La Jolla Institute
La Jolla Institute
News Article | May 16, 2017
La Jolla, Calif., May 16, 2017 -- New research led by Alexey Terskikh, Ph.D., associate professor at Sanford Burnham Prebys Medical Discovery Institute (SBP), and Alex Strongin, Ph.D., professor at SBP, could be a first step toward a drug to treat Zika infections. Publishing in Antiviral Research, the scientific team discovered a compound that prevents the virus from spreading. "We identified a small molecule that inhibits the Zika virus protease, and show that it blocks viral propagation in human cells and in mice," Terskikh says. "Anti-Zika drugs are desperately needed. The fact that the compound seems to work in vivo is really promising, so we plan to use it as a starting point to make an even more potent and effective drug." The Zika virus has been declared a public health emergency of international concern by the World Health Organization, a rare designation indicating that a coordinated global response is needed. The reason Zika is considered such a threat is that it's spreading rapidly through the Americas, including parts of the U.S., and can cause severe complications. Zika has been linked to an increase in cases of microcephaly, a birth abnormality in which the head and brain are unusually small, and Guillain-Barre syndrome, a rapidly developing neurological condition that causes weakness of the arms and legs and can progress to life-threatening respiratory failure. "Microcephaly is likely just the tip of the iceberg in terms of the potential adverse effects of maternal Zika infection," comments Terskikh. "There may be other, less obvious impacts on brain development that wouldn't be apparent until later. That's something we're also investigating." The scientific team took advantage of a library of compounds that Strongin's lab had previously shown to inhibit the same component of the related West Nile virus. They also tested structurally similar molecules available at the SBP's Conrad Prebys Center for Chemical Genomics (Prebys Center) to determine whether any also blocked the protease. The screening process identified three promising compounds, which were then tested for their ability to prevent Zika infection of human brain cells. The best one of these also reduced the amount of virus circulating in the blood of Zika-infected mice. "The inhibitor's efficacy in animals is the key to the study's significance," Terskikh adds. "This, and the fact that the compound is likely to be safe make it especially promising. The compound blocks a part of the protease that's unique to viruses, so it doesn't inhibit similar human proteases. It's also much more potent than previously identified inhibitors of the Zika protease." This future drug is just one part of the fight against Zika. An experimental vaccine is set to move into phase 2 clinical trials in June. "In addition to a Zika vaccine, we still need antivirals," explains Terskikh. "Some people may be exposed who haven't been vaccinated. Having a way to treat the infection could help stop Zika from spreading and prevent its sometimes devastating effects." This research was performed in collaboration with scientists at the La Jolla Institute for Allergy & Immunology. Funding was provided by the National Institutes of Health (R21NS10047). Sanford Burnham Prebys Medical Discovery Institute (SBP) is an independent nonprofit medical research organization that conducts world-class, collaborative, biological research and translates its discoveries for the benefit of patients. SBP focuses its research on cancer, immunity, neurodegeneration, metabolic disorders and rare children's diseases. The Institute invests in talent, technology and partnerships to accelerate the translation of laboratory discoveries that will have the greatest impact on patients. Recognized for its world-class NCI-designated Cancer Center and the Conrad Prebys Center for Chemical Genomics, SBP employs about 1,100 scientists and staff in San Diego (La Jolla), Calif., and Orlando (Lake Nona), Fla. For more information, visit us at SBPdiscovery.org or on Facebook at facebook.com/SBPdiscovery and on Twitter @SBPdiscovery.
News Article | May 8, 2017
The initial study will assess immune responses of 10 healthy adults (ages 40-80) to a licensed hepatitis B vaccine. It will feature one of the most comprehensive analyses of how people respond to vaccinations to learn why some individuals are protected from a single dose, while others are not. The study will expand to include several hundred people – from neonates to the elderly in middle and low-income countries. "Developing a better understanding of why some groups of people are protected from disease is a goal that simply must be achieved," said Co-Principal Investigator Tobias Kollmann, M.D., Ph.D., professor of pediatrics at the University of British Columbia (UBC) and an investigator at the Vaccine Evaluation Center in Vancouver, Canada. "The licensed hepatitis B vaccine, which only works in about 30 percent of people on the first shot, is an ideal model vaccine to study general principles of human immunological protection because it is one of the few vaccines for which we know how it protects." The study will take place at the at the Vaccine Evaluation Center, in Vancouver, Canada, and will be augmented by extensive immunological and bioinformatic analyses at the Project's San Diego Mesa Consortium, which includes the J. Craig Venter Institute, the La Jolla Institute, The Scripps Research Institute, and UC San Diego, with clinical coordination by the Vanderbilt Institute for Clinical and Translational Research. "With technological advances in biomedical, computational and engineering sciences, we have an unprecedented opportunity to decipher the immune system's components and core principles required to generate long-lasting immunity against disease, and usher in a new era of global health," added Stanley Plotkin, M.D., Chairman of the Human Vaccines Project's Board of Directors. About the Human Vaccines Project| The Human Vaccines Project is a nonprofit public-private partnership with a mission to decode the human immune system to accelerate the development of vaccines and immunotherapies against major infectious diseases and cancers. The Project brings together leading academic research centers, industrial partners, nonprofits and governments to address the primary scientific barriers to developing new vaccines and immunotherapies. Support and funding for the Project includes the Robert Wood Johnson Foundation, John D. and Catherine T. MacArthur Foundation, GSK, Illumina, MedImmune, Sanofi Pasteur, Crucell/Janssen, Regeneron, Pfizer, Moderna, Boehringer Ingelheim, Aeras, Vanderbilt University Medical Center, UC San Diego, The Scripps Research Institute, J. Craig Venter Institute and La Jolla Institute for Allergy and Immunology. To learn more, visit www.humanvaccinesproject.org. For media inquiries, please contact Kierstin Coatney, Kierstin@globalgatewayadvisors.com or +1-716-378-1602. To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/new-study-aims-to-explain-the-rules-of-how-the-immune-system-works-300453028.html
News Article | June 1, 2017
EMERYVILLE, Calif.--(BUSINESS WIRE)--Gritstone Oncology, a next-generation personalized cancer immunotherapy company, today announced the expansion of its Scientific Advisory Board (SAB) with the appointment of James L. Gulley, M.D., Ph.D., chief of the Genitourinary Malignancies Branch at the Center for Cancer Research (CCR) of the National Cancer Institute (NCI), and Alessandro Sette, Dr.Biol.Sci., center head of the Division of Translational Immunology and Vaccine Discovery at the La Jolla Institute for Allergy and Immunology. Both are renowned experts in the field of immuno-oncology and will provide strategic guidance and insight to Gritstone as it advances its drug development technology platform to create personalized neoantigen therapies that harness the patient’s own immune system to attack solid tumors. “Successful neoantigen-targeted therapy demands excellence in two scientific dimensions, and we are thrilled to have global leaders in both of those domains join our team of scientific advisors,” said Andrew Allen, M.D., Ph.D., co-founder, president and chief executive officer of Gritstone Oncology. “First, we must predict which of a cancer patient’s many DNA mutations create truly neoantigenic proteins, and Alessandro has blazed the trail in understanding immune system-protein interactions. His fundamental insights have empowered companies like ours to consider tackling this problem and his counsel has already proven invaluable. Second, we must deliver tumor-specific neoantigens to patients in a highly immunogenic format. James has studied human immune responses to cancer immunotherapies for many years, deriving key observations into the link between immune response and clinical outcomes. The collective expertise of Alessandro and James will be essential as we advance our first personalized neoantigen immunotherapy into human trials and continue to assess solid tumors for their capacity to generate tumor-specific neoantigens.” “Tumor neoantigens are an exciting actionable discovery, and Gritstone Oncology has the right team of seasoned individuals in place to advance this scientific understanding to the next level in order to improve response rates and survival in cancer patients. The team has already made exceptional progress in the 20 months since the company was founded,” said Dr. Sette. “With my long-term interest in how T cells recognize antigens, I am excited to join Gritstone’s Scientific Advisory Board to help advance its novel therapeutic concept into clinical trials next year.” Dr. Gulley also serves as senior investigator and head of the Immunotherapy Section and director of the Medical Oncology Service in the Office of the Clinical Director at the CCR. He is an internationally recognized expert in cancer immunotherapy, therapeutic cancer vaccines, immune checkpoint inhibitors, and the combination of immunotherapy with other therapies. Since 1998, he has conducted investigator-initiated clinical trials at the NCI evaluating cancer vaccines and other immunostimulatory agents, as well as the combination of immunotherapy with other treatment strategies. He played a central role in the clinical development of a prostate cancer vaccine that was created at the NCI, and currently serves as principal investigator of an international, randomized Phase 3 clinical trial of that vaccine. He is also the coordinating principal investigator for an international trial of an anti-PDL1 antibody. Dr. Sette also serves as director of the Center for Infectious Disease and Head of the Initiative for Emerging Diseases and Biodefense at the La Jolla Institute for Allergy and Immunology. He has devoted more than 30 years of study to understanding basic mechanisms of antigen recognition and immune responses, measuring and predicting immune activity, and developing disease intervention strategies against cancer, infectious diseases, autoimmune diseases and allergies. His research is focused on improving the understanding of how the body successfully battles infection, and conversely, how pathogens escape the immune system, causing the individual to succumb to disease. He has developed techniques to understand the T-cell response to common allergens, which has resulted in the development of bioinformatic tools used to map the human T-cell response to a large panel of common allergens. Dr. Sette earned a Doctor in Biological Sciences at the University of Rome and completed post-doctoral work at the Laboratory of Pathology, Cassaccia, in Rome, and at the National Jewish Center for Immunology and Respiratory Medicine in Denver. He has authored more than 650 scientific publications in peer-reviewed journals and has nearly 30 issued patents. Gritstone’s SAB Comprised of Pioneers in Immuno-Oncology and Other Relevant Disciplines In addition to Drs. Gulley and Sette, other members of Gritstone Oncology’s distinguished Scientific Advisory Board include: Gritstone Oncology is a privately-held, next-generation personalized cancer immunotherapy company. Gritstone brings together distinguished scientific founders, an experienced and diverse management team, a seasoned and successful board of directors, and deep financial backing to tackle fundamental challenges at the intersection of cancer genomics, immunology and immunotherapy design. The company’s initial goal is to identify and deploy therapeutic neoantigens from individual patients’ tumor to develop novel treatments for lung cancer. Gritstone Oncology is headquartered in the San Francisco Bay Area with certain key functions located in Cambridge, Mass. The company launched in October 2015 with a Series A financing of $102 million from leading blue-chip biotechnology investors, including Versant Ventures, The Column Group and Clarus Ventures. More information can be found at www.gritstoneoncology.com.
News Article | July 20, 2017
The Independent Citizens Oversight Committee of the California Institute for Regenerative Medicine (CIRM) today unanimously approved a $5.8 million award to University of California San Diego School of Medicine researchers to develop a new immunotherapy in which patients' cells would be equipped with a special receptor that recognizes and targets cancer stem cells, whose survival abilities often render standard therapies ineffective or short-term. The award, to a team of scientists and physicians headed by Ezra Cohen, MD, professor of medicine and associate director for translational science at UC San Diego Moores Cancer Center, builds upon earlier and on-going research involving the receptor tyrosine kinase-like orphan receptor or ROR1, which is expressed in both solid and blood cancers but not in normal tissues. Another UC San Diego team, headed by Thomas Kipps, MD, PhD, who holds the Evelyn and Edwin Tasch Chair in Cancer Research at Moores Cancer Center, is already conducting a first-in-human phase 1 clinical trial of cirmtuzumab, a ROR1-based humanized monoclonal antibody drug, on patients with relapsed or refractory chronic lymphocytic leukemia (CLL). The name cirmtuzumab is a nod to CIRM, which has provided sustained funding support for basic research and development of ROR1-based therapeutics at UC San Diego. The new CIRM grant to Cohen's team represents a new and more aggressive step toward addressing cancers that defy standard treatment. It is an example of emerging CAR T-cell therapies in which a patients T cells (a type of immune system cell) are extracted and altered in the lab. In this case, a gene is added to allow T-cell activation when interacting with ROR1. Large numbers of the altered T cells are grown and then infused into the patient where, it is hoped, they will seek out and destroy cancer stem cells expressing ROR1. Previous research at UC San Diego School of Medicine has shown that ROR1 CAR-T cells target and kill ROR1-expressing cancer stem cells in in vitro models of head and neck squamous cell carcinoma, triple-negative breast cancer, pancreatic cancer, ovarian cancer and chronic lymphocytic leukemia. All five cancers are among the most deadly, difficult to treat or most likely to recur. Cohen said the new CIRM grant will support work to create proof of concept and pilot safety data necessary before plans for human early phase clinical trials can begin. "Our overall goal by the end of this 30-month process is to have a full-fledged, pre-clinical plan in place, with input and support from the FDA, so that we develop a new drug and test it in clinical trials," he said. The effort is part of a larger immunotherapy program at Moores Cancer Center that is currently conducting multiple clinical trials exploring novel immune checkpoint inhibitors and tumor vaccines. Cohen, a noted head and neck cancer specialist, is co-director of the San Diego Center for Precision Immunotherapy, a collaboration with the La Jolla Institute for Allergy and Immunology. Philanthropists Ralph and Fernanda Whitworth and the Immunotherapy Foundation provided initial funding for Cohen's pilot research related to the CIRM grant. Ralph Whitworth was a well-known San Diego activist investor who died in 2016 of complications from cancer. CIRM was created in 2004 by California voters with $3 billion in funding support to accelerate stem cell research and treatments. Since 2004, UC San Diego researchers have received at least 95 CIRM awards, totaling more than $177 million.
News Article | November 17, 2016
The Human Vaccines Project and Boehringer Ingelheim are pleased to announce a three-year collaboration agreement to support their mutual objective to decode the human immune system with the aim of accelerating understanding and development of immunotherapies overall as well as better vaccines for cancer treatment. Under the terms of the agreement, Boehringer Ingelheim’s contributions to the Project will help catalyze the Project’s expanding programs. “We are tremendously honored that Boehringer Ingelheim has elected to partner with the Project, joining a growing number of leading, global biopharmaceutical companies committed to addressing the key scientific challenges impeding development of next generation vaccines and immunotherapies,” said Wayne C. Koff, Ph.D., President and CEO of the Human Vaccines Project. “Boehringer Ingelheim brings exceptional basic science and clinical research expertise in the areas of oncology and human immunology, and is at the forefront of biopharma innovation in these areas.” A revolution is ongoing in cancer immunotherapy, due to the recent realization of the importance of “checkpoints,” proteins that enable tumors to evade the immune system’s ability to kill the tumor, and novel therapeutics termed “checkpoint inhibitors” that have provided dramatic clinical benefit in managing a subset of cancers in a limited number of patients. “Despite these exciting breakthroughs, our understanding of how the immune system can best be harnessed to attack and eliminate tumors remains limited. A better understanding of the human immune system in healthy individuals as well as patients, and how best to measure and direct the immune system is needed,” said Clive R. Wood, Ph.D., Senior Corporate Vice President, Discovery Research at Boehringer Ingelheim. “We are pleased to become a partner in this groundbreaking project which offers the potential to open a new era in vaccine and immunotherapeutic development. This complements our strong commitment to cancer immunology with a pipeline that includes among others, a therapeutic cancer vaccine and next generation checkpoint inhibitors.” Within the Human Vaccines Project’s scientific network, investigators at leading academic research centers are seeking to determine the central components of the human immune system at the molecular and structural level, as well as the common rules by which the immune system generates specific and durable protective responses against a range of infectious and neoplastic diseases. Successful achievement of these goals should enable accelerated development of new and improved vaccines and therapeutics for major global diseases. “The Human Vaccines Project is one of the more promising projects to help transform the future of vaccine development and cancer immunotherapy. JCVI is pleased to be adding our bioinformatics acumen as part of this effort to help conquer some of the most devastating diseases of the 21st century,” said J. Craig Venter, Founder, Chairman and CEO of the J. Craig Venter Institute which recently joined together with the Scripps Research Institute, La Jolla Institute and UC San Diego to serve as a scientific hub for the Project. About the Human Vaccines Project The Human Vaccines Project is a non-profit public-private partnership with the mission to accelerate the development of vaccines and immunotherapies against major infectious diseases and cancers by decoding the human immune system. The Project has a growing list of partners and financial supporters including: Vanderbilt University Medical Center, the J. Craig Venter Institute, the La Jolla Institute, The Scripps Research Institute, UC San Diego, Aeras, Crucell/Janssen, GSK, Pfizer, MedImmune, Regeneron, Sanofi Pasteur, the Robert Wood Johnson Foundation and the John D. and Catherine T. MacArthur Foundation. The Project brings together leading academic research centers, industrial partners, nonprofits and governments to address the primary scientific barriers to developing new vaccines and immunotherapies, and has been endorsed by 35 of the world’s leading vaccine scientists.
News Article | December 12, 2016
Members of the TET family of proteins help protect against cancer by regulating the chemical state of DNA --and thus turning growth-promoting genes on or off. The latest findings reported by researchers at La Jolla Institute for Allergy and Immunology illustrate just how important TET proteins are in controlling cell proliferation and cell fate. For the study, published in the December 20, 2016, edition of Nature Immunology, Anjana Rao, PhD, a professor at the La Jolla Institute, genetically engineered mice to lack both TET2 and TET3 in T cells. The mice developed a lethal disease resembling lymphoma within weeks of birth, their spleens and livers bloated with iNKT cells, a normally rare kind of T cell. This finding recapitulated the features of many human blood cancers, including those involving T cells, in which TET2 is often mutated or lost. "We knew that TET proteins were involved in human cancer but we didn't know how they regulated T cell development," says Angeliki Tsagaratou, Ph.D., an instructor in the Rao lab and the study's first author. "In the new study we saw huge increases in the proliferation of the special iNKT cells in TET2/3 mutant mice. Once growth control was lost, those cells underwent the kind of malignant transformation that gives rise to T cell lymphoma in humans." The results demonstrate how TET proteins serve as anti-cancer factors called tumor suppressors and suggest ways to block malignancy in cancers marked by TET mutations. Members of the TET family of enzymes help rewrite the epigenome, the regulatory layer of chemical modifications that sits atop the genome and helps determine gene activity without changing the letters of DNA. In addition to the four letters or bases in DNA - A, C, G and T - there is a "fifth base" with a very important role. This base is formed from the DNA base cytosine (C) by addition of a methyl group, and so is called mC (m for methyl). The levels of mC are altered in cancer cells and during the development of embryos. However, until the discovery of TET proteins in 2009 in the laboratory of Rao, then at Harvard Medical School, it was not known how mC could be converted back to regain C. Dr. Rao's team showed that TET proteins were able to convert 5mC to a sixth base, known as 5hmC. 5hmC is indirectly converted back to C, thus restoring the status quo. DNA modifications of this type in part govern how compressed and "expressible" a strand is: in general, DNA methylation coils up genes to silence them, while less methylated DNA strands, or strands that possess 5hmC, are more accessible and more likely to be expressed, which means they are directing the synthesis of a particular protein. "When TET proteins are lost, iNKT cells that lack them apparently become trapped in an immature, highly proliferative state," explains Tsagaratou. "Unlike normal cells, they can't switch off growth-promoting genes: they just keep dividing." DNA sequencing followed by bioinformatic data-crunching revealed the kinds of abnormal DNA methylation patterns typically seen after TET protein loss. That suggested that improper DNA modifications in the TET2/3 mutant T cells allowed unchecked expression of cancer- and inflammation-associated genes. Edahí González-Avalos, one of the two second authors of the study, conducted most of that analysis. "Without computer analysis of sequencing results, we would not have been able to determine relationships between DNA methylation, how accessible regions of the genome were, global gene expression, or the emergence of cancer cells," says González-Avalos, a graduate student in UCSD's Bioinformatics Graduate Program. "Without computational tools, this study could have taken many, many years!" A critical test reported in the paper demonstrates how insidious even a few perpetually immature iNKT cells can be. In it, the team transferred a small number of iNKT cells lacking Tet2/3 from mutant mice into adult mice with a robust immune system. But even those mice soon developed lymphoproliferative disease as lethal as that seen in TET2/3 mutant mice. "We weren't expecting this," says Tsagaratou. "When we transferred mutant cells we thought healthy mice would control their expansion. But in three months mutant cells took over the mouse's immune system and rapidly gave rise to tumors." The lesson of this story? That a functional immune system is no defense against malignancy once deregulated, pro-inflammatory iNKT cells gain a foothold. In a 2015 Nature Communications paper, Rao, who heads LJI's Division of Signaling and Gene Expression, reported that TET2/3 mutations caused myeloid disease resembling acute myeloid leukemia in mice. The new study extends these findings to a different class of hematological cancers, namely lymphoid cancer, which is caused by abnormal activity of immune T or B cells. "Right now we don't know how TET mutations specifically contribute to either T cell lymphomas or leukemias. But we think these mutations are early events in both," says Tsagaratou. Thus the search is on is to discover additional cancer-causing genes "downstream" of TET mutations that drive uncontrolled cell division in either context. "Identification of additional factors would give us a broad idea of all steps in pathway and provide multiple targets to hit." In addition to Tsagaratou and González-Avalos, Sini Rautio of Aalto University School of Science, in Aalto, Finland, was a co-second author of the paper, contributing significantly to the bioinformatic analysis of genome-wide sequencing data. Also contributing were James Scott Browne, Ph.D., Susan Togher, and William A. Pastor, Ph.D., all from LJI; Ellen V. Rothenberg, Ph.D., of Caltech; and bioinformaticians Lukas Chavez Ph.D., of the German Cancer Research Center in Heidelberg and Harri Lähdesmäki, Ph.D., of Aalto University School of Science, the PhD thesis supervisor of Sini Rautio. The study was funded by the NIH (R01 grants AI44432, CA151535 and R35CA210043); a Leukemia & Lymphoma Society grant (6187-12, to A.R.); and an Academy of Finland Centre of Excellence in Molecular Systems Immunology and Physiology Research grant (to H.L.). Other funding was from the Cancer Research Institute, the Academy of Finland Centre of Excellence in Molecular Systems, Immunology and Physiology Research program, the Damon Runyon Cancer Research Foundation (DRG-2069-11), and the National Science Foundation. doi:10.1038/ni.3630 About La Jolla Institute for Allergy and Immunology The La Jolla Institute for Allergy and Immunology is dedicated to understanding the intricacies and power of the immune system so that we may apply that knowledge to promote human health and prevent a wide range of diseases. Since its founding in 1988 as an independent, nonprofit research organization, the Institute has made numerous advances leading toward its goal: life without disease.
News Article | December 20, 2016
LA JOLLA, CA--Aedes aegypti mosquitoes harboring parasitic Zika virus (ZIKV) are the primary transmitters of virus to humans, potentially causing catastrophic congenital microcephaly in babies born to women bitten by infected mosquitoes. But confirmation earlier this year by the Centers for Disease Control and Prevention (CDC) that ZIKV can also be sexually transmitted raised new alarm that virus could be passed between sexual partners in venues far from mosquito habitats. Now La Jolla Institute for Allergy & Immunology (LJI) investigator Sujan Shresta, Ph.D., employs two different mouse models to confirm that live ZIKV placed directly in the vagina infects the mouse's reproductive tract, replicates, moves into the bloodstream, and causes clinical signs of disease. Intriguingly, that study published in the December 20, 2016 issue of Cell Reports, also reports that the stage of the reproductive cycle during which a female mouse is exposed to virus determines vulnerability to infection. If applicable to humans, this discovery has public health implications for virus transmission to a population of great concern, women of child-bearing age. "Currently, almost all of our efforts in terms of Zika prevention focus on mosquito control," says Shresta, an associate professor in LJI's Center for Infectious Disease. "Our new work begs clinicians to also address whether sexual transmission of the virus constitutes a small or large proportion of cases." Investigators knew that virus hides in semen of men who contract ZIKV from mosquitoes and that virus is transmitted vaginally in rodent models. But the biological questions--what cells are infected, how stable the virus is in bodily fluids--were unanswered. Shresta's group began to explore them by placing live ZIKV in the vaginas of female mice that had been genetically engineered to be immunocompromised. But before the procedure, they treated mice with hormones to create two groups that differed with regard to where they were in their menstrual cycle. Dramatic differences emerged post-infection: mice infected in the diestrus or in between phase became progressively sick, lost weight, and died in 2-3 weeks, as one might predict in these mice. Remarkably, the same strain of immunocompromised AG129 mice infected in estrus phase showed no sign of disease. William Weihao Tang, the study's first author, calls this one the paper's most intriguing findings. "The strain of mice we used, called AG129, were originally engineered to be extremely vulnerable to infection," he says. "But even these mice, when infected in estrus phase, appeared completely resistant to virus. That surprised us." Shresta says that a caveat is that responses in mouse strains like AG129, which were purposely engineered to serve as a "lethal" model of infection, must be tested in mice with greater immune function. "For science to be relevant to humans, we always confirm results in the most 'immunocompetent' mouse that better reflects a normal human immune system." To do that, her team repeated experiments in an entirely different type of engineered mouse, one only moderately susceptible to infection, which scientists call a "non-lethal" model. When infected in diestrus phase, those mice lost weight and exhibited clinical signs of disease but, unlike their AG129 counterparts, eventually recovered. However, just like the AG129 mice, when infected in estrus phase "non-lethal" mice showed no sign of Zika-like disease. This trend was reflected in other experimental outcomes. For example, in both lethal and non-lethal strains, viral RNA, which serves as direct evidence of virus, persisted in the vaginal canal sometimes as long as 10 days post-infection in diestrus. By contrast, viral RNA disappeared three days after infection in estrus phase. Virus persistence in vaginal fluids may account for why diestrus-infected mice become sick, regardless of mouse strain, yet the molecular or cellular basis for susceptibility remains unclear. Mice analyzed in the study were experimentally synchronized or "staged" at one of two reproductive phases by hormonal injection, which may provide a clue. "Hormones changed the mouse female reproductive tract in ways that either enhanced or protected against sexual transmission," says Tang, although he and Shresta caution it is much too early to generalize mouse findings to humans. But if similar mechanisms prove relevant to human transmission, they are cause for concern, largely because most Zika-infected men or women show few or no symptoms. Thus they could unwittingly engage in sexual activity resulting in adult disease or even in utero transfer of virus to an unborn child. Recent CDC "case counts" suggest that thus far that few Zika cases in the US were likely transmitted sexually. But these numbers are estimates, and sexual transmission of ZIKV is taken extremely seriously in other regions, such as South America. In fact, one mathematical modeling study of Baranquilla, Colombia, estimated that as many as 47% of Zika cases reported there emerged from sexual contact. "In humans sexual transmission may be a bigger deal than has been thought," says Shresta, emphasizing that currently we know very little about this mode of Zika transmission. "We know that in males virus can remain in semen for possibly months, while a man shows no symptoms. During that time he could unknowingly pass it to a sexual partner." The next step for the Shresta lab is to take advantage of these two mouse models to define immune signals that make mice susceptible to or protected from ZIKV infection. "We are ultimately interested in drugs or vaccines to prevent the disease," says Shresta, who has also used immunodeficient mice as models to study dengue virus infection. "Being able to test interventions in two animal models, one that succumbs to infection and another that recovers, is a plus. Developing vaccines requires access to models representing all scenarios." Other contributors include Matthew Perry Young, Anila Mamidi, Jose Angel Regla-Nava, PhD, and Kenneth Kim, DVM, all from LJI. The study was funded by NIAID/NIH grant 1R01 AI116813 and by institutional support from the La Jolla Institute for Allergy and Immunology. La Jolla Institute for Allergy and Immunology is dedicated to understanding the intricacies and power of the immune system so that we may apply that knowledge to promote human health and prevent a wide range of diseases. Since its founding in 1988 as an independent, nonprofit research organization, the Institute has made numerous advances leading towards its goal: life without disease®.
Huang Y.,La Jolla Institute |
Huang Y.,Texas A&M University |
Rao A.,La Jolla Institute
Trends in Genetics | Year: 2014
DNA methylation has been linked to aberrant silencing of tumor suppressor genes in cancer, and an imbalance in DNA methylation-demethylation cycles is intimately implicated in the onset and progression of tumors. Ten-eleven translocation (TET) proteins are Fe(II)- and 2-oxoglutarate (2OG)-dependent dioxygenases that successively oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC), thereby mediating active DNA demethylation. In this review, we focus on the pathophysiological role of TET proteins and 5hmC in cancer. We present an overview of loss-of-function mutations and abnormal expression and regulation of TET proteins in hematological malignancies and solid tumors, and discuss the potential prognostic value of assessing TET mutations and 5hmC levels in cancer patients. We also address the crosstalk between TET and two critical enzymes involved in cell metabolism: O-linked β-. N-acetylglucosamine transferase (OGT) and isocitrate dehydrogenase (IDH). Lastly, we discuss the therapeutic potential of targeting TET proteins and aberrant DNA methylation in cancer. © 2014 Elsevier Ltd.
News Article | December 7, 2016
LA JOLLA, CA--The fate of stem cells is determined by series of choices that sequentially narrow their available options until stem cells' offspring have found their station and purpose in the body. Their decisions are guided in part by TET proteins rewriting the epigenome, the regulatory layer of chemical flags that adorn the genome and influence gene activity, report researchers at La Jolla Institute for Allergy and Immunology and UC San Diego. Publishing in this week's Early Edition of the Proceedings of the National Academy of Sciences, the study led by LJI professor Anjana Rao, Ph.D., details how TET proteins help stem cells strike the proper balance between developing into neural tissue or taking the heart and muscle route at an early and crucial intersection. "In particular, TET proteins are important to steer stem cells toward the neural lineage during early embryogenesis," says postdoctoral researcher and first author Xiang Li. "It confirmed what we had suspected--that TET proteins help drive early neurogenesis--but until now the formal proof had been missing." As a clearer picture of the molecular signals triggering certain cell fate decisions emerges, Li hopes that "it brings us closer to using stem cells to treat neuronal disease." TET proteins influence gene expression by specifically modifying methyl groups attached to cytosine, one of the four letters in DNA. Although these methyl group alterations are important in their own right, they also facilitate the complete removal of methyl groups from cytosine. While methylation and the enzymes required to add methyl groups have been extensively studied as a fundamental force that that helps guide stem cells toward their future lineage during embryonic development, much less is known about the reverse process. "During early embryogenesis waves of demethylation sweep the genome but we haven't really understood what the relevance is," senior author Sylvia Evans, Ph.D., a professor in the Skaggs School of Pharmacy and Pharmaceutical Sciences at UC San Diego, who collaborated with Rao's team. "By creating triple knockouts that miss all three genes coding for TET proteins and studying them, in vivo, we have learned that yes, the dynamic modulation of the methylation status is critically important for driving developmental gene expression programs in the early embryo." Li started his investigations with mouse embryonic stem cells (mES) deficient for Tet3 only, or deficient for all three members (Tet1/2/3) of the Tet protein family. During differentiation, cell types from both mouse strains steered clear from committing to the neuroectodermal lineage, which goes on to form the brain and spinal cord and is considered the "default" pathway for mECs cultured under certain culture conditions. A genome-wide analysis revealed that Tet3 exerts its effect through the inhibition of Wnt-signaling. Wnt signalling is necessary for the proper formation of heart and muscle. "Without Tet3, Wnt signaling is no longer suppressed and can push differentiating stem cells toward a mesodermal cell fate," explains Li. The mesoderm develops into connective tissue, muscle, bone, as well as the urogenital and circulatory system including the heart. The results from lab-grown mECs prompted the researchers to look for developmental abnormalities in Tet3 and Tet1/2/3-deficient mice. The Tet3 knock-out showed no overt cardiac or neuronal abnormalities, which pointed to functional redundancies between different Tet family members. Tet1/2/3-deficient mice, however, had major defects in neural development, confirming a key role for TET proteins in guiding stem cells down the right path. The work was partly funded by NIH R01 grants CA151535 and HD065812 and the CIRM UCSD Interdisciplinary Stem Cell Research & Training Grant II (TG2-01154). Full citation: "TET proteins influence the balance between neuroectodermal and mesodermal fate choice by inhibiting Wnt signaling." Xiang Li, Xiaojing Yue, William A. Pastor, Lizhu Lin, Romain Georges, Lukas Chavez, Sylvia M. Evans, Anjana Rao. PNAS 2016. doi:10.1073/pnas.1617802113 La Jolla Institute for Allergy and Immunology is dedicated to understanding the intricacies and power of the immune system so that we may apply that knowledge to promote human health and prevent a wide range of diseases. Since its founding in 1988 as an independent, nonprofit research organization, the Institute has made numerous advances leading towards its goal: life without disease®.
Gillies L.A.,La Jolla Institute |
Kuwana T.,La Jolla Institute
Journal of Cellular Biochemistry | Year: 2014
Mitochondria play a critical role in apoptosis, or programmed cell death, by releasing apoptogenic factors from the intermembrane space. This process, known as mitochondrial outer membrane permeabilization (MOMP), is tightly regulated by the Bcl-2 family proteins. Pro-apoptotic Bcl-2 family members, Bax and Bak, change their conformation when activated by BH3 domain-only proteins in the family and permeabilize the MOM, whereas pro-survival members inhibit permeabilization. The precise nature of the apoptotic pore in the MOM is unknown, but is probably lipidic. Furthermore, it has been realized that there is another layer of MOMP regulation by a protein factor termed the catalyst in the MOM in order for Bax/Bak to achieve efficient and complete membrane permeabilization. Mitochondrial dynamics do not affect MOMP directly, but seem closely coordinated with MOMP for swift protein efflux from mitochondria. This review will present current views on the molecular mechanisms and regulation of MOMP and conclude with recent developments in clinical applications based on the knowledge gleaned from the investigation. J. Cell. Biochem. 115: 632-640, 2014. © 2013 Wiley Periodicals, Inc. © 2013 Wiley Periodicals, Inc.