TLR7

A type of nanoparticle called a metal organic framework (MOF) could be used to deliver vaccines and act as an adjuvant. Researchers find these particles provoke a strong immune response by activating the innate immune system through cell proteins called toll-like receptors. Many vaccines, including vaccines for hepatitis B and whooping cough, consist of fragments of viral or bacterial proteins. These vaccines often include other molecules called adjuvants, which help to boost the immune system's response to the protein. Most of these adjuvants consist of aluminum salts or other molecules that provoke a nonspecific immune response. A team of MIT researchers has now shown that a type of nanoparticle called a metal organic framework (MOF) can also provoke a strong immune response, by activating the innate immune system -- the body's first line of defense against any pathogen -- through cell proteins called toll-like receptors. In a study of mice, the researchers showed that this MOF could successfully encapsulate and deliver part of the SARS-CoV-2 spike protein, while also acting as an adjuvant once the MOF is broken down inside cells. While more work would be needed to adapt these particles for use as vaccines, the study demonstrates that this type of structure can be useful for generating a strong immune response, the researchers say. "Understanding how the drug delivery vehicle can enhance an adjuvant immune response is something that could be very helpful in designing new vaccines," says Ana Jaklenec, a principal investigator at MIT's Koch Institute for Integrative Cancer Research and one of the senior authors of the new study. Robert Langer, an MIT Institute Professor and member of the Koch Institute, and Dan Barouch, director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center and a professor at Harvard Medical School, are also senior authors of the paper, which appears today in Science Advances. The paper's lead author is former MIT postdoc and Ibn Khaldun Fellow Shahad Alsaiari. Immune activation In this study, the researchers focused on a MOF called ZIF-8, which consists of a lattice of tetrahedral units made up of a zinc ion attached to four molecules of imidazole, an organic compound. Previous work has shown that ZIF-8 can significantly boost immune responses, but it wasn't known exactly how this particle activates the immune system. To try to figure that out, the MIT team created an experimental vaccine consisting of the SARS-CoV-2 receptor-binding protein (RBD) embedded within ZIF-8 particles. These particles are between 100 and 200 nanometers in diameter, a size that allows them to get into the body's lymph nodes directly or through immune cells such as macrophages. Once the particles enter the cells, the MOFs are broken down, releasing the viral proteins. The researchers found that the imidazole components then activate toll-like receptors (TLRs), which help to stimulate the innate immune response. "This process is analogous to establishing a covert operative team at the molecular level to transport essential elements of the Covid-19 virus to the body's immune system, where they can activate specific immune responses to boost vaccine efficacy," Alsaiari says. RNA sequencing of cells from the lymph nodes showed that mice vaccinated with ZIF-8 particles carrying the viral protein strongly activated a TLR pathway known as TLR-7, which led to greater production of cytokines and other molecules involved in inflammation. Mice vaccinated with these particles generated a much stronger response to the viral protein than mice that received the protein on its own. "Not only are we delivering the protein in a more controlled way through a nanoparticle, but the compositional structure of this particle is also acting as an adjuvant," Jaklenec says. "We were able to achieve very specific responses to the Covid protein, and with a dose-sparing effect compared to using the protein by itself to vaccinate." Vaccine access While this study and others have demonstrated ZIF-8's immunogenic ability, more work needs to be done to evaluate the particles' safety and potential to be scaled up for large-scale manufacturing. If ZIF-8 is not developed as a vaccine carrier, the findings from the study should help to guide researchers in developing similar nanoparticles that could be used to deliver subunit vaccines, Jaklenec says. "Most subunit vaccines usually have two separate components: an antigen and an adjuvant," Jaklenec says. "Designing new vaccines that utilize nanoparticles with specific chemical moieties which not only aid in antigen delivery but can also activate particular immune pathways have the potential to enhance vaccine potency." One advantage to developing a subunit vaccine for Covid-19 is that such vaccines are usually easier and cheaper to manufacture than mRNA vaccines, which could make it easier to distribute them around the world, the researchers say. "Subunit vaccines have been around for a long time, and they tend to be cheaper to produce, so that opens up more access to vaccines, especially in times of pandemic," Jaklenec says. The research was funded by Ibn Khaldun Fellowships for Saudi Arabian Women and in part by the Koch Institute Support (core) Grant from the U.S. National Cancer Institute.

Systemic lupus erythematosus (SLE) is an autoimmune disease, in which the immune system that normally protects the body from invading microbes turns against the body's own cells. Researchers studied four patients from two families who developed symptoms of SLE in the first years of life. As familial occurrence of SLE in young children is highly unusual, the team searched for a primary genetic cause and found a mutation in the UNC93B1 gene in all affected family members. Systemic lupus erythematosus (SLE) is an autoimmune disease, in which the immune system that normally protects the body from invading microbes, turns against the body´s own cells. This autoimmune attack can affect any organ and patients commonly develop skin rashes, joint inflammation, blood clots, kidney failure, heart disease, fatigue and psychiatric problems. Until to date, there is no cure for SLE and patients are treated with immunosuppressing drugs with considerable side effects. A group of researchers lead by Min Ae Lee-Kirsch from the Department of Pediatrics, Medical Faculty, TUD Dresden University of Technology (Germany), studied four patients from two families who developed symptoms of SLE in the first years of life. As familial occurrence of SLE in young children is highly unusual, her team searched for a primary genetic cause and found a mutation in the UNC93B1 gene in all affected family members. UNC93B1 is a membrane-spanning structural protein required for maturation and trafficking of a group of receptors that play an important role in the defense against viral infections. These receptors recognize the nucleic acid component of the virus and activate type I interferons, which instruct cells to fight a viral infection. However, nucleic acids, such as DNA and RNA, are not only found in viruses, but are also present in every cell of the human body. This means that the immune system must be capable of discriminating foreign from self nucleic acids. The identified UNC93B1 mutations lead to selective overactivation of TLR7, one of the UNC93B1-regulated receptors that specifically recognizes RNA, leading to erroneous recognition of self RNA with uncontrolled overproduction of type I interferon. This results in an immune attack on normal cells which then triggers inflammation. Moreover, this also stimulates the survival of self-reactive B cells that produce autoantibodies directed against the body´s own cells, fueling the autoimmune attack. These findings demonstrate that UNC93B1 controls the activity of specific nucleic acid receptors, such as TLR7, thereby preventing autoimmunity. Remarkably, people lacking functional UNC93B1 are prone to viral infections with a severe course, such as herpes simplex virus encephalitis and severe COVID-19, highlighting the essential role of UNC93B1 for a healthy immune system. The findings of this study are also of clinical relevance regarding the development of novel targeted therapies for patients with common forms of SLE, who often show signs of overactivation of the TLR7 pathway. Professor Lee-Kirsch says: "Our study demonstrates a direct causal link between an overactive UNC93B1/TLR7 axis and lupus pathogenesis and indicates that blocking overactive TLR7 might be therapeutically effective. As such, our findings are expected to accelerate further development of TLR7 inhibitors for patients with SLE and related autoimmune diseases." The study was funded in part by the German Research Foundation (Deutsche Forschungsgemeinschaft; DFG) and the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung; BMBF). Results were published in Science Immunology as early release on January 11, 2024.

For years, researchers and clinicians have known that lupus, an autoimmune condition, occurs in women at a rate nine times higher than in men. Some of the factors that cause the disease's high prevalence in women have eluded discovery, but in a new study investigating the immune system processes in lupus and the X chromosome, researchers have uncovered answers about the disease's frequency in females. For years, researchers and clinicians have known that lupus, an autoimmune condition, occurs in women at a rate nine times higher than in men. Some of the factors that cause the disease's high prevalence in women have eluded discovery, but in a new study investigating the immune system processes in lupus and the X chromosome, Johns Hopkins Medicine researchers have uncovered answers about the disease's frequency in females. A number of dysregulated genetic and biological pathways contribute to the development of lupus and its varied symptoms of muscle and joint pain, skin rashes, kidney problems and other complications throughout the body. One such pathway involves a protein in the immune system called toll-like receptor 7 (TLR7), which, in lupus, reacts to the body's own RNA, molecules that act as messengers of genetic information. TLR7's reaction to RNA triggers an immune response that damages healthy tissue. In the full article, published in the October volume of the Journal of Clinical Investigation Insight, researchers honed in on this TLR7 immune response in lupus, looking specifically at how a piece of genetic material only found in women, known as X-inactive specific transcript (XIST), could trigger TLR7's immune system response. XIST is a type of RNA that plays a crucial role in inactivating one of the two X chromosomes found in female cells so that females do not have imbalanced gene expression. "XIST has previously been implicated in autoimmunity, but more as something that could prevent autoimmune conditions like lupus, rather than drive the disease's development," says study author Erika Darrah, Ph.D., adjunct professor of medicine at the Johns Hopkins University school of Medicine. She has since left the university, but led the project. "Our findings show the opposite, that XIST actually plays a role in promoting autoimmunity -- increasing the susceptibility to lupus and its severity in women." The research team first tested whether XIST could bind to TLR7 and initiate the receptor's immune response using cellular experiments. They observed that XIST could strongly bind to TLR7 and trigger the production of molecules called interferons, an immune system protein seen at high levels in lupus that contributes to tissue damage in this disease. Rather than protect from TLR7 and interferon's negative effects on the body, these tests illustrated that XIST drove the process of an overactive immune response and therefore contributed to lupus development. "XIST has now taken on a different role, an alarm signal related to autoimmunity," says study author Brendan Antiochos, M.D., assistant professor of medicine at the Johns Hopkins University School of Medicine. "The immune system activation through XIST and TLR7 is female-specific, helping explain the observation that lupus is so much more common in women compared to men." To further study XIST's role in lupus, researchers also examined XIST levels in patients from two lupus cohorts. The team tested blood samples from patients at the Johns Hopkins Lupus Center for XIST levels, and also used publicly available data from another study that showed XIST and interferon levels in white blood cells taken from the kidneys of people with lupus. They assessed that not only did the levels of XIST in the kidney correlate with higher interferon levels, but also, those with more XIST in their blood cells experienced greater disease severity and worsened lupus symptoms. Darrah and Antiochos say these findings may implicate XIST in other autoimmune conditions that are more often seen in women, and that more research should be conducted to investigate this female-specific process. Researchers also say that understanding XIST's role in lupus development may open the doors for creative therapies to treat the condition that target the XIST-TLR7 pathway, as well as offer an additional explanation for patients who may wonder about the origins of their disease. Additional study authors include Jonathan Crawford, Hong Wang, Daniela Trejo-Zambrano, Raffaello Cimbro, C. Conover Talbot Jr., Mekha Thomas, Ashley Curran, Alexander Girgis, John Schroeder, Andrea Fava, Daniel Goldman, Michelle Petri, and Antony Rosen, all from Johns Hopkins University School of Medicine. C. Conover Talbot Jr. reports ownership of Merck & Co. common stock. Erika Darrah is an author of US Patents 14/617,412 (awarded), 10,874,726 (awarded), 62/481,158 (provisional), 048317-642P01US (provisional), and 63/515,854 (provisional) and is a cofounder of Simmbion, LLC. Michell Petri receives research support from Eli Lilly & Co., GlaxoSmithKline, Janssen, and Aurinia. Erika Darrah and Raffaello Cimbro are current employees of AstraZeneca, and Jonathan Crawford is a current employee of Eli Lilly & Co. and may receive stock options.