Research Highlights, June 2020

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.
Saurabh Mehta

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.
Olivier Elemento

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.
Melissa DavisOlivier Elemento

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.
 Brian Rudd

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.
Gary Whittaker