In this study, the Saeed lab discovered SARS-CoV-2 elements being identified by human T cells to initiate an immune attack against the virus. As a background, the human immune system has two arms: innate immunity and adaptive immunity. While innate immunity launches a quick, non-specific fight against the virus, adaptive immunity is slow and utilizes specific viral components to get activated and unleash severe attack on the virus. A distinctive feature of adaptive immunity is that it “remembers” the viral identity, and if encountered by the same virus in the future, sets in motion a quick and intense campaign to overpower the virus. The adaptive immunity can be further divided into two subgroups: B cell immunity (a.k.a. humoral immunity) and T cell immunity (a.k.a. cellular immunity). While B cell immunity acts by generating antibodies against the virus, T cell immunity employs specialized cells to destroy the virus-infected cells.
Although a number of studies have reported SARS-CoV-2 elements being recognized by human B cells to produce antibodies, there remained a paucity of knowledge regarding viral components being identified by human T cells, and this is despite the fact that the role of T cells in SARS-CoV-2 clearance has been increasingly recognized. To fill this knowledge gap, the Saeed lab collaborated with a research group at the Broad Institute of MIT and Harvard and performed mass spectrometry-based analysis of viral peptides (protein fragments) that have the ability to activate T cells. This led to the discovery of 37 peptides. Strikingly, eight of these peptides originated from the hidden, non-canonical SARS-CoV-2 proteins that are often overlooked by the scientists.
The team then performed a series of experiments in human and mice to test if the identified viral peptides were capable of activating T cells. Most of them indeed were. To scientists’ surprise, some peptides derived from the hidden viral proteins provoked the strongest immune response, highlighting an unexpected yet critical role of these proteins in virus biology. These findings will change the way scientists study the human immune responses to SARS-CoV-2 and will also inform the development of next-generation vaccines. Incorporation of viral components capable of invoking strong T cell responses is expected to produce a vaccine that is more effective and broadly protective against newly emerging SARS-CoV-2 variants.
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As of June 1, 2021 Dr. Valentina Perissi has replaced Dr. Caroline Apovian as Co- PI and Director of the Boston Nutrition Obesity Research Center (BNORC). This leadership change has been approved by the Center’s Executive Committee and NIH National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK). Dr. Valentina Perissi will co-lead the Center with Dr. Andy Greenberg.
The Boston Nutrition Obesity Research Center is funded by the NIH/NIDDK. BNORC is a consortium of institutions that includes Boston Medical Center, Boston University School of Medicine, Tufts University, Jean Mayer USDA Human Nutrition Research Center on Aging, the Harvard T.H. Chan School of Public Health, and Beth Israel Deaconess Medical Center. The Center’s Cores, Pilot and Feasibility Program and Enrichment programs promote inter- and multi-disciplinary research in nutrition and obesity. The Center’s Pilot and Feasibility Program has helped support many promising early career investigators who have gone on to exceptionally successful scientific careers.
Research News: New Research will Allow Convenient Investigation of Human Innate Immune Response to Viral Infections
New Research will Allow Convenient Investigation of Human Innate Immune Response to Viral Infections
(Boston)—Researchers from Boston University School of Medicine (BUSM) report the formation of human cells containing a green fluorescent protein or GFP (one of the most important proteins in biology and fluorescence imaging) genetically fused with two interferon stimulated genes (ISGs), namely Viperin and ISG15. This new creation makes these cells highly valuable reagents for reporting innate immune responses to viral infections, including those caused by coronaviruses.
These engineered cells, which turn green when treated with interferon, are highly novel because this is the first time a reporter gene (a gene that enables the detection or measurement of gene expression), such as GFP, has been inserted into endogenous loci of ISGs.
Viral infections cause human cells to sound a biochemical alarm via interferon signaling, leading to a high-level expression of ISGs. However, ISGs are very tightly regulated genes, because too much expression and an inability to later tamp down ISG levels can be just as detrimental to cellular health.
This overactive innate immune signaling leads to a ‘cytokine storm’ (when an infection triggers the immune system to flood your bloodstream with inflammatory proteins called cytokines) that distinguishes a mild case of virus infection from fully debilitating symptoms, an outcome all too prevalent in the COVID19 pandemic. “Better research tools for studying ISG regulation are still needed, not just now for coronavirus research but for many other viruses that our society will contend with,” explained co-corresponding author Nelson Lau, PhD, associate professor of biochemistry at BUSM.
In order to successfully tag human antiviral genes with GFP, the researchers first needed to produce a new methodology for creating a long DNA repair template for more efficient and authentic CRISPR-Cas9 genome editing in animal cells. They named his template methodology the BL3SSO (sounds like “blasso”) because it sets up the DNA for more accurate repair and for introduction of a fluorescent transgene like GFP into the site cut by Cas-9 during genome editing.
These findings are the result of a collaboration between the Lau lab and the lab of Mohsan Saeed, PhD, both faculty members in BUSM’s department of biochemistry and investigators at the BU National Emerging Infectious Diseases Laboratories (NEIDL).
These findings appear online in the journal G3 : Genes | Genomes | Genetics.
This work was supported by Brandeis University Sprout Grants, the Leir Foundation, a donation from M.H.Y. Lau, Boston University start-up funds, and the National Institutes of Health via R21HD088792, R01AG052465 and R01GM135215 to NCL. MS was supported by Boston University start-up funds.
Congratulations to graduate student Jarrod Moore of the Emili Lab, now a Kilachand Fellow in the Multicellular Design Program (MDP). Jarrod's research will focus on studying the pro-fibrotic cross-talk between cardiomyocytes and cardiac fibroblasts in a novel model for hypertrophic cardiomyopathy, a leading cause of sudden cardiac death in young adults. This research seeks to generate holistic molecular maps of these interactions, which will assist in discovering novel approaches for counteracting this irreversible scarring process and advancing cardiac research for these patients.
The Department of Biochemistry Henry I. Russek Achievement Day Awards Committee is pleased to announce this year’s award winners. Nathan Kingston [Dr. Xaralabos (Bob) Varelas’s lab] is the first prize winner, and Joseph Kern [Dr. Xaralabos (Bob) Varelas’s lab] is the second prize winner. Our congratulations go out to the winners as well as their advisor! We look forward to hearing about their work on Henry I. Russek Achievement Day; remember it’s this week (Thursday, May 6th and Friday, May 7th) so mark your calendars for the virtual events.
The keynote address will be delivered on Thursday May 6th at 9:20 AM by Dr. Daniel Haber, Director of the MGH Cancer Center, “Circulating Tumor Cells: Insights into Cancer Metastasis”. Please go to the following site for updated information and to register so as to get the Zoom link:
A recently published study from the Varelas laboratory has identified new mechanisms contributing to the development of precancer lesions in lung airways. Precancer lesions that arise in airways are associated with chronic lung damage, such as that induced by cigarette smoke, and such lesions are predisposed to transitioning into lung squamous cell carcinoma, a poorly treatable subtype of non-small cell lung cancers.
The study shows that disrupted epithelial polarity leads to airway epithelial stem cell expansion, resulting in pathologies that resemble human precancer. Aberrant epithelial polarity was induced by the conditional deletion of the polarity regulator Crumbs3, which the group showed leads to activation of the transcriptional regulators YAP and TAZ. The study showed that YAP/TAZ-regulated gene expression drives a gene expression program that stimulates epithelial plasticity and stem cell growth, and associates with the progression of precancer lesions in human patients. Through analysis of YAP/TAZ-regulated genes, an important role was uncovered for the growth factor Neuregulin-1, which is directly induced by YAP/TAZ and stimulates signaling via the ERBB-receptors. Notably, the study showed that inhibition of ERBB receptors was capably of preventing and treating precancer lesions in polarity-defective animals.
The study, which was published on April 26, 2021 in PNAS, offers new knowledge into the etiology of lung precancer pathology, and provides directions for identifying and intercepting lung squamous cell carcinoma at the earliest stages.
The Center for Biomedical Mass Spectrometry (CBMS) has been awarded a grant by the Massachusetts Life Science Center to advance the ability to characterize spike protein glycosylation as respiratory viruses evolve. The CBMS applies mass spectrometry methods to meet the emerging needs in biomedicine. As part of this award, CBMS has just installed a new Waters SELECT SERIES Cyclic IMS system. The Cyclic system represents a breakthrough technology that will facilitate rapid and accurate characterization of virus spike protein glycosylation to support virus surveillance and vaccine development.
Respiratory viruses including influenza and coronaviruses evolve rapidly as they circulate in the human population. These proteins are coated with a spike protein that recognizes receptors in host airway cells. Spike proteins are decorated by sugar molecules known as glycans. These glycans enhance the structures and functions of proteins, including the virus spike proteins. Researchers track the genetic sequences of viruses as they evolve. The genetic sequences do not predict the manner in which glycans alter the structure and function of virus spike proteins.
The Garcia-Marcos laboratory has discovered that heterotrimeric G-proteins, which are critical molecular switches in cellular communication processes, can trigger different responses in cells depending on the type of protein that activates them.
Heterotrimeric G-proteins are typically activated by G-protein-coupled receptors (GPCRs), which are the target for over one-third of drugs approved for use in the clinic. But G-proteins can also be activated by other proteins that are not GPCRs, a mechanism with important implications for human physiology and disease. The Garcia-Marcos laboratory has used an innovative approach to dissect and compare the consequences of G-protein stimulation by different activators, including GPCRs and various non-GPCR proteins. The approach leveraged a recently developed type of biosensors capable of detecting different forms of active G-proteins in living cells in real time. These were combined with engineered G-protein activator constructs that could be turned on at will with an exogenous synthetic chemical.
The main conclusion is that, contrary to previous beliefs, GPCR and non-GPCR activators elicit different forms of G-protein activation in cells. These findings have important implications in our understanding of pharmacologically actionable signaling hubs in cells, which could be leveraged to envision and design new therapeutic agents.
You can read the article here:
Garcia-Marcos M. Complementary biosensors reveal different G-protein signaling modes triggered by GPCRs and non-receptor activators. Elife. 2021 Mar 31;10:e65620. PMID: 33787494 https://pubmed.ncbi.nlm.nih.gov/33787494/
Robert Mercer, a Postdoctoral Associate in the Harris Lab, was recently awarded a Discovery Award research grant funded by the Department of Defense. This two-year, $200,000 grant is entitled “ Identification of Receptors for TAR DNA-binding Protein 43 (TDP-43) That Mediate Cellular Uptake and Neurotoxicity ”. This project aims to identify the cellular receptors of the pathological TDP-43 assemblies found in the brains of patients with Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Lobar Degeneration (FTLD), and Chronic Traumatic Encephalopathy (CTE). The identification of these receptors will provide novel therapeutic targets to combat these devastating and currently untreatable diseases.
Dr. Alla Grishok, Associate Professor of Biochemistry has been awarded a 2021 Shipley Prostate Cancer Research Pilot Grant Award. She will act as coordinator of a multi-center, multi-PI initiative involving Dr. Christopher Heaphy (Department of Medicine), Dr. Joshua Campbell (Department of Medicine), and Dr. Rachel Flynn (Department of Pharmacology and Experimental Therapeutics, GSI) across Boston Medical Center (BMC) Pathology department, Shipley Prostate Cancer Research Center, BU-BMC Cancer Center, and Genome Science Institute (GSI) at BUSM.
The goals of this pilot research are: "to (1) identify coding and non-coding genomic alterations that are associated with more aggressive disease in Black men with prostate cancer and to (2) establish a pipeline that will integrate the genomic data with other biomarker measurements, such as the presence of circulating tumor DNA or alterations in the gut microbiome, and with the overall clinical outcomes in a large cohort of men". The success of this project may lead to better predictions of the severity of the disease in individual men and to informed selection of the appropriate treatment options in the future.