbert RR, Lai Polo SH, Altomare A, Kruglyak S, Levy S, Ariyapala I, Beer J, Zhang B, Hudson BM, Rininger A, Church SE, Beheshti A, Church GM, Smith SM, Crucian BE, Zwart SR, Matei I, Lyden DC, Garrett-Bakelman F, Krumsiek J, Chen Q, Miller D, Shuga J, Williams S, Nemec C, Trudel G, Pelchat M, Laneuville O, De Vlaminck I, Gross S, Bolton KL, Bailey SM, Granstein R, Furman D, Melnick AM, Costes SV, Shirah B, Yu M, Menon AS, Mateus J, Meydan C, Mason CE
Spaceflight induces molecular, cellular and physiological shifts in astronauts and poses myriad biomedical challenges to the human body, which are becoming increasingly relevant as more humans venture into space. Yet cur...Spaceflight induces molecular, cellular and physiological shifts in astronauts and poses myriad biomedical challenges to the human body, which are becoming increasingly relevant as more humans venture into space. Yet current frameworks for aerospace medicine are nascent and lag far behind advancements in precision medicine on Earth, underscoring the need for rapid development of space medicine databases, tools and protocols. Here we present the Space Omics and Medical Atlas (SOMA), an integrated data and sample repository for clinical, cellular and multi-omic research profiles from a diverse range of missions, including the NASA Twins Study, JAXA CFE study, SpaceX Inspiration4 crew, Axiom and Polaris. The SOMA resource represents a more than tenfold increase in publicly available human space omics data, with matched samples available from the Cornell Aerospace Medicine Biobank. The Atlas includes extensive molecular and physiological profiles encompassing genomics, epigenomics, transcriptomics, proteomics, metabolomics and microbiome datasets, which reveal some consistent features across missions, including cytokine shifts, telomere elongation and gene expression changes, as well as mission-specific molecular responses and links to orthologous, tissue-specific mouse datasets. Leveraging the datasets, tools and resources in SOMA can help to accelerate precision aerospace medicine, bringing needed health monitoring, risk mitigation and countermeasure data for upcoming lunar, Mars and exploration-class missions.
Mason CE, Green J, Adamopoulos KI
… +81 more, Afshin EE, Baechle JJ, Basner M, Bailey SM, Bielski L, Borg J, Borg J, Broddrick JT, Burke M, Caicedo A, Castañeda V, Chatterjee S, Chin CR, Church G, Costes SV, De Vlaminck I, Desai RI, Dhir R, Diaz JE, Etlin SM, Feinstein Z, Furman D, Garcia-Medina JS, Garrett-Bakelman F, Giacomello S, Gupta A, Hassanin A, Houerbi N, Irby I, Javorsky E, Jirak P, Jones CW, Kamal KY, Kangas BD, Karouia F, Kim J, Kim JH, Kleinman AS, Lam T, Lawler JM, Lee JA, Limoli CL, Lucaci A, MacKay M, McDonald JT, Melnick AM, Meydan C, Mieczkowski J, Muratani M, Najjar D, Othman MA, Overbey EG, Paar V, Park J, Paul AM, Perdyan A, Proszynski J, Reynolds RJ, Ronca AE, Rubins K, Ryon KA, Sanders LM, Glowe PS, Shevde Y, Schmidt MA, Scott RT, Shirah B, Sienkiewicz K, Sierra MA, Siew K, Theriot CA, Tierney BT, Venkateswaran K, Hirschberg JW, Walsh SB, Walter C, Winer DA, Yu M, Zea L, Mateus J, Beheshti A
The recent acceleration of commercial, private and multi-national spaceflight has created an unprecedented level of activity in low Earth orbit, concomitant with the largest-ever number of crewed missions entering space...The recent acceleration of commercial, private and multi-national spaceflight has created an unprecedented level of activity in low Earth orbit, concomitant with the largest-ever number of crewed missions entering space and preparations for exploration-class (lasting longer than one year) missions. Such rapid advancement into space from many new companies, countries and space-related entities has enabled a 'second space age'. This era is also poised to leverage, for the first time, modern tools and methods of molecular biology and precision medicine, thus enabling precision aerospace medicine for the crews. The applications of these biomedical technologies and algorithms are diverse, and encompass multi-omic, single-cell and spatial biology tools to investigate human and microbial responses to spaceflight. Additionally, they extend to the development of new imaging techniques, real-time cognitive assessments, physiological monitoring and personalized risk profiles tailored for astronauts. Furthermore, these technologies enable advancements in pharmacogenomics, as well as the identification of novel spaceflight biomarkers and the development of corresponding countermeasures. In this Perspective, we highlight some of the recent biomedical research from the National Aeronautics and Space Administration, Japan Aerospace Exploration Agency, European Space Agency and other space agencies, and detail the entrance of the commercial spaceflight sector (including SpaceX, Blue Origin, Axiom and Sierra Space) into aerospace medicine and space biology, the first aerospace medicine biobank, and various upcoming missions that will utilize these tools to ensure a permanent human presence beyond low Earth orbit, venturing out to other planets and moons.
Human spaceflight has historically been managed by government agencies, such as in the NASA Twins Study, but new commercial spaceflight opportunities have opened spaceflight to a broader population. In 2021, the SpaceX I...Human spaceflight has historically been managed by government agencies, such as in the NASA Twins Study, but new commercial spaceflight opportunities have opened spaceflight to a broader population. In 2021, the SpaceX Inspiration4 mission launched the first all-civilian crew to low Earth orbit, which included the youngest American astronaut (aged 29), new in-flight experimental technologies (handheld ultrasound imaging, smartwatch wearables and immune profiling), ocular alignment measurements and new protocols for in-depth, multi-omic molecular and cellular profiling. Here we report the primary findings from the 3-day spaceflight mission, which induced a broad range of physiological and stress responses, neurovestibular changes indexed by ocular misalignment, and altered neurocognitive functioning, some of which match those of long-term spaceflight, but almost all of which did not differ from baseline (pre-flight) after return to Earth. Overall, these preliminary civilian spaceflight data suggest that short-duration missions do not pose a significant health risk, and moreover present a rich opportunity to measure the earliest phases of adaptation to spaceflight in the human body at anatomical, cellular, physiological and cognitive levels. Finally, these methods and results lay the foundation for an open, rapidly expanding biomedical database for astronauts, which can inform countermeasure development for both private and government-sponsored space missions.
Stankey CT, Bourges C, Haag LM
… +40 more, Turner-Stokes T, Piedade AP, Palmer-Jones C, Papa I, Silva Dos Santos M, Zhang Q, Cameron AJ, Legrini A, Zhang T, Wood CS, New FN, Randzavola LO, Speidel L, Brown AC, Hall A, Saffioti F, Parkes EC, Edwards W, Direskeneli H, Grayson PC, Jiang L, Merkel PA, Saruhan-Direskeneli G, Sawalha AH, Tombetti E, Quaglia A, Thorburn D, Knight JC, Rochford AP, Murray CD, Divakar P, Green M, Nye E, MacRae JI, Jamieson NB, Skoglund P, Cader MZ, Wallace C, Thomas DC, Lee JC
Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health. This is compounded by the limited efficacy of available treatments and high failure rates during drug development, high...Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health. This is compounded by the limited efficacy of available treatments and high failure rates during drug development, highlighting an urgent need to better understand disease mechanisms. Here we show how functional genomics could address this challenge. By investigating an intergenic haplotype on chr21q22-which has been independently linked to inflammatory bowel disease, ankylosing spondylitis, primary sclerosing cholangitis and Takayasu's arteritis-we identify that the causal gene, ETS2, is a central regulator of human inflammatory macrophages and delineate the shared disease mechanism that amplifies ETS2 expression. Genes regulated by ETS2 were prominently expressed in diseased tissues and more enriched for inflammatory bowel disease GWAS hits than most previously described pathways. Overexpressing ETS2 in resting macrophages reproduced the inflammatory state observed in chr21q22-associated diseases, with upregulation of multiple drug targets, including TNF and IL-23. Using a database of cellular signatures, we identified drugs that might modulate this pathway and validated the potent anti-inflammatory activity of one class of small molecules in vitro and ex vivo. Together, this illustrates the power of functional genomics, applied directly in primary human cells, to identify immune-mediated disease mechanisms and potential therapeutic opportunities.