Biology subjects

Busch, M.

Publications and source records attributed to Busch, M..

17 recordsLinked to original sources

bioRxiv2026

Near real-time data on the human neutralizing antibody landscape to influenza virus in summer of 2026 shows antigenic advance of H3N2 subclade K region D mutants and H1N1 D.3.1.1 Sa mutants

Human seasonal influenza evolves rapidly, necessitating twice yearly decisions about whether to update the strains in the vaccine. To help inform this decision, we have been using high-throughput sequencing-based neutralization assays to make twice yearly measurements of how recent human sera neutralize current human H3N2 and H1N1 strains. Here we provide the third installment in this series of measurements by reporting 52,268 titers representing neutralization of 148 viral strains by 355 human sera collected between April and August of 2026. Our measurements show that new H3N2 subclade K strains with mutations in antigenic region D and new H1N1 subclade D.3.1.1 strains with mutations in antigenic region Sa (such as G155E) have reduced neutralization by human sera, with notable heterogeneity in the impact of some of these mutations across sera from different individuals. This paper is accompanied by an interactive summary (https://jbloomlab.github.io/flu-seqneut-2026/summary.html) that enables detailed exploration of the results, and all titer data are publicly available for further analysis to aid vaccine antigen selection and studies of viral evolution.

microbiology↗

bioRxiv2026

The dynamic inositol phosphate network during development in Drosophila melanogaster

Inositol phosphates (InsPs) and inositol pyrophosphates (PP-InsPs) are key regulators of cellular signaling and metabolism, yet developmental changes in the InsP/PP-InsP network in eukaryotic systems remain poorly understood. Here, we combine isomer-resolved capillary electrophoresis-mass spectrometry (CE-MS) with genetic perturbations to characterize InsP metabolism during the Drosophila melanogaster development. Our analyses reveal extensive developmental reprogramming of the InsP pathway, with early developmental stages exhibiting broad lower-order isomer diversity that progressively narrows into a more restricted metabolic state enriched in Ins(1,3,4,5,6)P5, InsP6, and PP-InsPs at later stages. Metamorphosis is characterized by a marked increase in 5-PP-InsP5, which emerges as the predominant pyrophosphate species in adults. Perturbation of dedicated kinases suggests that this metabolic remodeling is essential for developmental progression. RNAi-mediated IPK2 depletion disrupts higher-order InsP synthesis by reducing InsP5 levels, and results in failed metamorphosis. IPK1 depletion delays development and induces pronounced isomer-selective redistribution within the InsP5 pool, indicating network-level changes beyond simple precursor accumulation. IP6K depletion specifically abolishes 5-PP-InsP5 production, impairs tissue morphogenesis during pupal stages, and causes rapid post-eclosion lethality. Unexpectedly, depletion of either IPK2 or IP6K leads to the presence of 2-PP-InsP5. Collectively, these findings establish the Drosophila melanogaster InsP pathway as a dynamically regulated developmental network, particularly rich in previously undescribed InsP isomers, in which stage-specific metabolic remodeling parallels metamorphosis, tissue maturation, and adult viability.

biochemistry↗

bioRxiv2026

Conformational dynamics of the membrane-anchored foldase LipH from Pseudomonas aeruginosa governs recognition and release of its client lipase

The lipase LipA from Pseudomonas aeruginosa is an extracellular enzyme that plays an important role in bacterial infections. Prior its export via the type II secretion system, LipA requires the cognate membrane-anchored foldase LipH for maturation in the periplasm. Though structural studies elucidated the architecture of the LipH:lipase complex, how the full-length, membrane-tethered foldase recognizes, folds, and releases its client has remained barely understood. Here, we combine in silico and in vitro analysis to resolve the conformational dynamics and function of the full-length LipH in a membrane context. Simulations reveal that the membrane-anchored LipH is highly dynamic, sampling a broad ensemble of conformations. The chaperoning cavity is transiently closed or occluded by both the proximal membrane and the linker polypeptide, which is further confirmed by structural analysis. Despite the steric hindrance, the full-length LipH reconstituted into lipid-based nanodiscs and amphipols efficiently activates LipA, though it displays substantially reduced affinity for the client. We propose that the negatively charged membrane promotes release of the folded client, enabling multiple chaperoning cycles. Hydrogen/deuterium exchange analysis reveals that the MD2 domain of LipH in engaged in stable interactions with the lipase, whereas MD1 contacts are transient. Consistently, LipH readily captures N-terminal fragments of LipA, indicating that initial recognition relies on local interactions via the MD2 domain. Together, our results show how membrane coupling and intrinsic conformational plasticity modulate the function of the steric chaperone, and suggest that the membrane-anchored LipH balances capture, folding, and release of the client LipA to enable its efficient secretion.

biochemistry↗

bioRxiv2026

Near real-time data on the human neutralizing antibody landscape to influenza virus as of early 2026 to inform vaccine-strain selection

Twice each year, a decision is made on whether to update the strains included in the seasonal influenza vaccine to better match the most recent circulating viral strains. To characterize the antigenic properties of current seasonal influenza A strains to inform the upcoming decision about which strains to include in the 2026-2027 Northern Hemisphere vaccine, here we perform high-throughput sequencing-based neutralization assays using a library of 57 H3N2 and 34 H1N1 influenza hemagglutinins reflecting the circulating diversity of strains in late 2025 to early 2026. We assay this library against 302 human sera collected in late 2025. The resulting data set encompasses 27,409 titers, and provides a near real-time portrait of the human neutralizing antibody landscape against influenza virus. We find that many human sera have lower titers against the K subclade of H3N2 and the D.3.1.1 subclade of H1N1; these subclades have recently become dominant among their respective subtypes. Our measurements also reveal variability in titers to different subvariants within the K subclade of H3N2, with titers especially low to subclade K strains with additional mutations in antigenic regions D and E. We make all our data and accompanying visualizations publicly available to enable their use in vaccine-strain selection and analyses of influenza evolution and immunity.

microbiology↗

bioRxiv2025

Substrate-induced assembly and functional mechanism of the bacterial membrane protein insertase SecYEG-YidC

The Sec translocon and the YidC/Oxa1-type insertases universally mediate biogenesis of -helical membrane proteins, but the molecular basis of their cooperation has remained disputed. Recent discoveries of multi-subunit insertases assembled at the back of the translocon in fungi and higher eukaryotes have raised the question about the architecture and mechanism of the putative bacterial ortholog SecYEG-YidC. Here, we combine cryogenic electron microscopy with cell-free protein synthesis to visualize biogenesis of SecYEG/YidC-dependent multipass membrane protein NuoK. We demonstrate that the nascent chain of NuoK does not enter the lateral gate of SecYEG, but crosses over the translocon towards its back side, whereto YidC is recruited in the nascent chain-dependent manner. The SecY-YidC interface promotes folding of the transmembrane helices prior their insertion, in agreement with thermodynamic principles of membrane protein folding. YidC forms extensive contacts with the nascent chain, suggesting its key role in the insertion event. Our data provide detailed insights on the insertase machinery, suggest the evolutionary conservation of the gate-independent insertion route, and offer an expanded view on membrane protein biogenesis.

biochemistry↗

bioRxiv2024

Defining the cardiac fibroblast secretome in the healthy and infarcted mouse heart

Cardiac fibroblasts (CF) are key players after myocardial infarction (MI), but their signaling is only incompletely understood. Here we report a first secretome atlas of CF in control (cCF) and post-MI hearts (miCF), combining a rapid cell isolation technique with SILAC and click chemistry. In CF, numerous paracrine factors involved in immune homeostasis were identified. Comparing secretome, transcriptome (SLAMseq), and cellular proteome disclosed protein turnover. In miCF at day 5 post-MI, significantly upregulated proteins included SLIT2, FN1, and CRLF1 in mouse and human samples. Comparing the miCF secretome at day 3 and 5 post-MI showed the dynamic nature of protein secretion. Specific in-vivo labeling of miCF proteins via biotin ligase TurboID using the POSTN promotor mirrored the in-vitro data. In summary, we have identified numerous paracrine factors specifically secreted from CF in mice and humans. This secretome atlas may lead to new biomarkers and/or therapeutic targets for the activated CF.

physiology↗

bioRxiv2024

Microgliosis, astrogliosis and loss of aquaporin-4 polarity in frontal cortex of COVID-19 patients

The severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), causing human coronavirus disease 2019 (COVID-19), not only affects the respiratory tract, but also impacts other organs including the brain. A considerable number of COVID-19 patients develop neuropsychiatric symptoms that may linger for weeks and months and contribute to "long-COVID". While the neurological symptoms of COVID-19 are well described, the cellular mechanisms of neurologic disorders attributed to the infection are still enigmatic. Here, we studied the effect of an infection with SARS-CoV-2 on the structure and expression of marker proteins of astrocytes and microglial cells in the frontal cortex of patients who died from COVID-19 in comparison to non-COVID-19 controls. Most of COVID-19 patients had microglial cells with retracted processes and rounded and enlarged cell bodies in both gray and white matter, as visualized by anti-Iba1 staining and confocal fluorescence microscopy. In addition, gray matter astrocytes in COVID-19 patients were frequently labeled by intense anti-GFAP staining, whereas in non-COVID-19 controls, most gray matter astrocytes expressed little GFAP. The most striking difference between astrocytes in COVID-19 patients and controls was found by anti-aquaporin-4 (AQP4) staining. In COVID-19 patients, a large number of gray matter astrocytes showed an increase in AQP4. In addition, AQP4 polarity was lost and AQP4 covered the entire cell, including the cell body and all cell processes, while in controls, AQP4 immunostaining was mainly detected in endfeet around blood vessels and did not visualize the cell body. In summary, our data suggest neuroinflammation upon SARS-CoV-2 infection including microgliosis and astrogliosis, including loss of AQP4 polarity.

neuroscience↗

bioRxiv2024

The fungal protein Jps1 facilitates unconventional protein secretion through a direct phosphoinositide interaction

Protein secretion is indispensable for essential cellular processes in eukaryotic cells, contributing significantly to nutrient acquisition, defense or communication. Alternative pathways bypassing the endomembrane system collectively referred to as unconventional secretion are gaining increasing attention. A number of important molecules such as cytokines, fibroblast growth factor or viral proteins are being exported through these mechanistically diverse pathways. In the fungal model Ustilago maydis, cytokinesis-dependent unconventional secretion mediates export of the chitinase Cts1 via the fragmentation zone. This membrane-rich compartment is formed during cytokinesis between mother and daughter cells. Recently, we identified Jps1, a previously uncharacterized protein, as a crucial factor for Cts1 localization and export. Combining biochemical experiments and in vivo studies, we here uncover two pivotal features of Jps1: dimerization and phosphoinositide (PIP) binding. Our findings reveal that a conserved structural core domain mediates homodimerization, while surrounding flexible variable regions suggest potential diversification in different basidiomycete species. Jps1 does not harbor a canonical PIP-binding domain but instead specificity of the interaction with the preferred PIP PI(4,5)P2 is determined by basic residues. Importantly, loss of PI(4,5)P2 binding specificity results in mis-localisation, morphological defects and reduced extracellular Cts1 activity, particularly at low cell densities. This discovery sheds light on previously unknown key features of Jps1, elucidating its role in supporting Cts1 secretion, and representing a crucial step towards understanding the broader implications of unconventional secretion in eukaryotic cells.

biochemistry↗

bioRxiv2023

S100A1's single cysteine is an indispensable redox-switch for the protection against diastolic calcium leakage in cardiomyocytes

The EF-hand calcium (Ca2+) sensor protein S100A1 combines inotropic with antiarrhythmic potency in cardiomyocytes (CM). Oxidative posttranslational modification (ox-PTM) of S100A1s conserved, single cysteine residue (C85) via reactive nitrogen species (i.e. S-nitrosylation or glutathionylation) was proposed to modulate conformational flexibility of intrinsically disordered sequence fragments and to increase the molecules affinity towards Ca2+. In light of the unknown biological functional consequence, we aimed to determine the impact of the C85 moiety of S100A1 as a potential redox-switch. We first uncovered that S100A1 is endogenously glutathionylated in the adult heart in vivo. To prevent glutathionylation of S100A1, we generated S100A1 variants that were unresponsive to ox-PTMs. Overexpression of wildtype (WT) and C85-deficient S100A1 protein variants in isolated CM demonstrated equal inotropic potency, as shown by equally augmented Ca2+ transient amplitudes under basal conditions and {beta}-adrenergic receptor ({beta}AR) stimulation. However, in contrast ox-PTM defective S100A1 variants failed to protect against arrhythmogenic diastolic sarcoplasmic reticulum (SR) Ca2+ leak and ryanodine receptor (RyR2) hypernitrosylation during {beta}-AR stimulation. Despite diastolic performance failure, C85-deficient S100A1 protein variants exerted similar Ca2+-dependent interaction with the RyR2 than WT-S100A1. Dissecting S100A1s molecular structure-function relationship, our data indicate for the first time that the conserved C85 residue potentially acts as a redox-switch that is indispensable for S100A1s antiarrhythmic but not its inotropic potency in CM. We therefore propose a model where C85s ox-PTM determines S100A1s ability to beneficially control diastolic but not systolic RyR2 activity.

molecular biology↗

bioRxiv2023

Cardiac-targeted rAAV5-S100A1 gene therapy protects against adverse remodeling and contractile dysfunction in post-ischemic hearts

Toxicity by recombinant adeno-associated viruses (rAAV) in clinical gene therapy trials (e.g., by rAAV9-mediated fatal liver failure) significantly impairs translation of preclinical rAAV-based cardiac gene therapies employing these vectors. For rAAV5 - a capsid that has shown long-term safety in clinical trials - our translational study demonstrates effective transduction of the left ventricle (LV) of healthy pigs via catheter-based retrograde intravenous delivery (CRID) by means of luciferase reporter gene biodistribution analyses. Combination of rAAV5 with the cardioprotective human gene S100A1 (hS100A1) prevents LV myocardial infarct (MI) enlargement and improves LV systolic contractile performance in a porcine model of post-MI chronic cardiac dysfunction. Use of a cardiac-biased promoter ensured the cardiac-directed expression of the therapeutic human transgene without signs of clinical toxicity. The beneficial effects of rAAV5-hS100A1 were linked to an attenuated activity of post-MI inflammatory gene networks and this was further validated in a murine model. These novel data together with proven scalable producibility and low pre-existing immunity against rAAV5 in humans may collectively advance clinical translation of rAAV5-hS100A1 as a gene therapy medicinal product (GTMP) for a common cardiovascular disease, such as chronic heart failure (CHF). HighlightsO_LIRecent fatal adverse events in recombinant adeno-associated virus (AAV)-based clinical gene therapy trials advise the use of rAAV serotypes with proven long-term clinical safety, such as rAAV5, for the pre-clinical development and clinical translation of rAAV-based cardiac gene therapy medicinal products. C_LIO_LIIn a biodistribution and therapeutic proof-of-concept study in farm pigs, rAAV5 was identified as an effective viral vector for cardiac gene transfer and gene therapy for post-ischemic cardiac dysfunction when applied by a standardized cardiac-targeted catheter-based route of administration with the luciferase reporter and cardioprotective human gene S100A1 (hS100A1), respectively. C_LIO_LIA systems biology analysis linked the novel finding of mitigated inflammatory and activated cardioprotective gene network activities in rAAV5-hS100A1 treated postischemic myocardium with improved study left ventricular ejection fraction and prevention of myocardial infarct extension, respectively, which warrants further mechanistic molecular studies. C_LIO_LISince rAAV5 has been recently approved for clinical use in a non-cardiac indication and cardiac-targeted S100A1 gene therapy has been effective in numerous pre-clinical animal models of acute and chronic cardiac dysfunction, our translational data support an expedited developmental path for rAAV5-hS100A1 throughout investigational new drug-enabling studies towards a first-in-human clinical trial for post-myocardial infarction heart failure. C_LI

pathology↗

bioRxiv2023

SUMO interacting motif (SIM) of S100A1 is critical for S100A1 post-translational protein stability

S100A1 is a small EF-type Ca2+ sensor protein that belongs to the multigenic S100 protein family. It is abundantly expressed in cardiomyocytes (CMs) and has been described as a key regulator of CM performance due to its unique ability to interact with structural contractile proteins, regulators of cardiac Ca2+ cycling, and mitochondrial proteins. However, our understanding of the molecular mechanisms regulating S100A1 protein levels is limited. We used the bioinformatics tool GPS-SUMO2.0 to identify a putative SUMO interacting motif (SIM) on S100A1. Consistently, a S100A1:SUMO interaction assay showed a Ca2+-dependent interaction of S100A1 with SUMO proteins. In neonatal rat ventricular myocytes (NRVM) and COS1 cells, S100A1 protein abundance increased in the presence of overexpressed SUMO1 without affecting the S100A1 mRNA transcript. We then generated S100A1 truncation mutants, where the SIM motif was removed by truncation or in which the core residues of the SIM motif (residues 77-79) were deleted or replaced by alanine. In COS1 cells and NRVM, overexpression of these S100A1 mutants led to elevated S100A1 mutant mRNA levels but failed to produce respective protein levels. Protein expression of these mutants could be rescued from degradation by addition of the proteasome inhibitor MG-132. By using an information-driven approach to dock the three-dimensional structures of S100A1 and SUMO, we predict a novel interaction mode between the SIM in S100A1 and SUMO. This study shows an important role of SUMO:SIM-mediated protein:protein interaction in the regulation of post-translational protein stability, and provides mechanistic insights into the indispensability of the core SIM for S100A1 post-translational stability.

biochemistry↗

bioRxiv2022

The periplasmic chaperone Skp prevents misfolding of the secretory lipase A from Pseudomonas aeruginosa

Pseudomonas aeruginosa is a wide-spread opportunistic human pathogen and a high-risk factor for immunodeficient people and patients with cystic fibrosis. The extracellular lipase A belongs to the virulence factors of P. aeruginosa. The lipase undergoes folding and activation in the periplasm prior the secretion. Here, we demonstrate that the ubiquitous periplasmic chaperone Skp of P. aeruginosa, but not SurA, FkpA, PpiD or YfgM, efficiently prevents misfolding of the aggregation-prone lipase A and facilitates its activation by a specific foldase LipH. Small-angle X-ray scattering visualizes the trimeric architecture of P. aeruginosa Skp and identifies two primary conformations of the chaperone, a compact and a widely open. We describe two binding modes of Skp to the lipase, with affinities of 20 nM and 2 M, which correspond to 1:1 and 1:2 stoichiometry of the lipase:Skp complex. Two Skp trimers are required to stabilize the lipase via the apolar interactions, which are not affected by high salt concentrations typical for the sputum of cystic fibrosis patients. The chaperoning effect of Skp points to its potent role in maturation and secretion of the lipase in Pseudomonas species.

biochemistry↗

bioRxiv2022

Ex Vivo Validation of Six FDA-Approved Non-Receptor Tyrosine Kinase Inhibitors (NRTKIs) as Antivirals to Pandemic and Seasonal Influenza A Viruses

Influenza viruses are important respiratory pathogens that cause substantial morbidity and mortality annually. In addition to seasonal influenza outbreaks, new emerging influenza A viruses (IAV) can cause pandemic influenza outbreaks. Apart from effective vaccines, there is a need for better treatment options to combat infections with these viruses when vaccines are not available or show reduced efficacy (e.g., in immmunocompromised patients). The limited range of licensed antiviral drugs and emergence of drug-resistance mutations highlight the need for novel intervention strategies like host-targeted antivirals. Repurposing FDA-approved kinase inhibitors may offer a fast-track for a new generation of host-targeted antivirals. Small molecule kinase inhibitors (SMKIs) can inhibit replication of viruses and improve survival in vivo; however, no SMKI has been approved for clinical use against IAV infections. In the present study, we tested eight non-receptor tyrosine kinase-inhibitors (NRTKIs) used to treat cancer and autoimmune diseases for their antiviral potential. Six of those potently inhibited virus replication ([≥]1,000-fold) in A549 cells infected with either A(H1N1)pdm09 or seasonal A(H3N2) strains. These compounds were validated in a biologically relevant ex vivo model of human precision-cut lung slices (hPCLS) to provide proof of principle and show efficacy against contemporary seasonal and pandemic IAVs. We identified the steps of the virus infection cycle affected by these inhibitors and assessed the effect of these NRTKIs on the host response. Considering their established safety profiles, our studies show that the use of these NRTKI shows promise and warrants further development as an alternative strategy to treat influenza virus infections.

microbiology↗

bioRxiv2021

Fluorescent and bioluminescent calcium indicators with tuneable colors and affinities

We introduce a family of bright, rhodamine-based calcium indicators with tuneable affinities and colors. The indicators can be specifically localized to different cellular compartments and are compatible with both fluorescence and bioluminescence readouts through conjugation to HaloTag fusion proteins. Importantly, their increase in fluorescence upon localization enables no-wash live-cell imaging, which greatly facilitates their use in biological assays. Applications as fluorescent indicators in rat hippocampal neurons include the detection of single action potentials and of calcium fluxes in the endoplasmic reticulum (ER). Applications as bioluminescent indicators include the recording of the pharmacological modulation of nuclear calcium in high-throughput-compatible assays. The versatility and remarkable ease of use of these indicators make them powerful tools for bioimaging and bioassays. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/468356v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@b7aa92org.highwire.dtl.DTLVardef@1f7141org.highwire.dtl.DTLVardef@447f30org.highwire.dtl.DTLVardef@fa34c2_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2020

Bioorthogonal red and far-red fluorogenic probes for wash-free live-cell and super-resolution microscopy

Small-molecule fluorophores enable the observation of biomolecules in their native context with fluorescence microscopy. Specific labelling via bioorthogonal tetrazine chemistry confers minimal label size and rapid labelling kinetics. At the same time, fluorogenic tetrazine-dye conjugates exhibit efficient quenching of dyes prior to target binding. However, live-cell compatible long-wavelength fluorophores with strong fluorogenicity have been difficult to realize. Here, we report close proximity tetrazine-dye conjugates with minimal distance between tetrazine and fluorophore. Two synthetic routes give access to a series of cell permeable and impermeable dyes including highly fluorogenic far-red emitting derivatives with electron exchange as dominant excited state quenching mechanism. We demonstrate their potential for live-cell imaging in combination with unnatural amino acids, wash-free multi-colour and super-resolution STED and SOFI imaging. These dyes pave the way for advanced fluorescence imaging of biomolecules with minimal label size.

cell biology↗

bioRxiv2018

Interpreting Diagnostic Histories into HIV Infection Time Estimates: Framework and Online Tool

BackgroundIt is frequently of epidemiological and/or clinical interest to estimate the date of HIV infection or time-since-infection of individuals. Yet, for over 15 years, the only widely-referenced infection dating algorithm that utilises diagnostic testing data to estimate time-since-infection has been the Fiebig staging system. This defines a number of stages of early HIV infection through various standard combinations of contemporaneous discordant diagnostic results, using tests of different sensitivity.\n\nObjectiveTo develop a new, more nuanced infection dating algorithm, we generalised the Fiebig approach to accommodate positive and negative diagnostic results generated on the same or different dates, and arbitrary current or future tests - as long as the test sensitivity is known. For this purpose, test sensitivity is conceptualised as the probability that a specimen will produce a positive result, expressed as a function of time since infection. This can be summarised as a median diagnostic delay parameter, together with a measure of inter-subject variability.\n\nMethodsThe present work outlines the analytical framework for infection date estimation using subject-level diagnostic testing histories, and data on test sensitivity. We introduce a publicly-available online HIV infection dating tool that implements this estimation method, bringing together 1) curatorship of HIV test performance data, and 2) infection date estimation functionality, to calculate plausible intervals within which infection likely became detectable for each individual. The midpoints of these intervals are interpreted as infection time point estimates and referred to as Estimated Dates of Detectable Infection (EDDIs).\n\nResultsIn many settings, including most research studies, detailed diagnostic testing data are routinely recorded, and can provide reasonably precise estimates of the timing of HIV infection. We present a simple logic to the interpretation of diagnostic testing histories into infection time estimates, either as a point estimate (EDDI) or an interval (earliest plausible to latest plausible dates of detectable infection), along with a publicly-accessible online tool that supports wide application of this logic.\n\nConclusionsThis tool, available at https://tools.incidence-estimation.org/idt/, is readily updatable as test technology evolves, given the simple architecture of the system and its nature as an open source project.

epidemiology↗

bioRxiv2017

Fine-mapping of genetic loci driving spontaneous clearance of hepatitis C virus infection

Approximately three quarters of acute HCV infections evolve to a chronic state, while one quarter are spontaneously cleared. Genetic predispositions strongly contribute to the development of chronicity. We have conducted a genome-wide association study to identify genomic variants underlying HCV spontaneous clearance using Immunochip in European and African ancestries. We confirmed two previously reported significant associations, in the IL28B/IFNL41,2 and MHC regions, with spontaneous clearance in the European population. We further fine-mapped the MHC association to a region of about 50 kilo base pairs, down from 1 mega base pairs in the previous study. Additional analyses suggested that the association in the MHC locus might be significantly stronger for virus subtype 1a than 1b, suggesting that viral subtype may have influenced the genetic mechanism underlying the clearance of HCV.

immunology↗