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Fine-mapping to plausible causal variation may be more effective in multi-ancestry cohorts, particularly in the MHC, which has population-specific structure. To enable such studies, we constructed a large ( n  = 21,546) HLA reference panel spanning five global populations based on whole-genome sequences. Despite population-specific long-range haplotypes, we demonstrated accurate imputation at G-group resolution (94.2%, 93.7%, 97.8% and 93.7% in admixed African (AA), East Asian (EAS), European (EUR) and Latino (LAT) populations). Applying HLA imputation to genome-wide association study data for HIV-1 viral load in three populations (EUR, AA and LAT), we obviated effects of previously reported associations from population-specific HIV studies and discovered a novel association at position 156 in HLA-B. We pinpointed the MHC association to three amino acid positions (97, 67 and 156) marking three consecutive pockets (C, B and D) within the HLA-B peptide-binding groove, explaining 12.9% of trait variance. A high-resolution reference panel based on whole-genome sequencing data enables accurate imputation of HLA alleles across diverse populations and fine-mapping of HLA association signals for HIV-1 host response.

Angiotensin-converting enzyme 2 (ACE2) and accessory proteases (TMPRSS2 and CTSL) are needed for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cellular entry, and their expression may shed light on viral tropism and impact across the body. We assessed the cell-type-specific expression of ACE2 , TMPRSS2 and CTSL across 107 single-cell RNA-sequencing studies from different tissues. ACE2 , TMPRSS2 and CTSL are coexpressed in specific subsets of respiratory epithelial cells in the nasal passages, airways and alveoli, and in cells from other organs associated with coronavirus disease 2019 (COVID-19) transmission or pathology. We performed a meta-analysis of 31 lung single-cell RNA-sequencing studies with 1,320,896 cells from 377 nasal, airway and lung parenchyma samples from 228 individuals. This revealed cell-type-specific associations of age, sex and smoking with expression levels of ACE2 , TMPRSS2 and CTSL . Expression of entry factors increased with age and in males, including in airway secretory cells and alveolar type 2 cells. Expression programs shared by ACE2 + TMPRSS2 + cells in nasal, lung and gut tissues included genes that may mediate viral entry, key immune functions and epithelial–macrophage cross-talk, such as genes involved in the interleukin-6, interleukin-1, tumor necrosis factor and complement pathways. Cell-type-specific expression patterns may contribute to the pathogenesis of COVID-19, and our work highlights putative molecular pathways for therapeutic intervention. An integrated analysis of over 100 single-cell and single-nucleus transcriptomics studies illustrates severe acute respiratory syndrome coronavirus 2 viral entry gene coexpression patterns across different human tissues, and shows association of age, smoking status and sex with viral entry gene expression in respiratory cell populations.

The association between gene polymorphisms and plasma virus load at the set point (SP-PVL) was investigated in Mauritian macaques inoculated with SIV. Among 44 macaques inoculated with 50 AID50, six individuals were selected: three with SP-PVL among the highest and three with SP-PVL among the lowest. The exons of 390 candidate genes of these six animals were sequenced. Twelve non-synonymous single nucleotide polymorphisms (NS-SNPs) lying in nine genes potentially associated with PVL were genotyped in 23 animals. Three NS-SNPs with probabilities of association with PVL less than 0.05 were genotyped in a total of 44 animals. One NS-SNP lying in exon 1 of the IL37 gene displayed a significant association ( p  = 3.33 × 10 −4 ) and a strong odds ratio (19.52). Multiple linear regression modeling revealed three significant predictors of SP-PVL, including the IL37 exon 1 NS-SNP ( p  = 0.0004) and the MHC Class IB haplotypes M2 ( p  = 0.0007) and M6 ( p  = 0.0013). These three factors in conjunction explained 48% of the PVL variance ( p  = 4.8 × 10 −6 ). The potential role of IL37 in the control of SIV infection is discussed.

Chronic hepatitis B virus (HBV) infection is a major cause of liver disease and cancer worldwide for which there are no curative therapies. The major challenge in curing infection is eradicating or silencing the covalent closed circular DNA (cccDNA) form of the viral genome. The circadian factors BMAL1/CLOCK and REV-ERB are master regulators of the liver transcriptome and yet their role in HBV replication is unknown. We establish a circadian cycling liver cell-model and demonstrate that REV-ERB directly regulates NTCP-dependent hepatitis B and delta virus particle entry. Importantly, we show that pharmacological activation of REV-ERB inhibits HBV infection in vitro and in human liver chimeric mice. We uncover a role for BMAL1 to bind HBV genomes and increase viral promoter activity. Pharmacological inhibition of BMAL1 through REV-ERB ligands reduces pre-genomic RNA and de novo particle secretion. The presence of conserved E-box motifs among members of the Hepadnaviridae family highlight an evolutionarily conserved role for BMAL1 in regulating this family of small DNA viruses. The circadian factors BMAL1/CLOCK and REV-ERB are master regulators of the human liver transcriptome but their role in hepatitis B virus infection is largely unknown. Here, Zhuang et al. show that REV-ERB regulates hepatitis B virus entry and BMAL1 directly binds HBV DNA and activates viral genome transcription.

Ali Gharavi and colleagues report a genome-wide association analysis of IgA nephropathy in over 20,000 individuals of European and East Asian ancestry. They identify genome-wide significant signals at three new loci near VAV3 , CARD9 and ITGAM - ITGAX and correlations between genetic risk and pathogen diversity. We performed a genome-wide association study (GWAS) of IgA nephropathy (IgAN), the most common form of glomerulonephritis, with discovery and follow-up in 20,612 individuals of European and East Asian ancestry. We identified six new genome-wide significant associations, four in ITGAM - ITGAX , VAV3 and CARD9 and two new independent signals at HLA-DQB1 and DEFA . We replicated the nine previously reported signals, including known SNPs in the HLA-DQB1 and DEFA loci. The cumulative burden of risk alleles is strongly associated with age at disease onset. Most loci are either directly associated with risk of inflammatory bowel disease (IBD) or maintenance of the intestinal epithelial barrier and response to mucosal pathogens. The geospatial distribution of risk alleles is highly suggestive of multi-locus adaptation, and genetic risk correlates strongly with variation in local pathogens, particularly helminth diversity, suggesting a possible role for host–intestinal pathogen interactions in shaping the genetic landscape of IgAN.

The impact of variation in host genetics on replication of human immunodeficiency virus type 1 (HIV-1) in demographically diverse populations remains uncertain. In the current study, we performed a genome-wide screen for associations of single-nucleotide polymorphisms (SNPs) to viral load (VL) in antiretroviral therapy–naive participants (n = 2440) with varying demographics from the Strategic Timing of AntiRetroviral Treatment (START) trial. Associations were assessed using genotypic data generated by a customized SNP array, imputed HLA alleles, and multiple linear regression. Genome-wide significant associations between SNPs and VL were observed in the major histocompatibility complex class I region (MHC I), with effect sizes ranging between 0.14 and 0.39 log10 VL (copies/mL). Supporting the SNP findings, we identified several HLA alleles significantly associated with VL, extending prior observations that the (MHC I) is a major host determinant of HIV-1 control with shared genetic variants across diverse populations and underscoring the limitations of genome-wide association studies as being merely a screening tool.

Many genes of large double-stranded DNA viruses have a cellular origin, suggesting that host-to-virus horizontal transfer (HT) of DNA is recurrent. Yet, the frequency of these transfers has never been assessed in viral populations. Here we used ultra-deep DNA sequencing of 21 baculovirus populations extracted from two moth species to show that a large diversity of moth DNA sequences (n = 86) can integrate into viral genomes during the course of a viral infection. The majority of the 86 different moth DNA sequences are transposable elements (TEs, n = 69) belonging to 10 superfamilies of DNA transposons and three superfamilies of retrotransposons. The remaining 17 sequences are moth sequences of unknown nature. In addition to bona fide DNA transposition, we uncover microhomology-mediated recombination as a mechanism explaining integration of moth sequences into viral genomes. Many sequences integrated multiple times at multiple positions along the viral genome. We detected a total of 27,504 insertions of moth sequences in the 21 viral populations and we calculate that on average, 4.8% of viruses harbor at least one moth sequence in these populations. Despite this substantial proportion, no insertion of moth DNA was maintained in any viral population after 10 successive infection cycles. Hence, there is a constant turnover of host DNA inserted into viral genomes each time the virus infects a moth. Finally, we found that at least 21 of the moth TEs integrated into viral genomes underwent repeated horizontal transfers between various insect species, including some lepidopterans susceptible to baculoviruses. Our results identify host DNA influx as a potent source of genetic diversity in viral populations. They also support a role for baculoviruses as vectors of DNA HT between insects, and call for an evaluation of possible gene or TE spread when using viruses as biopesticides or gene delivery vectors.

Neisseria meningitidis is a major cause of meningitis and septicaemia. A MenB vaccine (4CMenB) was licensed by the European Medicines Agency in January 2013. Here we describe the blood transcriptome and proteome following infant immunisations with or without concomitant 4CMenB, to gain insight into the molecular mechanisms underlying post‐vaccination reactogenicity and immunogenicity. Infants were randomised to receive control immunisations (PCV13 and DTaP‐IPV‐Hib) with or without 4CMenB at 2 and 4 months of age. Blood gene expression and plasma proteins were measured prior to, then 4 h, 24 h, 3 days or 7 days post‐vaccination. 4CMenB vaccination was associated with increased expression of ENTPD7 and increased concentrations of 4 plasma proteins: CRP, G‐CSF, IL‐1RA and IL‐6. Post‐vaccination fever was associated with increased expression of SELL , involved in neutrophil recruitment. A murine model dissecting the vaccine components found the concomitant regimen to be associated with increased gene perturbation compared with 4CMenB vaccine alone with enhancement of pathways such as interleukin‐3, ‐5 and GM‐CSF signalling. Finally, we present transcriptomic profiles predictive of immunological and febrile responses following 4CMenB vaccine. SYNOPSIS A randomised clinical trial evaluates transcriptomic and proteomic profiles following infant concomitant 4CMenB vaccination, compared with control vaccines alone. A novel framework is provided for both understanding and predicting vaccine immunogenicity and reactogenicity. 4CMenB vaccination is associated with a distinct gene expression and plasma protein signature. Post‐vaccination fever is associated with increased expression of SELL, involved in neutrophil recruitment. Transcriptomic profiles predictive of immunological and febrile responses following 4CMenB vaccine are presented. Graphical Abstract A randomised clinical trial evaluates transcriptomic and proteomic profiles following infant concomitant 4CMenB vaccination, compared with control vaccines alone. A novel framework is provided for both understanding and predicting vaccine immunogenicity and reactogenicity.

It is assumed that intracellular pathogenic bacteria have to cope with DNA alkylating stress within host cells. Here we use single-cell reporter systems to show that the pathogen Brucella abortus does encounter alkylating stress during the first hours of macrophage infection. Genes encoding direct repair and base-excision repair pathways are required by B. abortus to face this stress in vitro and in a mouse infection model. Among these genes, ogt is found to be under the control of the conserved cell-cycle transcription factor GcrA. Our results highlight that the control of DNA repair in B. abortus displays distinct features that are not present in model organisms such as Escherichia coli . It is assumed that intracellular pathogenic bacteria must cope with DNA alkylating stress within host cells. Here, Poncin et al. show that the pathogen Brucella abortus does encounter alkylating stress within macrophages, and shed light into the pathways required for DNA repair in this organism.

Abstract Rationale Human rhinovirus infections cause colds and trigger exacerbations of lower airway diseases. Objectives To define changes in gene expression profiles during in vivo rhinovirus infections. Methods Nasal epithelial scrapings were obtained before and during experimental rhinovirus infection, and gene expression was evaluated by microarray. Naturally acquired rhinovirus infections, cultured human epithelial cells, and short interfering RNA knockdown were used to further evaluate the role of viperin in rhinovirus infections. Measurements and Main Results Symptom scores and viral titers were measured in subjects inoculated with rhinovirus or sham control, and changes in gene expression were assessed 8 and 48 hours after inoculation. Real-time reverse transcription-polymerase chain reaction for viperin and rhinoviruses was used in naturally acquired infections, and viperin mRNA levels and viral titers were measured in cultured cells. Rhinovirus-induced changes in gene expression were not observed 8 hours after viral infection, but 11,887 gene transcripts were significantly altered in scrapings obtained 2 days postinoculation. Major groups of up-regulated genes included chemokines, signaling molecules, interferon-responsive genes, and antivirals. Viperin expression was further examined and also was increased in naturally acquired rhinovirus infections, as well as in cultured human epithelial cells infected with intact, but not replication-deficient, rhinovirus. Knockdown of viperin with short interfering RNA increased rhinovirus replication in infected epithelial cells. Conclusions Rhinovirus infection significantly alters the expression of many genes associated with the immune response, including chemokines and antivirals. The data obtained provide insights into the host response to rhinovirus infection and identify potential novel targets for further evaluation.