Monthly Archives: July 2022

image:For innate immune system activation against HIV-1, Scripps Research scientists have found that the protein PQBP1s recognition of incoming HIV-1 particles (depicted in red) is required for cGAS activation, a production of cGAMP (depicted in green), in human dendritic cells. Nuclei (Dapi) are depicted in blue. view more

Credit: Scripps Research

LA JOLLA, CA Human immunodeficiency virus 1, more commonly known as HIV-1, is known for its uncanny ability to evade the immune system. Scientists at Scripps Research and collaborators have now uncovered how our innate immune system the bodys first line of quick defense in attacking foreign invaders detects HIV-1, even when the virus is present in very small amounts.

The findings, published on July 8, 2022, in Molecular Cell, reveal the two-step molecular strategy that jolts the innate immune response into action when exposed to HIV-1. This discovery could impact drug development for HIV treatments and vaccines, as well as shape our understanding of how the innate immune response is implicated in other areas including neurodegenerative disorders such as Alzheimers.

This research delineates how the immune system can recognize a very cryptic virus, and then activate the downstream cascade that leads to immunological activation, says Sumit Chanda, PhD, professor in the Department of Immunology and Microbiology. From a therapeutic potential perspective, these findings open up new avenues for vaccines and adjuvants that mimic the immune response and offer additional solutions for preventing HIV infection.

The innate immune system is activated before the adaptive immune system, which is the bodys secondary line of defense that involves more specialized functions, such as generating antibodies. One of the innate immune systems primary responsibilities is recognizing between self (our own proteins and genetic material) and foreign elements (such as viruses or other pathogens). Cyclic GMP-AMP synthase (cGAS) is a key signaling protein in the innate immune system that senses DNA floating in a cell. If cGAS does detect a foreign presence, it activates a molecular pathway to fight off the invader.

However, because HIV-1 is an RNA virus, it produces very little DNA so little, in fact, that scientists have not understood how cGAS and the innate immune system are able to detect it and distinguish it from our own DNA.

Scripps Research scientists discovered that the innate immune system requires a two-step security check for it to activate against HIV-1. The first step involves an essential protein polyglutamine binding protein 1 (PQBP1) recognizing the HIV-1 outer shell as soon as it enters the cell and before it can replicate. PQBP1 then coats and decorates the virus, acting as an alert signal to summon cGAS. Once the viral shell begins to disassemble, cGAS activates additional immune-related pathways against the virus.

The researchers were initially surprised to find that two steps are required for innate immune activation against HIV-1, as most other DNA-encoding viruses only activate cGAS in one step. This is a similar concept to technologies that use two-factor authentication, such as requiring users to enter a password and then respond to a confirmation email.

This two-part mechanism also opens the door to vaccination approaches that can exploit the immune cascade that is initiated before the virus can start to replicate in the host cell, after PQBP1 has decorated the molecule.

While the adaptive immune system has been a main focus for HIV research and vaccine development, our discoveries clearly show the critical role the innate immune response plays in detecting the virus, says Sunnie Yoh, PhD, first author of the study and senior staff scientist in Chandas lab. In modulating the narrow window in this two-step process after PQBP1 has decorated the viral capsid, and before the virus is able to insert itself into the host genome and replicate there is the potential to develop novel adjuvanted vaccine strategies against HIV-1.

By shedding light on the workings of the innate immune system, these findings also illuminate how our bodies respond to other autoimmune or neurodegenerative inflammatory diseases. For example, PQBP1 has been shown to interact with tau the protein that becomes dysregulated in Alzheimers disease and activate the same inflammatory cGAS pathway. The researchers will continue to investigate how the innate immune system is involved in disease onset and progression, as well as how it distinguishes between self and foreign cells.

In addition to Yoh and Chanda, authors of the study, Recognition of HIV-1 Capsid Licenses Innate Immune Response to Viral Infection, include Na Rae Ahn and Heather Curry of Scripps Research; Joao I. Mamede of Northwestern University and Rush University Medical Center; Gianguido C. Cianci, Lacy M. Simons, Judd F. Hultquist and Thomas J. Hope of Northwestern University; Derrick Lau, Andrew Tuckwell and Till Bocking of the University ofNew South Wales; Maria T Sanchez-Aparicio and Adolfo Garcia-Sastre of the Icahn School of Medicine at Mount Sinai; Joshua Temple and Yong Xiong of Yale University; Nina V. Fuchs and Renate Konig of Paul-Ehrlich-Institute; Stephanie Gambut of Rush University Medical Center; Laura Riva of Calibr; and Xin Yin of the Harbin Veterinary Research Institute.

Funding was provided by NIAID of the National Institutes of Health, the Gilead Sciences Research Scholars Program in HIV and the German Research Foundation.

About Scripps Research

Scripps Research is an independent, nonprofit biomedical institute ranked the most influential in the world for its impact on innovation by Nature Index. We are advancing human health through profound discoveries that address pressing medical concerns around the globe. Our drug discovery and development division, Calibr, works hand-in-hand with scientists across disciplines to bring new medicines to patients as quickly and efficiently as possible, while teams at Scripps Research Translational Institute harness genomics, digital medicine and cutting-edge informatics to understand individual health and render more effective healthcare. Scripps Research also trains the next generation of leading scientists at our Skaggs Graduate School, consistently named among the top 10 US programs for chemistry and biological sciences. Learn more atwww.scripps.edu.

Recognition of HIV-1 Capsid Licenses Innate Immune Response to Viral Infection

8-Jul-2022

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Immune system uses two-step verification to defend against HIV - EurekAlert

When she was in her 30s, Molly Cassidy was handed a death sentence. Traditional treatments failed to fight the aggressive head and neck cancer that was running rampant through her body. Doctors were out of options, until a clinical trial at the University of Arizona Health Sciences offered a glimmer of hope and, eventually, a second chance at life thanks to immunotherapy.

Immunotherapy is a treatment that uses a person's own immune system to fight cancer, while molecular therapies use drugs and other substances to target specific molecules involved in disease progression. In Cassidys case, she received a personalized cancer vaccine in combination with an immunotherapy drug that helps the immune system fight certain kinds of cancer, and it worked. A year after the UArizona Cancer Center clinical trial ended, there were no traces of cancer left in her body.

Researchers and physician-scientists are increasingly using precision medicine to develop new cell- and gene-based therapeutical options for diseases, building on the idea that the most effective defense against health issues is the bodys natural immune system. At UArizona Health Sciences, the Center for Advanced Molecular and Immunological Therapies, or CAMI, is being developed to advance knowledge of the immunology of cancers, infectious diseases and autoimmune conditions to develop novel strategies for the diagnosis, prevention and treatment of diseases.

Immunotherapy is one of the most promising approaches to cancer treatment, as it has the potential to sidestep the effects of therapies that can compromise patients long-term health and wellness. But cancer isnt the only target researchers, including bioengineer Michael Kuhns, PhD, have in their sights.

Bioengineers solve fundamental problems with technologies that can have many applications, said Dr. Kuhns, associate professor in the UArizona College of Medicine Tucson and member of the BIO5 Institute. If you can make something run more efficiently in certain circumstances for example, make T cells in the immune system more effective at combating a particular disease then the only limit to immunotherapy is your imagination.

Dr. Kuhns research in the Department of Immunobiology focuses on engineering chimeric antigen receptors, or CARs, a relatively new type of gene therapy. He built a biomimetic five-module chimeric antigen receptor, or 5MCAR, to direct killer T cells to target and destroy autoimmune T cells. When tested in a non-obese diabetic mouse model, the 5MCAR T cells recognized and destroyed pathogenic T cells, effectively preventing Type 1 diabetes.

The Center for Advanced Molecular and Immunological Therapies will focus on developing precision therapies that stimulate or suppress the immune system to fight diseases including cancers, infectious diseases and autoimmune conditions.

This technology has clear implications for autoimmune disease, but also for cancer, said Dr. Kuhns, who serves on the 21-member CAMI Advisory Committee. This technology emerged from basic science, is taking hold in the laboratory and is showing promise to go to the clinic. This is a prime example of what we can do.

CAMI will build on UArizona Health Sciences expertise in basic science, translational medicine and investigator-initiated clinical trials to advance immunotherapies research in four areas: cancer, infectious diseases, autoimmune diseases and real-time immune system monitoring.

Other examples of potential research include identifying biomarkers for response to immunotherapy that may help determine the precise drugs to fight specific cancers in individual patients, understanding individual immune responses to autoimmune diseases such as lupus, rheumatoid arthritis or Crohns disease, and creating ways to analyze immune health at the cellular level to identify how individuals might respond to a disease and to predict their health outcomes.

CAMI will serve as the anchor for an innovation district that aims to differentiate Phoenix from other emerging life sciences hubs, establishing the Phoenix Bioscience Core as a center of cell and gene therapy research, startup activity and corporate engagement. Its location is expected to facilitate strong connections with partners such as Arizona State University, Northern Arizona University, the Mayo Clinic and the Translational Genomics Research Institute, among others.

We expect CAMI to be nothing short of a national biomedical research hub, said Michael D. Dake, MD, senior vice president for UArizona Health Sciences. CAMI will be a beacon for people who are involved in this type of research to work, collaborate and engage on the Phoenix Bioscience Core.

The research will take place in connected buildings that are being designed to include laboratories to support translational research, clinical research space and startup incubator space to create a synergistic environment for commercialization opportunities. Student education will be prioritized in learning spaces dedicated to academic programs that will allow CAMI faculty and researchers to mentor and train the next generation of scientists.

There is not a field with more explosive growth than immunotherapy. There is rapid growth in research investment and increased formation of academic and industry partnerships around the world, Dr. Dake said said during a Tomorrow is Here Lecture Series presentation in Phoenix. My hopes are that CAMI is going to provide opportunities to accelerate the development and delivery of revolutionary treatments for the management of cancer, autoimmune and infectious diseases.

We are going to see diversification of drug classes and different types of combination therapies, delivery mechanisms and monitoring, he added. Going forward, I think were going to see a wide array of therapies that are going to be vastly different than any past generations ever had. Suffice it to say, in the future, pills and syringes are going to be obsolete.

Read more:
CAMI Set to Transform Immunotherapy Field Through Research - University of Arizona

* WHO provides technical support to the study on investigating seroprevalence of SARS-CoV-2 and dengue infections in Sri Lankan childrenFri, Jul 8, 2022, 12:23 pm SL Time, ColomboPage News Desk, Sri Lanka.

July 08, Colombo: Sri Lanka too experienced a rapid rise in number of cases and deaths, with the community spread of the Delta variant of the SARS-CoV -2 virus. However, deaths were predominantly seen among adults, with children rarely developing severe disease, as observed in other countries.

Sri Lanka experienced two massive COVID-19 outbreaks due to the Alpha and Delta variants of the SARS-CoV -2 virus, resulting in a large number of individuals being infected in the community. It was estimated that surveillance of SARS-CoV-2 with the Real-time polymerase chain reaction (RT-PCR) testing alone may underestimate the true prevalence of the disease by tenfold. Therefore, conducting a seroprevalence study remained an option for Sri Lanka to determine prevalence of SARS CoV-2 specific antibodies due to infection or vaccines in the country.

Seroprevalence studies help understand the true extent of an outbreak and provide valuable insights in to efforts that help project the trend of future outbreaks, and their transmission dynamics. However, in Sri Lanka, a majority of infections was reported in adults, most of whom experienced more severe and symptomatic infections. On the other hand, true infection rates among children in the country were not clearly known. One of the reasons for this could be limited PCR testing in children, largely because they do not show symptoms following infection with SARS-CoV-2 virus. Also, infection rates could be very different across districts, based on the intensity of transmission reported in different geographical regions.

Considering the above, the Allergy Immunology and Cell Biology Unit, Department of Immunology and Molecular Medicine, University of Sri Jayewardenepura and the Ministry of Health supported by WHO Country Office for Sri Lanka planned a study on seroprevalence of SARS-CoV-2 infections and dengue infections in Sri Lankan children.

In order to submit the study protocol to WHOs Ethical Review Committee, a joint review of study protocols was undertaken by the Unity trial desk of WHO Headquarters, the SEA Regional Office and the WHO country office for Sri Lanka. After revising the study protocol based on WHO recommendations, investigators submitted the finalized protocol to the Regional Review Committee.

The proposed study will help Sri Lanka determine the proportion of children who have been infected with COVID-19 and also with dengue, by studying the presence of antibodies to these viruses in children of different age groups. Additionally, it will determine genetic associations that predispose children to severe disease of dengue. Further, the study will provide information that will help understand how COVID-19 and dengue have spread geographically in the Sri Lankan population.

The seroprevalence in this study will be determined by biological assays, which are both qualitative and quantitative (ELISA, Luminex). The patient data will be collected on clinical features, clinical disease severity and complications.

The findings of this investigation will be used to inform public health response to COVID-19. Specifically, it can provide estimates of otherwise unrecognized SARS-CoV-2 infection in the population, as well as likely susceptibility of the population to further epidemic peaks. The findings may also supplement other supportive evidence used to inform decision-making about vaccine prioritization for target groups, based on demonstrated susceptibility by age groups.

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Sri Lanka : WHO provides technical support to the study on investigating seroprevalence of SARS-CoV-2 and dengue infections in Sri Lankan children -...

Summary: Targeting the GAT3 protein in the thalamus could help block and prevent long-term damage following brain injury.

Source: Gladstone Institute

For days, and even years, after someone suffers a stroke or traumatic brain injury, they have an increased risk of developing epilepsy.

Now, researchers at Gladstone Institutes discovered that star-shaped cells called astrocytes in the thalamus play a key role in making mice with brain injuries susceptible to seizures.

The team also analyzed human post-mortem brain tissue and showed that the same cells identified in mice might be altered in the thalamus of people affected by brain injury and stroke.

The findings,published in the journalScience Translational Medicine,suggest that targeting a protein in these cells could prevent the long-term damage that follows brain injury.

In the aftermath of brain injuries, the thalamus has been relatively understudied compared to other brain regions, saysJeanne Paz, PhD,an associate investigator at Gladstone and senior author of the new study. Im hoping this is just the beginning of many new lines of research about how important this region is in determining how we can help the brain be resilient to consequences of injuries.

A Cascade of Inflammation Deep in the Brain

At the time of a stroke or traumatic brain injury, many cells at the site of the injury die almost immediately. Inflammatory cells and molecules begin to gather, cleaning up the dead cells and molecular debris. In the thalamus, an area deep in the center of the brain that may be far from the site of injury, cells called astrocytes become activated, leading to a cascade of inflammatory changes.

Previous studies from the teamhave shown, in rodent models, that activation of astrocytes in the thalamus is a common consequence of brain injury. However, astrocytes also play key roles that support neurons, including controlling their connections and providing them with nutrients.

In this study, the scientists wanted to determine whether the activation of astrocytes in the thalamus helps the brain recover, leads to additional damage, or has both positive and negative effects.

Astrocytes are so important to the brain that you cant just get rid of them to treat disease, says Frances Cho, a graduate student at Gladstone and UC San Francisco (UCSF), and the first author of the new study. We needed to determine whether we could separate the damaging actions of activated astrocytes from their protective actions.

Focus on the Thalamus

Paz, Cho, and their collaborators hypothesized that activated thalamic astrocytes might play a role in some of the longer-term symptoms of brain injuryincluding an increased risk of seizures and sleep problems. So, rather than study mice with brain injuries, the team initially tested the consequences of activating thalamic astrocytes in otherwise healthy animals.

They found that just activating thalamic astrocytes was enough to cause altered patterns of brain activity similar to those seen after injury, and made the mice susceptible to seizures.

When the researchers then analyzed the molecular properties of the activated astrocytes, in collaboration with the team ofAnna Molofsky, MD, PhD,at UCSF, they discovered that these cells lost a protein called GAT3, which is responsible for regulating the levels of a specific inhibitory neurotransmitter molecule.

As a result, the neighboring neurons were exposed to too much of the neurotransmitter, which resulted in neuronal hyperexcitability and susceptibility to seizures.

We wondered, if the loss of GAT3 in thalamic astrocytes caused neuronal dysfunction, could boosting the level of this protein solve the problem and restore the neurons function? says Paz, who is also an associate professor at UCSF.

To answer this question, the team collaborated withBaljit S. Khakh, PhD,and his group at UCLA who had developed a tool to increase GAT3 specifically in astrocytes. Remarkably, increasing levels of GAT3 specifically in thalamic astrocytes was enough to prevent neuronal hyperexcitability and increased seizure risk caused by activated astrocytes.

The team next tested whether the results held true in mice with brain injuries. Increasing levels of GAT3 in the thalamic astrocytes of these mice also reduced the risk of seizure and the rate of mortality.

These activated astrocytes are quite different in many ways than astrocytes that are not activated, so it was surprising we could pinpoint a single molecular change that we could target to prevent the consequences of brain injury, says Cho.

A Potential Therapeutic

Samples of human thalamus are rarely collected during post-mortem brain biopsies. But, in collaboration withEleonora Aronica, MD, PhD,and her group at the University of Amsterdam, the researchers were able to obtain a small number of post-mortem thalamus samplesthree from individuals with no known brain injuries, three from people who had had a stroke, and four from people with traumatic brain injury.

The post-mortem brains with stroke and traumatic brain injury seemed to have lower levels of GAT3 in their thalamic astrocytes, just as we had seen in the mouse model, says Cho.

We hope that with increased attention to the thalamus, it will become more routine to collect thalamus samples from post-mortem biopsies in the future.

The researchers hope to continue collecting longer-term data on both mice and humans to study the time course of astrocyte activation in the thalamus after brain injury.

Since these changes to the thalamus occur after the initial brain injury, there is a window of time in which clinicians might be able to intervene to stop or reverse themand prevent the increased risk of developing epilepsy, says Paz.

Other authors are Yuliya Voskobiynyk, Allison Morningstar, Bryan Higashikubo, and Agnieszka Ciesielska of Gladstone; Ilia Vainchtein and Francisco Aparicio of UCSF; Diede Broekaart, Jasper Anink, Erwin van Vliet and Eleonora Aronica of University of Amsterdam; and Xinzhu Yu of UCLA.

Funding: The work was supported by funding from the National Institute of Neurological Disorders and Stroke (F31 NS111819, R01 NS096369, R01 R01NS121287, R00 NS078118, R35 NS111583), the National Institute of Mental Health (DP1 MH104069, DP2 MH116507, R01 MH119349), the National Cancer Institute (P30 CA082103), the National Science Foundation (1144247), a UCSF Discovery Fellowship, the Department of Defense (EP150038, EP190020), a Gladstone Institutes Animal Facility grant (RR18928), Pew Charitable Trusts, an EU Seventh Framework Programme EPITARGET grant (602102), an EU Horizon 2020 Research and Innovation Programme Marie Sklodowska-Curie grant (722053), and the Dutch Epilepsy Foundation (project 16-05).

Author: Julie LangelierSource: Gladstone InstitutesContact: Julie Langelier Gladstone Institutes Image: The image is in the public domain

Original Research: Open access.Enhancing GAT-3 in thalamic astrocytes promotes resilience to brain injury in rodents by Jeanne Paz et al. Science Translational Medicine

Abstract

Enhancing GAT-3 in thalamic astrocytes promotes resilience to brain injury in rodents

Inflammatory processes induced by brain injury are important for recovery; however, when uncontrolled, inflammation can be deleterious, likely explaining why most anti-inflammatory treatments have failed to improve neurological outcomes after brain injury in clinical trials. In the thalamus, chronic activation of glial cells, a proxy of inflammation, has been suggested as an indicator of increased seizure risk and cognitive deficits that develop after cortical injury.

Furthermore, lesions in the thalamus, more than other brain regions, have been reported in patients with viral infections associated with neurological deficits, such as SARS-CoV-2. However, the extent to which thalamic inflammation is a driver or by-product of neurological deficits remains unknown.

Here, we found that thalamic inflammation in mice was sufficient to phenocopy the cellular and circuit hyperexcitability, enhanced seizure risk, and disruptions in cortical rhythms that develop after cortical injury.

In our model, down-regulation of the GABA transporter GAT-3 in thalamic astrocytes mediated this neurological dysfunction. In addition, GAT-3 was decreased in regions of thalamic reactive astrocytes in mouse models of cortical injury.

Enhancing GAT-3 in thalamic astrocytes prevented seizure risk, restored cortical states, and was protective against severe chemoconvulsant-induced seizures and mortality in a mouse model of traumatic brain injury, emphasizing the potential of therapeutically targeting this pathway.

Together, our results identified a potential therapeutic target for reducing negative outcomes after brain injury.

Read more from the original source:
Pathway Deep in the Brain Makes It Resilient After Injury - Neuroscience News