While mRNA vaccines are administrated worldwide in an effort to contain the COVID-19 pandemic, the heterogeneity of the humoral immune response they induce at the population scale remains unclear. ...Here, in a prospective, longitudinal, cohort-study, including 1245 hospital care workers and 146 nursing home residents scheduled for BNT162b2 vaccination, together covering adult ages from 19 to 99 years, we analyse seroconversion to SARS-CoV-2 spike protein and amount of spike-specific IgG, IgM and IgA before vaccination, and 3-5 weeks after each dose. We show that immunogenicity after a single vaccine dose is biased to IgG, heterogeneous and reduced with increasing age. The second vaccine dose normalizes IgG seroconversion in all age strata. These findings indicate two dose mRNA vaccines is required to reach population scale humoral immunity. The results advocate for the interval between the two doses not to be extended, and for serological monitoring of elderly and immunosuppressed vaccinees.
Cachexia represents a leading cause of morbidity and mortality in various cancers, chronic inflammation and infections. Understanding of the mechanisms that drive cachexia has remained limited, ...especially for infection-associated cachexia (IAC). In the present paper we describe a model of reversible cachexia in mice with chronic viral infection and identify an essential role for CD8
T cells in IAC. Cytokines linked to cancer-associated cachexia did not contribute to IAC. Instead, virus-specific CD8
T cells caused morphologic and molecular changes in the adipose tissue, which led to depletion of lipid stores. These changes occurred at a time point that preceded the peak of the CD8
T cell response and required T cell-intrinsic type I interferon signaling and antigen-specific priming. Our results link systemic antiviral immune responses to adipose-tissue remodeling and reveal an underappreciated role of CD8
T cells in IAC.
Methylation of cytosines is a prototypic epigenetic modification of the DNA. It has been implicated in various regulatory mechanisms across the animal kingdom and particularly in vertebrates. We ...mapped DNA methylation in 580 animal species (535 vertebrates, 45 invertebrates), resulting in 2443 genome-scale DNA methylation profiles of multiple organs. Bioinformatic analysis of this large dataset quantified the association of DNA methylation with the underlying genomic DNA sequence throughout vertebrate evolution. We observed a broadly conserved link with two major transitions-once in the first vertebrates and again with the emergence of reptiles. Cross-species comparisons focusing on individual organs supported a deeply conserved association of DNA methylation with tissue type, and cross-mapping analysis of DNA methylation at gene promoters revealed evolutionary changes for orthologous genes. In summary, this study establishes a large resource of vertebrate and invertebrate DNA methylomes, it showcases the power of reference-free epigenome analysis in species for which no reference genomes are available, and it contributes an epigenetic perspective to the study of vertebrate evolution.
Immune responses are tightly regulated to ensure efficient pathogen clearance while avoiding tissue damage. Here we report that Setdb2 was the only protein lysine methyltransferase induced during ...infection with influenza virus. Setdb2 expression depended on signaling via type I interferons, and Setdb2 repressed expression of the gene encoding the neutrophil attractant CXCL1 and other genes that are targets of the transcription factor NF-κB. This coincided with occupancy by Setdb2 at the Cxcl1 promoter, which in the absence of Setdb2 displayed diminished trimethylation of histone H3 Lys9 (H3K9me3). Mice with a hypomorphic gene-trap construct of Setdb2 exhibited increased infiltration of neutrophils during sterile lung inflammation and were less sensitive to bacterial superinfection after infection with influenza virus. This suggested that a Setdb2-mediated regulatory crosstalk between the type I interferons and NF-κB pathways represents an important mechanism for virus-induced susceptibility to bacterial superinfection.
The liver is a central regulator of metabolic homeostasis and serum metabolite levels. Hepatocytes are the functional units of the liver parenchyma and not only responsible for turnover of ...biomolecules but also act as central immune signaling platforms. Hepatotropic viruses infect liver tissue, resulting in inflammatory responses, tissue damage and hepatitis. Combining well-established in vitro and in vivo model systems with transcriptomic analyses, we show that type I interferon signaling initiates a robust antiviral immune response in hepatocytes. Strikingly, we also identify IFN-I as both, sufficient and necessary, to induce wide-spread metabolic reprogramming in hepatocytes. IFN-I specifically rewired tryptophan metabolism and induced hepatic tryptophan oxidation to kynurenine via Tdo2, correlating with altered concentrations of serum metabolites upon viral infection. Infected Tdo2-deficient animals displayed elevated serum levels of tryptophan and, unexpectedly, also vast increases in the downstream immune-suppressive metabolite kynurenine. Thus, Tdo2-deficiency did not result in altered serum homeostasis of the tryptophan to kynurenine ratio during infection, which seemed to be independent of hepatocyte-intrinsic compensation via the IDO-axis. These data highlight that inflammation-induced reprogramming of systemic tryptophan metabolism is tightly regulated in viral hepatitis.
RNA-dependent RNA polymerases (RdRps) play a key role in the life cycle of RNA viruses and impact their immunobiology. The arenavirus lymphocytic choriomeningitis virus (LCMV) strain Clone 13 ...provides a benchmark model for studying chronic infection. A major genetic determinant for its ability to persist maps to a single amino acid exchange in the viral L protein, which exhibits RdRp activity, yet its functional consequences remain elusive. To unravel the L protein interactions with the host proteome, we engineered infectious L protein-tagged LCMV virions by reverse genetics. A subsequent mass-spectrometric analysis of L protein pulldowns from infected human cells revealed a comprehensive network of interacting host proteins. The obtained LCMV L protein interactome was bioinformatically integrated with known host protein interactors of RdRps from other RNA viruses, emphasizing interconnected modules of human proteins. Functional characterization of selected interactors highlighted proviral (DDX3X) as well as antiviral (NKRF, TRIM21) host factors. To corroborate these findings, we infected Trim21-/- mice with LCMV and found impaired virus control in chronic infection. These results provide insights into the complex interactions of the arenavirus LCMV and other viral RdRps with the host proteome and contribute to a better molecular understanding of how chronic viruses interact with their host.
Patients on hemodialysis (HD) are at higher risk for COVID-19, overall are poor responders to vaccines, and were prioritized in the Portuguese vaccination campaign.
This work aimed at evaluating in ...HD patients the immunogenicity of BTN162b2 after the two doses induction phase, the persistence of specific antibodies along time, and factors predicting these outcomes.
We performed a prospective, 6-month long longitudinal cohort analysis of 156 HD patients scheduled to receive BTN162b2. ELISA quantified anti-spike IgG, IgM, and IgA levels in sera were collected every 3 weeks during the induction phase (t0 before vaccine; t1, d21 post first dose; and t2 d21 post second dose), and every 3-4 months during the waning phase (t3, d140, and t4, d180 post first dose). The age-matched control cohort was similarly analyzed from t0 to t2.
Upon exclusion of participants identified as previously exposed to SARS-CoV-2, seroconversion at t1 was lower in patients than controls (29 and 50%, respectively,
= 0.0014), while the second vaccine dose served as a boost in both cohorts (91 and 95% positivity, respectively, at t2,
= 0.2463). Lower response in patients than controls at t1 was a singularity of the participants ≤ 70 years (
= 2.01 × 10
), associated with immunosuppressive therapies (
= 0.013), but not with lack of responsiveness to hepatitis B. Anti-spike IgG, IgM, and IgA levels decreased at t3, with IgG levels further waning at t4 and resulting in >30% seronegativity. Anti-spike IgG levels at t1 and t4 were correlated (ρ = 0.65,
< 2.2 × 10
).
While most HD patients seroconvert upon 2 doses of BNT162b2 vaccination, anti-spike antibodies levels wane over the following 4 months, leading to early seroreversion in a sizeable fraction of the patients. These findings warrant close monitoring of COVID-19 infection in vaccinated HD patients, and advocate for further studies following reinforced vaccination schedules.
Infections induce complex host responses linked to antiviral defense, inflammation, and tissue damage and repair. We hypothesized that the liver, as a central metabolic hub, may orchestrate systemic ...metabolic changes during infection. We infected mice with chronic lymphocytic choriomeningitis virus (LCMV), performed RNA sequencing and proteomics of liver tissue, and integrated these data with serum metabolomics at different infection phases. Widespread reprogramming of liver metabolism occurred early after infection, correlating with type I interferon (IFN-I) responses. Viral infection induced metabolic alterations of the liver that depended on the interferon alpha/beta receptor (IFNAR1). Hepatocyte-intrinsic IFNAR1 repressed the transcription of metabolic genes, including Otc and Ass1, which encode urea cycle enzymes. This led to decreased arginine and increased ornithine concentrations in the circulation, resulting in suppressed virus-specific CD8+ T cell responses and ameliorated liver pathology. These findings establish IFN-I-induced modulation of hepatic metabolism and the urea cycle as an endogenous mechanism of immunoregulation.
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•Chronic viral infection causes long-term transcriptome and proteome changes in the liver•Hepatocyte-intrinsic type I interferon (IFN-I) signaling regulates hepatic metabolism•IFN-I signaling reprograms the urea cycle in hepatocytes and alters serum metabolites•Serum levels of arginine and ornithine modulate T cell responses and pathology
The liver is a central regulator of metabolism, but how infection-induced changes in liver metabolism affect immune responses and pathology remains enigmatic. Lercher et al. demonstrate that hepatocyte-intrinsic type I interferon (IFN-I) represses metabolism during chronic viral infection. Specifically, IFN-I disrupts the urea cycle in hepatocytes, altering serum arginine and ornithine levels, which dampen antiviral T cells responses and liver pathology.
Abstract
Transmissible cancer is a rare, but mechanistically not understood form of cancer that can directly spread between individuals. At least six species in the animal kingdom harbor clonal ...cancers that spread horizontally. These diseases include the fatal devil facial tumor disease (DFTD) in Tasmanian devils, a sexually transmitted sarcoma in dogs, and leukemia-like cancers in mollusks. DFTD is an allogeneic graft of Schwann cell origin, which is transmitted by direct transfer of cancer cells from one individual to another as a result of biting behavior. Two strains of DFTD, DFT1 and DFT2, emerged independently in the population of Tasmanian devils. It is essential to gain mechanistic understanding of horizontal cancers to understand how cancer cells escape host immune cells. We designed an integrative systems biology approach using primary biopsies, established Tasmanian devil tumor and control cell lines and mouse xenograft model. Specifically, we combined pharmacological drug screening, transcriptomics, epigenetics, proteomics and comparative pathology to unveil aberrant signaling pathways in DFTD. We found that DFT1 tumor cells express high levels of phosphorylated ERBB2 and ERBB3 tyrosine kinase receptor and they are exquisitely vulnerable to ERBB kinase inhibitors. Blockade of the hyperactive ERBB-STAT3 axis with ERBB inhibitor sapitinib or with the STAT3 inhibitor DR-1-55 led to recovery of MHC-I expression, suggesting that immune escape could be antagonized by blockade of hyperactive ERBB-STAT3 action. In contrary to DFT1, progression of DFT2 is known to be associated with PDGF receptor amplification. This proposed an attractive pharmacological approach of targeted inhibition of PDGFR by broad kinase inhibitor imatinib. We validated in xenograft mouse model that targeted inhibition of PDGFR results in the efficient reduction of tumor growth as well as restoration of MHC-I gene expression. In summary, we identified a critical role for hyperactive tyrosine kinase-STAT signaling whose pharmacological inhibition resulted in arrested growth and possible restoration of immune cell recognition. We validated that DFT2 displays a distinct oncogene mechanism than DFT1, but pharmacologic inhibition of hyperactive driver kinase pathway leads to similar restoration of MHC-I expression. This link between the hyperactive pathway and MHC-I-mediated tumor immunosurveillance in both DFTD strains provides mechanistic insights into horizontal transmissibility and suggests a strategy to save Tasmanian devils from extinction.
Citation Format: Anna Orlova, Lindsay Kosack, Alexandra M. Popa, Csilla Viczenczova, Alexander Lercher, Elvin D. de Araujo, Patrick Gunning, Richard Moriggl, Andreas Bergthaler. Restoration of tumor immunosurveillance in tasmanian devil facial tumor disease abstract. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5636.
The marsupial Tasmanian devil (Sarcophilus harrisii) faces extinction due to transmissible devil facial tumor disease (DFTD). To unveil the molecular underpinnings of this transmissible cancer, we ...combined pharmacological screens with an integrated systems-biology characterization. Sensitivity to inhibitors of ERBB tyrosine kinases correlated with their overexpression. Proteomic and DNA methylation analyses revealed tumor-specific signatures linked to the evolutionary conserved oncogenic STAT3. ERBB inhibition blocked phosphorylation of STAT3 and arrested cancer cells. Pharmacological blockade of ERBB or STAT3 prevented tumor growth in xenograft models and restored MHC class I expression. This link between the hyperactive ERBB-STAT3 axis and major histocompatibility complex class I-mediated tumor immunosurveillance provides mechanistic insights into horizontal transmissibility and puts forward a dual chemo-immunotherapeutic strategy to save Tasmanian devils from DFTD.
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•Tasmanian devil proteome and DNA methylome reveal modulated tumor environment•Identification of cancer-driving hyperactive ERBB-STAT3 axis as a druggable target•ERBB-STAT3-driven suppression of MHC class I genes may facilitate immune evasion•Successful pharmacological treatments of Tasmanian devil tumors in a xenograft model
Kosack et al. identify the ERBB-STAT3 signaling axis as a central molecular driver of Tasmanian devil transmissible facial tumors. Inhibition of ERBB or STAT3 prevents tumor growth in xenograft models and restores MHC class I expression, suggesting a chemo-immunotherapeutic strategy to save Tasmanian devils.
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