Below is a sampling of scholarly works published by center members from across different areas of investigation in June, 2020.
TBL1XR1 Mutations Drive Extranodal Lymphoma by Inducing a Pro-Tumorigenic Memory Fate
Venturutti, Leandro, et al. “TBL1XR1 Mutations Drive Extranodal Lymphoma by Inducing a Pro-Tumorigenic Memory Fate.” Cell, vol. 182, no. 2, July 2020, pp. 297–316. EBSCOhost, doi:10.1016/j.cell.2020.05.049.
The most aggressive B cell lymphomas frequently manifest extranodal distribution and carry somatic mutations in the poorly characterized gene TBL1XR1. Here, we show that TBL1XR1 mutations skew the humoral immune response toward generating abnormal immature memory B cells (MB), while impairing plasma cell differentiation. At the molecular level, TBL1XR1 mutants co-opt SMRT/HDAC3 repressor complexes toward binding the MB cell transcription factor (TF) BACH2 at the expense of the germinal center (GC) TF BCL6, leading to pre-memory transcriptional reprogramming and cell-fate bias. Upon antigen recall, TBL1XR1 mutant MB cells fail to differentiate into plasma cells and instead preferentially reenter new GC reactions, providing evidence for a cyclic reentry lymphomagenesis mechanism. Ultimately, TBL1XR1 alterations lead to a striking extranodal immunoblastic lymphoma phenotype that mimics the human disease. Both human and murine lymphomas feature expanded MB-like cell populations, consistent with a MB-cell origin and delineating an unforeseen pathway for malignant transformation of the immune system.
Equine pegiviruses cause persistent infection of bone marrow and are not associated with hepatitis
Tomlinson, Joy E., et al. “Equine Pegiviruses Cause Persistent Infection of Bone Marrow and Are Not Associated with Hepatitis.” PLoS Pathogens, vol. 16, no. 7, July 2020, pp. 1–23. EBSCOhost, doi:10.1371/journal.ppat.1008677.
Pegiviruses frequently cause persistent infection (as defined by >6 months), but unlike most other Flaviviridae members, no apparent clinical disease. Human pegivirus (HPgV, previously GBV-C) is detectable in 1–4% of healthy individuals and another 5–13% are seropositive. Some evidence for infection of bone marrow and spleen exists. Equine pegivirus 1 (EPgV-1) is not linked to disease, whereas another pegivirus, Theiler’s disease-associated virus (TDAV), was identified in an outbreak of acute serum hepatitis (Theiler’s disease) in horses. Although no subsequent reports link TDAV to disease, any association with hepatitis has not been formally examined. Here, we characterized EPgV-1 and TDAV tropism, sequence diversity, persistence and association with liver disease in horses. Among more than 20 tissue types, we consistently detected high viral loads only in serum, bone marrow and spleen, and viral RNA replication was consistently identified in bone marrow. PBMCs and lymph nodes, but not liver, were sporadically positive. To exclude potential effects of co-infecting agents in experimental infections, we constructed full-length consensus cDNA clones; this was enabled by determination of the complete viral genomes, including a novel TDAV 3′ terminus. Clone derived RNA transcripts were used for direct intrasplenic inoculation of healthy horses. This led to productive infection detectable from week 2–3 and persisting beyond the 28 weeks of study. We did not observe any clinical signs of illness or elevation of circulating liver enzymes. The polyprotein consensus sequences did not change, suggesting that both clones were fully functional. To our knowledge, this is the first successful extrahepatic viral RNA launch and the first robust reverse genetics system for a pegivirus. In conclusion, equine pegiviruses are bone marrow tropic, cause persistent infection in horses, and are not associated with hepatitis. Based on these findings, it may be appropriate to rename the group of TDAV and related viruses as EPgV-2. Author summary: Transmissible hepatitis in horses (Theiler’s disease) has been known for 100 years without knowledge of causative infectious agents. Recently, two novel equine pegiviruses (EPgV) were discovered. Whereas EPgV-1 was not associated to disease, the other was identified in an outbreak of acute serum hepatitis and therefore named Theiler’s disease-associated virus (TDAV). This finding was surprising since human and monkey pegiviruses typically cause long-term infection without associated clinical disease. Whereas no subsequent reports link TDAV to disease, the original association to hepatitis has not been formally examined. Here, we studied EPgV-1 and TDAV and found that their natural history of infection in horses were remarkably similar. Examination of various tissues identified the bone marrow as the primary site of replication for both viruses with no evidence of replication in the liver. To exclude potential effects of other infectious agents, we developed molecular full-length clones for EPgV-1 and TDAV and were able to initiate infection in horses using derived synthetic viral genetic material. This demonstrated long-term infection, but no association with hepatitis. These findings call into question the connection between TDAV, liver infection, and hepatitis in horses
Gerlinde Van de Walle
Modulating microbiome metabolites in vivo
Guo, Chun-Jun. “Modulating Microbiome Metabolites in Vivo.” Science (New York, N.Y.), vol. 369, no. 6500, July 2020, p. 153. EBSCOhost, doi:10.1126/science.abc5620.
Decades of microbiome studies, using a combination of multiomics approaches, have revealed strong associations between microbiota and human health. The next step is to identify the causal molecular mechanisms behind this association: Which microbes, genes, and their metabolites, if any, are responsible for a host phenotype? And if these molecules do affect us, how can we modulate their concentrations in the host to promote gut health?
Human Endogenous Retrovirus K in Cancer: A Potential Biomarker and Immunotherapeutic Target
Curty, Gislaine, et al. “Human Endogenous Retrovirus K in Cancer: A Potential Biomarker and Immunotherapeutic Target.” VIRUSES-BASEL, vol. 12, no. 7. EBSCOhost, doi:10.3390/v12070726.
In diseases where epigenetic mechanisms are changed, such as cancer, many genes show altered gene expression and inhibited genes become activated. Human endogenous retrovirus type K (HERV-K) expression is usually inhibited in normal cells from healthy adults. In tumor cells, however, HERV-K mRNA expression has been frequently documented to increase. Importantly, HERV-K-derived proteins can act as tumor-specific antigens, a class of neoantigens, and induce immune responses in different types of cancer. In this review, we describe the function of the HERV-K HML-2 subtype in carcinogenesis as biomarkers, and their potential as targets for cancer immunotherapy.
Going back in time for an antibody to fight COVID-19
Whittaker, Gary R., and Susan Daniel. “Going Back in Time for an Antibody to Fight COVID-19.” Nature: International Weekly Journal of Science, vol. 583, no. 7815, 2020, p. 203. EBSCOhost, doi:10.1038/d41586-020-01816-5.
Efforts are intensifying to try to harness antibodies as a therapy for COVID-19. A study reveals the insights that can be gained from antibodies made by a person who had a coronavirus infection that caused the disease SARS.
Microbial tryptophan metabolites regulate gut barrier function via the aryl hydrocarbon receptor|
Scott, Samantha A., et al. “Microbial Tryptophan Metabolites Regulate Gut Barrier Function via the Aryl Hydrocarbon Receptor.” Proceedings of the National Academy of Sciences of the United States, no. 32, 2020, p. 19376. EBSCOhost, doi:10.1073/pnas.2000047117.
Inflammatory bowel diseases (IBDs), including Crohn’s disease and ulcerative colitis, are associated with dysbiosis of the gut microbiome. Emerging evidence suggests that small-molecule metabolites derived from bacterial breakdown of a variety of dietary nutrients confer a wide array of host benefits, including amelioration of inflammation in IBDs. Yet, in many cases, the molecular pathways targeted by these molecules remain unknown. Here, we describe roles for three metabolites—indole-3-ethanol, indole-3-pyruvate, and indole-3-aldehyde—which are derived from gut bacterial metabolism of the essential amino acid tryptophan, in regulating intestinal barrier function. We determined that these metabolites protect against increased gut permeability associated with a mouse model of colitis by maintaining the integrity of the apical junctional complex and its associated actin regulatory proteins, including myosin IIA and ezrin, and that these effects are dependent on the aryl hydrocarbon receptor. Our studies provide a deeper understanding of how gut microbial metabolites affect host defense mechanisms and identify candidate pathways for prophylactic and therapeutic treatments for IBDs.
Immunoprophylactic and immunotherapeutic control of hormone receptor-positive breast cancer
Buqué, Aitziber, et al. “Immunoprophylactic and Immunotherapeutic Control of Hormone Receptor-Positive Breast Cancer.” Nature Communications, vol. 11, no. 1, 2020. EBSCOhost, doi:10.1038/s41467-020-17644-0.
Hormone receptor (HR)+ breast cancer (BC) causes most BC-related deaths, calling for improved therapeutic approaches. Despite expectations, immune checkpoint blockers (ICBs) are poorly active in patients with HR+ BC, in part reflecting the lack of preclinical models that recapitulate disease progression in immunocompetent hosts. We demonstrate that mammary tumors driven by medroxyprogesterone acetate (M) and 7,12-dimethylbenz[a]anthracene (D) recapitulate several key features of human luminal B HR+HER2− BC, including limited immune infiltration and poor sensitivity to ICBs. M/D-driven oncogenesis is accelerated by immune defects, demonstrating that M/D-driven tumors are under immunosurveillance. Safe nutritional measures including nicotinamide (NAM) supplementation efficiently delay M/D-driven oncogenesis by reactivating immunosurveillance. NAM also mediates immunotherapeutic effects against established M/D-driven and transplantable BC, largely reflecting increased type I interferon secretion by malignant cells and direct stimulation of immune effector cells. Our findings identify NAM as a potential strategy for the prevention and treatment of HR+ BC.
Lorenzo Galluzzi, Olivier Elemento
A team of scientists from Weill Cornell Medicine and Texas A&M University has identified a tuberculosis (TB) protein that future drugs might be able to target, with minimal side-effects compared to current treatments—potentially a critical discovery given the global public health crisis of drug-resistant TB.
Susan Daniel and Gary Whittaker – along with numerous other colleagues across the university’s colleges and campuses, and a working group of core laboratories – have been collaborating to better understand the virus at the center of this global pandemic, with the aim of treatment and containment.
Below is a sampling of scholarly works published by center members from across different areas of investigation in June, 2020.
Nutritional assessment among adult patients with suspected or confirmed active tuberculosis disease in rural India
Yu, E. A, et al. “Nutritional Assessment among Adult Patients with Suspected or Confirmed Active Tuberculosis Disease in Rural India.” PLoS ONE, vol. 15, no. 5. EBSCOhost, doi:10.1371/journal.pone.0233306. Accessed 22 Sept. 2020.
Our study goal was to evaluate a set of nutritional indicators among adults with confirmed or suspected active tuberculosis disease in southern India, given the limited literature on this topic. Study objectives were to assess the: I) double burden of malnutrition at individual and population levels; II) relative performance of anthropometric indicators (body mass index, waist circumference) in diabetes screening; and III) associations between vitamin D and metabolic abnormalities. Among participants, 91.7% had ≥ 1 malnutrition indicator; 34.6% had both undernutrition and overnutrition indicators. Despite the fact that >80% of participants would be considered low-risk in diabetes screening based on low body mass index and waist circumference, approximately one-third had elevated glycated hemoglobin (≥ 5.7%). The lowest quintile of serum 25-hydroxyvitamin D was associated with an increased risk of glycated hemoglobin ≥ 5.7% (adjusted risk ratio 1.61 [95% CI 1.02, 2.56]) compared to the other quintiles, adjusting for age and trunk fat. Malnutrition and diabetes were prevalent in this patient population; since both can predict poor prognosis of active tuberculosis disease, including treatment outcomes and drug resistance, this emphasizes the importance of dual screening and management of under- and overnutrition-related indicators among patients with suspected or active tuberculosis disease. Further studies are needed to determine clinical implications of vitamin D as a potential modifiable risk factor in metabolic abnormalities, and whether population-specific body mass index and waist circumference cut-offs improve diabetes screening.
Demographic and genetic factors influence the abundance of infiltrating immune cells in human tissues
Marderstein, A. R., et al. “Demographic and Genetic Factors Influence the Abundance of Infiltrating Immune Cells in Human Tissues.” Nature Communications, vol. 11, no. 1. EBSCOhost, doi:10.1038/s41467-020-16097-9. Accessed 22 Sept. 2020.
Despite infiltrating immune cells having an essential function in human disease and patients’ responses to treatments, mechanisms influencing variability in infiltration patterns remain unclear. Here, using bulk RNA-seq data from 46 tissues in the Genotype-Tissue Expression project, we apply cell-type deconvolution algorithms to evaluate the immune landscape across the healthy human body. We discover that 49 of 189 infiltration-related phenotypes are associated with either age or sex (FDR < 0.1). Genetic analyses further show that 31 infiltration-related phenotypes have genome-wide significant associations (iQTLs) (P < 5.0 × 10−8), with a significant enrichment of same-tissue expression quantitative trait loci in suggested iQTLs (P < 10−5). Furthermore, we find an association between helper T cell content in thyroid tissue and a COMMD3/DNAJC1 regulatory variant (P = 7.5 × 10−10), which is associated with thyroiditis in other cohorts. Together, our results identify key factors influencing inter-individual variability of immune infiltration, to provide insights on potential therapeutic targets.
Identification of Distinct Heterogenic Subtypes and Molecular Signatures Associated with African Ancestry in Triple Negative Breast Cancer Using Quantified Genetic Ancestry Models in Admixed Race Populations
Davis, M., et al. “Identification of Distinct Heterogenic Subtypes and Molecular Signatures Associated with African Ancestry in Triple Negative Breast Cancer Using Quantified Genetic Ancestry Models in Admixed Race Populations.” Cancers, vol. 12, no. 5. EBSCOhost, doi:10.3390/cancers12051220. Accessed 22 Sept. 2020.
Triple negative breast cancers (TNBCs) are molecularly heterogeneous, and the link between their aggressiveness with African ancestry is not established. We investigated primary TNBCs for gene expression among self-reported race (SRR) groups of African American (AA, n = 42) and European American (EA, n = 33) women. RNA sequencing data were analyzed to measure changes in genome-wide expression, and we utilized logistic regressions to identify ancestry-associated gene expression signatures. Using SNVs identified from our RNA sequencing data, global ancestry was estimated. We identified 156 African ancestry-associated genes and found that, compared to SRR, quantitative genetic analysis was a more robust method to identify racial/ethnic-specific genes that were differentially expressed. A subset of African ancestry-specific genes that were upregulated in TNBCs of our AA patients were validated in TCGA data. In AA patients, there was a higher incidence of basal-like two tumors and altered TP53, NFB1, and AKT pathways. The distinct distribution of TNBC subtypes and altered oncologic pathways show that the ethnic variations in TNBCs are driven by shared genetic ancestry. Thus, to appreciate the molecular diversity of TNBCs, tumors from patients of various ancestral origins should be evaluated.
Building a T cell compartment: how immune cell development shapes function
Davenport, Miles P., et al. “Building a T Cell Compartment: How Immune Cell Development Shapes Function.” Nature Reviews Immunology, vol. 20, no. 8, 2020, p. 499. EBSCOhost, doi:10.1038/s41577-020-0332-3.
We are just beginning to understand the diversity of the peripheral T cell compartment, which arises from the specialization of different T cell subsets and the plasticity of individual naive T cells to adopt different fates. Although the progeny of a single T cell can differentiate into many phenotypes following infection, individual T cells are biased towards particular phenotypes. These biases are typically ascribed to random factors that occur during and after antigenic stimulation. However, the T cell compartment does not remain static with age, and shifting immune challenges during ontogeny give rise to T cells with distinct functional properties. Here, we argue that the developmental history of naive T cells creates a ‘hidden layer’ of diversity that persists into adulthood. Insight into this diversity can provide a new perspective on immunity and immunotherapy across the lifespan.
Coronavirus membrane fusion mechanism offers a potential target for antiviral development
Tang, Tiffany, et al. “Coronavirus Membrane Fusion Mechanism Offers a Potential Target for Antiviral Development.” Antiviral Research, vol. 178, June 2020. EBSCOhost, doi:10.1016/j.antiviral.2020.104792.
The coronavirus disease 2019 (COVID-19) pandemic has focused attention on the need to develop effective therapies against the causative agent, SARS-CoV-2, and also against other pathogenic coronaviruses (CoV) that have emerged in the past or might appear in future. Researchers are therefore focusing on steps in the CoV replication cycle that may be vulnerable to inhibition by broad-spectrum or specific antiviral agents. The conserved nature of the fusion domain and mechanism across the CoV family make it a valuable target to elucidate and develop pan-CoV therapeutics. In this article, we review the role of the CoV spike protein in mediating fusion of the viral and host cell membranes, summarizing the results of research on SARS-CoV, MERS-CoV, and recent peer-reviewed studies of SARS-CoV-2, and suggest that the fusion mechanism be investigated as a potential antiviral target. We also provide a supplemental file containing background information on the biology, epidemiology, and clinical features of all human-infecting coronaviruses, along with a phylogenetic tree of these coronaviruses.
The Cornell Rapid Research Response SARS-CoV-2 Seed Grant program – funded through the Office of the Vice Provost for Research, the Center for Vertebrate Genomics, the Center for Immunology and the Office of Academic Integration – is now accepting proposals on a rolling basis.
Gary Whittaker, professor of virology in the College of Veterinary Medicine, is senior author of “Phylogenetic Analysis and Structural Modeling of SARS-CoV-2 Spike Protein Reveals an Evolutionary Distinct and Proteolytically Sensitive Activation Loop,” which published April 19 in the Journal of Molecular Biology. The study of the structure of SARS-CoV-2, the virus that causes COVID-19, reveals a unique feature that could explain why it is so transmissible between people.
A class of immune cells push themselves into an inflammatory state by producing large quantities of a serotonin-making enzyme, according to a study in mice led by member scientists at Weill Cornell Medicine. The study, published March 10 in Immunity, found that the inflammatory and infection-fighting abilities of the cells, called type 2 innate lymphoid cells (ILC2s), are much impaired without the enzyme. The finding suggests possibilities for new treatments targeting ILC2s, which have been linked to asthma and other allergic disorders, to suppress their activation in inflammatory disorders.