immune system – Lightsources.org

SARS-CoV-2 protein caught severing critical immunity pathway

2022/09/082022/09/15

Powerful X-rays from SLAC’s synchrotron reveal that our immune system’s primary wiring seems to be no match for a brutal SARS-CoV-2 protein.

BY DAVID KRAUSE

Over the past two years, scientists have studied the SARS-CoV-2 virus in great detail, laying the foundation for developing COVID-19 vaccines and antiviral treatments. Now, for the first time, scientists at the Department of Energy’s SLAC National Accelerator Laboratory have seen one of the virus’s most critical interactions, which could help researchers develop more precise treatments.

The team caught the moment when a virus protein, called Mpro, cuts a protective protein, known as NEMO, in an infected person. Without NEMO, an immune system is slower to respond to increasing viral loads or new infections. Seeing how Mpro attacks NEMO at the molecular level could inspire new therapeutic approaches.

To see how Mpro cuts NEMO, researchers funneled powerful X-rays from SLAC’s Stanford Synchrotron Radiation Lightsource (SSRL) onto crystallized samples of the protein complex. The X-rays struck the protein samples, revealing what Mpro looks like when it dismantles NEMO’s primary function of helping our immune system communicate.

“We saw that the virus protein cuts through NEMO as easily as sharp scissors through thin paper,” said co-senior author Soichi Wakatsuki, professor at SLAC and Stanford. “Imagine the bad things that happen when good proteins in our bodies start getting cut into pieces.”

The images from SSRL show the exact location of NEMO’s cut and provide the first structure of SARS-CoV-2 Mpro bound to a human protein.

“If you can block the sites where Mpro binds to NEMO, you can stop this cut from happening over and over,” SSRL lead scientist and co-author Irimpan Mathews said. “Stopping Mpro could slow down how fast the virus takes over a body. Solving the crystal structure revealed Mpro’s binding sites and was one of the first steps to stopping the protein.”

The research team from SLAC, DOE’s Oak Ridge National Laboratory, and other institutions published their results today in Nature Communications.

Read more on the SLAC website

Understanding how the HIV virus evades immune surveillance

2022/05/252022/05/26

About 36 million people have died from AIDS-related illnesses and approximately 38 million people globally are living with HIV.

Dr. Jonathan Cook, a resident physician specializing in medical microbiology at the University of Toronto, is investigating key proteins on the HIV virus that are crucial to developing an effective vaccine.

“These proteins are so interesting because they are necessary for a virus to infect a human,” said Cook. “By blocking their function, we can avert the kinds of infections that you see routinely.”

He and Adree Khondker in the lab of Prof. Jeffrey E. Lee from the Temerty Faculty of Medicine published a paper in Communications Biology that reveals new information on how the HIV virus interacts with immune systems.

Using the CMFC beamline at the Canadian Light Source at the University of Saskatchewan, the research team analyzed the outer proteins on the HIV virus. They discovered that an area of one protein acts as a decoy — diverting the immune system’s response towards a false target.

This tactic allows the virus to successfully infect human cells and to cause disease.

“The immune system recognizes this sequence on the virus, which is usually a good thing. But, in this situation, the antibodies that the immune system makes don’t protect you from infection,” Cook said.

With the help of the CLS, the researchers confirmed that this decoy area on the HIV protein shapeshifts to entice an ineffective immune response.

Read more on the CLS website

Image: Micrographs of crystals from this project that were diffracted at CLS

Learning how breast cancer cells evade the immune system

2020/02/042020/02/20

Cancer cells have ways to evade the human immune system, but research at UK’s Synchrotron, Diamond could leave them with nowhere to hide.

Announced on World Cancer Day, the latest research (published in Frontiers in Immunology) by Dr Vadim Sumbayev, together with an international team of researchers, working in collaboration with Dr Rohanah Hussain and Prof Giuliano Siligardi at Diamond Light Source. They have been investigating the complex defence mechanisms of the human immune system and how cancer cells in breast tumours avoid it. In particular, they sought to understand one of the biochemical pathways leading to production of a protein called galectin-9, which cancer cells use to avoid immune surveillance. Dr Vadim Sumbayev explains, The human immune system has cells that can attack invading pathogens, protecting us from bacteria and viruses. These cells are also capable of killing cancer cells, but they don’t. Cancer cells have evolved defence mechanisms that protect them from our immune system, allowing them to survive and replicate, growing into tumours that may then spread across the body. Unfortunately, the molecular mechanisms that allow cancer cells to escape host immune surveillance remain poorly understood. So, with a growing body of evidence suggesting that some solid tumours also use proteins called Tim-3 and galectin-9 and to evade host immune attack, we chose to study the activity of this pathway in breast and other solid and liquid tumours.

Image: Breast cancer cell-based pathobiochemical pathways showing LPHN-induced activation of PKCα, which triggers the translocation of Tim-3 and galectin-9 onto the cell surface which is required for immune escape.

New possibilities against the HIV epidemic

2019/03/222019/03/22

Research identifies new antibodies with potent activity against virus and infected cells

The Human Immunodeficiency Virus type-1 (HIV-1) currently infects 37 million people worldwide, with an additional 2 million new infections each year. Following infection, the virus has a long period of latency, during which it multiplies without causing symptoms. HIV attacks the cells of the immune system, especially the cells called CD4+ T-lymphocytes, which are responsible for triggering the body’s response chain against infections. Thus, by suppressing the action of the immune system, the virus destroys the body’s ability to defend itself against other diseases, leading to the so-called Acquired Immunodeficiency Syndrome, or AIDS.
Even with the development of antiretroviral therapies that have improved quality of life and increased the life expectancy of patients with HIV/AIDS, it is widely accepted that the only way to effectively curb this devastating epidemic is through the development of an HIV-1 vaccine.

Image: Part of the structure of the CAP228-16H protein with the region of the V2 loop highlighted in yellow. (Full image here)

A new molecule could help put the STING on cancer

2019/03/132019/03/18

The protein STING (stimulator of interferon genes) is a component of the innate immune system. It plays a major role in the immune response to cancer, and abnormal STING signaling has been shown to be associated with certain cancers. Immunomodulatory approaches using agonists to target STING signaling are therefore being investigated as anticancer treatments. However, the compounds in clinical trials typically are injected intratumorally in patients with solid cancers. In this study, researchers discovered a novel STING agonist, known as an amidobenzimidazole (ABZI), which can be given by intravenous injection and could therefore potentially open up its evaluation as a treatment for hard-to-reach cancers. Using x-ray diffraction data collected at the U.S. Department of Energy’s Advanced Photon Source (APS), researchers from GlaxoSmithKline (GSK) investigated ABZI compounds and STING. Their results, published in the journal Nature, may have important implications for anticancer immunotherapy.

STING is a protein that mediates innate immunity, and one function of the STING signaling pathway is in mobilizing an immune response against tumors. STING proteins can be activated by cyclic dinucleotides, small molecules that are made by the cytosolic DNA sensor, cGAS, upon sensing of DNA leaking out of the nucleus as a result of DNA damage, including that which might be associated with cancer development.

Figure: X-ray crystal structure of the STING protein bound to one of the new molecules.

Targeting bacteria that cause meningitis and sepsis

2018/10/222018/10/25

The work provides molecular-level information about how the antibody confers broad immunity against a variable target and suggests strategies for further improvement of available vaccines.

Our central nervous systems (brain and spinal cord) are surrounded by three membranes called “meninges.” Meningitis is caused by the swelling of these membranes, resulting in headache, fever, and neck stiffness. Most cases of meningitis in the United States are the result of viral infections and are relatively mild. However, meningitis caused by bacterial infection, if left untreated, can be deadly or lead to serious complications, including hearing loss and neurologic damage.

The bacterium responsible for meningitis (Neisseria meningitidis) can also infect the bloodstream, causing another life-threatening condition known as sepsis. N. meningitidis is spread through close contact (coughing or kissing) or lengthy contact (e.g. in dorm rooms or military barracks). In this work, researchers were interested in understanding how humans develop immunity to bacterial meningitis and sepsis, collectively known as meningococcal disease, by vaccination with a new protein-based vaccine.

Image: The work provides molecular-level information about how the antibody confers broad immunity against a variable target and suggests strategies for further improvement of available vaccines.

Insights into the development of more effective anti-tumour drug

2018/04/182018/04/23

Natural killer cells are powerful weapons our body’s immune systems count on to fight infection and combat diseases like cancer, multiple sclerosis, and lupus. Finding ways to spark these potent cells into action could lead to more effective cancer treatments and vaccines.

While several chemical compounds have shown promise stimulating a type of natural killer cells, invariant natural killer T cells (iNKT) cells in animal models, their ability to activate human iNKT cells has been limited.

Now, an international team of top immunologists, structural biologists, and chemists published in Cell Chemical Biology the creation of a new compound that appears to have the properties researchers have been looking for. The research was co-led by Monash Biomedicine Discovery Institute’s (BDI) Dr Jérôme Le Nours, University of Connecticut’s Professor Amy Howell and Albert Einstein College of Medicine’s Dr Steve Porcelli. Dr Le Nours used the Micro Crystallography beamline (MX2) at the Australian Synchrotron as part of the study.

The compound – a modified version of an earlier synthesized ligand – is highly effective in activating human iNKT cells. It is also selective – encouraging iNKT cells to release a specific set of proteins known as Th1 cytokines, which stimulate anti-tumour immunity.

Image: 3D structure of proteins behind interaction of new drug that stimulates immune response to cancer cells. (Entire image here)

Scientists map important immune system enzyme for the first time

2018/03/292018/04/12

Biochemists from McGill University are getting a good look at just how a specific enzyme that is part of the human immune system interacts with a certain group of bacteria that are described as gram-negative.

Researchers around the world “have been studying the enzyme, known as AOAH, for more than 30 years. This is the first time anyone has been able to see exactly what it looks like,” according to Bhushan Nagar, an associate professor of biochemistry at McGill University in Montreal.

More than that, the 3D images captured a moment in time which shows just how AOAH inactivates a toxic molecule that is commonly part of various gram-negative bacteria. The research was conducted at the Canadian Light Source.

Numerous types of gram-negative bacteria exist throughout the environment. While some are harmless, many cause a variety of human illnesses, says Nagar. For example, several species such as E. coli and Salmonella, cause food borne illness. Others cause infections such as pneumonia, meningitis, bloodstream infections or gonorrhea.

>Read more on the Canadian Light Source

Image: Bhushan Nagar (principal investigator), Alexei Gorelik (first author of paper) and Katalin Illes (research assistant at Nagar lab) at their McGill University lab.
Credit: Bhushan Nagar.