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Arthropod-borne diseases account for 17% of all infectious illnesses, causing extensive morbidity and mortality worldwide. This Keystone Virtual Symposium will bring together panelists with complementary expertise in entomology, microbiology and immunology to have an inspiring debate about some of the most pressing and interdisciplinary issues related to vector-borne diseases. Five considerations will underpin this virtual discussion:

• deploy a joint set of concepts and pressing questions to promote mechanistic progress in vector-borne diseases
• elaborate on how skin immune cells and the microbiome contribute to immunity and disease in vector-borne illnesses
• examine the importance of new principles and technologies to decipher transkingdom interactions occurring at the interface
• elaborate about translational approaches to vector-borne diseases
• deliberate about mentoring the next generation of scientists and interdisciplinarity in science.

The roundtable will discuss:

Principles and Differences Among Arthropod-Borne Diseases
Are there unifying paradigms that can be applied to the spectrum of vector-borne diseases? Should we treat research in all arthropod vectors equally? What is the role of animal models in vector-borne diseases?

Skin and the Microbiome at the Interface of Disease and Immunity
What is the role of skin immune cells and the microbiome during arthropod blood feeding? How does the study of the microbiome and skin immunology enable a better understanding of vector-borne diseases? Which skin immune cells are essential to counteract and/or facilitate pathogen transmission?

Emerging Concepts and Technologies in Vector-Borne Diseases
How does one challenge the conventional thinking applied to vector-borne diseases? How does one act as a facilitator for the generation of new paradigms in the field? How do technologies change the landscape of research in vector-borne diseases?

The Interdisciplinary Nature of Vector-Borne Diseases
How do we break down silos among the entomology, microbiology and immunology communities? How should we train the next generation of scientists and promote interdisciplinary research? What are the best strategies to nurture interdisciplinary research for vector-borne diseases? Are there meeting venues and funding mechanisms that facilitate this type of mindset?

The panel will brainstorm ideas for subsequent meetings, including the joint Conferences on “Vector Biology: Emerging Concepts and Novel Technologies” and “Skin-Immune Crosstalk” on February 15-18, 2021 in Breckenridge, Colorado, USA.

#VKSarthropod

Video Previews

This ePanel, filmed during the Keystone Symposia Conference: The Malaria Endgame: Innovation in Therapeutics, Vector Control and Public Health Tools at Addis Ababa, Ethiopia, features field leaders Gordon Awandare, Lilian M. Ang’ang’o, Lemu Golassa and Fitsum G. Tadesse as they discuss the current state of the field, and future directions and challenges in the fight to eliminate malaria from endemic countries.

Topics will include:

• Current state of vaccines
• Impact of co-infections in Africa
• Genetically modified mosquitos—benefits, risks and community engagement challenges
• The disconnect between research and malaria control programs
• ...and more!

Panelists will conclude with their suggested “one innovation” to eliminate malaria. In addition, they will share insights into their career path and personal experiences fighting malaria infection, with tips for junior researchers aspiring to enter the field and make a difference against this global health threat.

Register now to watch on April 22, 2020 (and available on-demand thereafter) and submit your questions for our panelists! Selected questions will be answered after the event.

#VKSmalariaendgame

Video Previews

• Are patients with malaria at higher risk of contracting COVID-19, or at higher risk of experiencing severe symptoms? What are the dangers of co-infection?
• How do these compounded threats differentially impact certain at-risk populations or demographics, such as children, pregnant women, or the elderly? What public health measures might be taken to mitigate these impacts?
• The malaria drugs chloroquine and hydroxychloroquine have been suggested for treating COVID-19… what are the implications of this? Could patients being treated for malaria with these drugs be resistant to COVID-19 infection?
• What are the challenges in malaria endemic regions to balancing COVID-19 control with malaria control? What resources does the WHO provide to help countries balance these two agendas in order to devise and implement appropriate public health measures?
• What lessons did we learn from the Ebola outbreak in 2014 and 2015, that are being implemented today?
• How might COVID-19 affect critical WHO Global Malaria Program actions, like pilot studies of the RTS,S malaria vaccine, in sub-Saharan African countries?

In this Keynote Address, given on June 15, 2020 as part of the eSymposia “Vaccinology in the Age of Pandemics: Strategies Against COVID-19 & Other Global Threats,” Dr. Anthony Fauci outlines the latest vaccinology advances and approaches that have vastly accelerated the development of COVID-19 vaccines.

Dr. Fauci credits recent advances in technology for enabling this unprecedented rapid response, which in just the last few years have transformed vaccinology capabilities. These include:

• Rapid genetic sequencing of new pathogens
• Structure-based vaccine design and reverse vaccinology approaches
• New and diverse vaccine platforms combined with improved adjuvants
• Humanized animal models for vaccine testing

In addition, new preparedness strategies have accelerated vaccine development efforts. Since the early 2000s, researchers have been working preemptively on vaccines for emerging pathogens, and can now apply lesson learned from these efforts in COVID-19 vaccine design, development and testing. Meanwhile, preparation of clinical trial sites, manufacturing and other logistic considerations in the testing and deployment of a vaccine are critical to have ready prior to launch.

Ultimately, new partnerships between public and private sectors have enabled all of these pieces to come together at “warp speed” in the face of this new pandemic.

Explore more on the latest vaccinology advances and approaches from the eSymposia “Vaccinology in the Age of Pandemics: Strategies Against COVID-19 & Other Global Threats,” available on-demand through VKS:

Abstract Text

Mollie Huber1, Denise Drotar2, Helmut Hiller3, Maria Beery3, Paul Joseph3, Irina Kusmartseva3 , Stephan Speier2 , Todd Brusko1, Maigan Brusko1, Mark Atkinson3 , Edward Phelps4, and Clayton Mathews1

1Dept. of Pathology, University of Florida; 2Paul Langerhans Institute, Technische Universität Dresden; 3nPOD Laboratory, Dept. of Pathology, University of Florida; 4 J. Crayton Pruitt Family Dept. of Biomedical Engineering, University of Florida

Type 1 diabetes (T1D) results from the autoimmune destruction of pancreatic beta cells. Previously it has been difficult to study the islet microenvironment and corresponding islet-immune cell interactions in live, intact pancreatic tissue, particularly from human samples. The development and application of the slice methods allow for the in-depth study of T1D pathogenesis in the context of the genuine and live islet environment.

In these studies, mouse pancreas tissue slices were prepared from NOD-Rag1-/- and NOD-Rag1-/--AI4α/β TCR transgenic (AI4) mice. Due to the consistent development of T1D in this model, the effects of insulitis at various stages of disease progression on islet functionality and tissue condition can be observed. These observations were achieved through calcium flux recordings as well as immune cell staining and tracking performed using confocal microscopy. Furthermore, studies were conducted in live human pancreas tissue slices prepared from control donors, autoantibody-positive donors, and donors with recent-onset T1D. When CD3+ cells were stained in slices from an autoantibody positive donor, an islet was found with apparent focal insulitis. Using HLA-dextramer reagents we further identified autoreactive T cells within the insulitis. To our knowledge, these are the first ever images of live, endogenous human immune cells attacking insulin-producing beta cells in situ.

Through the application of the pancreatic slice model, the effects of insulitis on beta cell function, particularly at early stages of disease, can be studied in detail. T cells can be introduced in to live human pancreatic tissue slices and their interactions and functional impacts recorded. Differences in immune cell behavior can be studied in tissues from individuals at varying degrees of disease risk. Further studies using live pancreas slices will help to discern many of the processes and effects of islet-immune cell interactions.

Abstract:

Integration of human genetics and mutli-omics data implicates novel pathways in hydrocephalus

Andrew T. Hale¹, Lisa Bastarache², Diego M. Morales³, John C. Wellons III⁴, David D. Limbrick Jr.³, Steven J. Schiff,⁵ Eric R. Gamazon^6,7

¹Medical Scientist Training Program and ²Department of Bioinformatics, Vanderbilt University School of Medicine; ³Department of Neurological Surgery, St. Louis Children’s Hospital; ⁴Division of Pediatric Neurosurgery, Monroe Carell Jr. Children’s Hospital of Vanderbilt University; ⁵Center for Neural Engineering, Departments of Neurosurgery, Engineering Science and Mechanics, and Physics, Penn State University; ⁶Division of Genetic Medicine, Vanderbilt University Medical Center; ⁷Clare Hall, University of Cambridge.

Hydrocephalus is a component of ~200 genetic syndromes and a secondary consequence of many pathologies (infection, hemorrhage, etc.). Recent studies have suggested that hydrocephalus is caused, at least in part, by abnormal neurogenesis which may lead to alterations in white matter and total brain volume. Using PrediXcan (Gamazon et al. Nature Genetics 2018), we conducted a GWAS to identify genes associated with pediatric hydrocephalus in BioVU (287 cases and 18,740 controls). We identify maelstrom (MAEL), a gene involved in DNA transposon and epigenetic regulation, as a genome-wide predictor of hydrocephalus. We then used PrediXcan to identify genes associated with white matter and total brain volumes using MRI data from 8,428 individuals in the UK Biobank (controlling for age, sex, and genetic ancestry using 40 principal components). MAEL expression is associated with decreased white matter and total brain volumes (Bonferroni-adjusted pxtagstartz 0.05), suggesting that

Abstract Text

Deciphering the Warburg effect: the connection between metabolism, epigenetics and tumor differentiation

Jiangbin Ye¹, Yang Li¹, Joshua Gruber², Ulrike Litzenburger³, Yiren Zhou¹, Yu Miao¹, Edward LaGory¹, Albert Li¹, Zhen Hu⁴, Lori Hart⁵, John Maris⁵, Howard Chang^3,6, Amato Giaccia¹

¹Department of Radiation Oncology, ²Department of Genetics and ³Center for Personal Dynamic Regulomes, Stanford University ⁴Olivia Consulting Service ⁵Children's Hospital of Philadelphia  ⁶Howard Hughes Medical Institute

The Warburg effect is a metabolic hallmark of all cancer cells, characterized by increased glucose uptake and glycolysis for lactate generation. The generation and excretion of lactate would appear be a waste of carbon backbone and energy that is needed for proliferation. It was proposed by Warburg that the cause and consequence of the Warburg effect were the injury of respiration and cell dedifferentiation, respectively. One common factor that damages mitochondrial respiration is hypoxia, which is a metabolic stress that blocks cell differentiation and promotes cancer progression. The underlying mechanism by which this occurs is poorly understood, and no effective therapeutic strategy has been developed to overcome this resistance to differentiation. Using a neuroblastoma (NB) differentiation model, we have discovered that hypoxia represses the differentiation induced by retinoic acid (RA) as demonstrated by loss of neuron differentiation markers and changes in cell morphology, associated with reduction of global histone acetylation, that are caused by the induction of pyruvate dehydrogenase kinases (PDKs). PDKs phosphorylate pyruvate dehydrogenase (PDH), thereby blocking pyruvate entry into the TCA cycle, reducing acetyl-CoA generation, and promoting the Warburg effect. Genetic and pharmaceutical inhibition of PDK restores histone acetylation and NB cell differentiation morphology. Acetate supplementation restores histone acetylation, along with differentiation markers expression and neuron differentiation. In addition, ATAC-Seq analysis demonstrated that hypoxia treatment significantly reduces global chromatin accessibility, which can be restored by acetate supplementation. These findings suggest that (1) combining RA and acetate supplementation represents a potentially effective therapeutic strategy for neuroblastoma treatment; (2) diverting pyruvate away from acetyl-CoA generation is a key mechanism by which the Warburg effect blocks cell differentiation.