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National Institutes of Health (NIH) Research Updates – October 2021

The National Institutes of Health (NIH) is our nation’s medical research agency. Its mission focuses on scientific discoveries that improve health and save lives. Founded in 1870, the NIH conducts its own scientific research through its Intramural Research Program (IRP), which supports approximately 1,200 principal investigators and more than 4,000 postdoctoral fellows conducting basic, translational and clinical research. In this blog, we will highlight recent innovative NIH research.

Recent NIH Research

Infection hinders blood vessel repair following traumatic brain or cerebrovascular injuries

Traumatic brain injury, or TBI, occurs due to sudden external force to the brain resulting in damage to blood vessels and other internal tissue. Similarly, cerebrovascular injury (CVI) refers to a spectrum of injuries to the cervical carotid or vertebral arteries due to blunt force trauma. These conditions are a leading cause of long-term complications, disability or death depending on the severity of injury.

In a recent study, scientists from the National Institute of Neurological Disorders and Stroke (NINDS) have found that systemic infection, which often accompanies these types of conditions can negatively impact recovery and worsen outcomes. The research team, led by Dr. Dorian McGavern, discovered that viral, fungal, or a mimic for bacterial infections all impacted blood vessel repair within the meninges, the protective covering of the brain. Using a mouse model previously developed by the team for studying mild TBI (mTBI), they observed that some cells of the immune system no longer moved into the site of TBI injury, which occurred in the uninfected animals, suggesting they were responding to systemic infection. Similar findings were confirmed for CVI injury.

“Evolution prioritizes mobilizing the immune system to fight off infection over repair,” said Dr. McGavern. “Because the body is dealing with a greater threat, cells that would normally repair the damaged blood vessels in or around the brain are needed elsewhere.”

The infected mice were eventually able to repair the blood vessel damage at a later time unless a second infection was encountered. This timing is especially critical in the case of CVI mice, because the delay in response produced by infection led to permanent cognitive dysfunction and damage to the brain tissue.

Although the presence of infection was affecting the immune system’s ability to respond to mTBI, the exact cause remained unknown. The researchers observed that when cells in the body become infected, they release proteins that signal the immune system for help. One group of proteins released after viral infection are called type I interferons (IFN-I), which activate a variety of genes that affect the immune response. Following mTBI, the researchers saw a large increase in IFN-I-related genes in infected compared to non-infected mice. Additional experiments confirmed the role of IFN-I in shifting the focus of the immune system away from blood vessel repair.

Systemic infections are common among patients hospitalized for TBI and CVI, and have been linked to poorer outcomes. This study highlights the importance of controlling both bacterial and viral infections as quickly as possible, as a delay in repair can lead to permanent damage to the brain.

NIAID scientists find a key to Hepatitis C entry into cells

Hepatitis C is one of the most common bloodborne diseases in the United States. It is caused by the hepatitis C virus (HCV) from contact with infected blood. While the disease may be asymptomatic in its early stages, left untreated it can lead to severe liver damage, cancer and death. Currently, there is no vaccine to protect against HCV infection. Common routes of transmission are through exposure from unsafe injection practices such as intravenous drug use, unsafe healthcare or unscreened blood transfusions.

The Center for Disease Control reports that an estimated 2.4 million Americans are living with hepatitis C. More than half of all people infected with HCV are thought to develop a chronic infection. Effective antiviral medications are available to treat HCV infection for patients meeting the clinical criteria, however they will not prevent reinfection.

A team of researchers from the National Institute of Allergy and Infectious Diseases (NIAID) and colleagues examined the interaction between a protein expressed on the surface of the HCV, known as HCV E2, and a receptor called CD81 found on the surface of some human cells. Prior research had shown that antibodies interfered with interactions between these two proteins. This suggested that the interaction between HCV E2 and CD81 allowed HCV to enter and infect human cells. However, the exact mechanism of how this occurred was largely unknown.

In their new study, the team determined the exact structure of HCV E2 and CD81 and noted how the two proteins interacted when exposed to each other under different conditions. They found that under acidic conditions, HCV E2 easily binds to the CD81 receptor. Once the interaction between virus and receptor begins, HCV E2 changes shape, facilitating its entrance into the cell by putting the virus in closer contact with the cell membrane.

This ground-breaking research may provide the foundation for a vaccine against HCV that potentially could cause a person to make specific antibodies that prevent HCV E2 from binding with CD81, stopping the virus from entering the cell, and  thereby preventing HCV infection.

NINDS scientists build cellular map of multiple sclerosis lesions

Multiple Sclerosis (MS) is a chronic disease affecting the central nervous system, in which the immune system attacks myelin, the protective sheath surrounding nerve fibers. This causes inflammation and lesions that make it difficult for the brain to transmit signal to rest of the body. Chronic active plaques or lesions with inflamed rims have been linked to progressive MS, a more aggressive and disabling form of the disease. There is no cure for MS, and no therapies that directly treat chronic active lesions.

Scientists at the National Institute of Neurological Disorders and Stroke (NINDS) have constructed a cellular map of chronic MS lesions through the identification of the genes that play a vital role in the repair of lesions. This map, or ‘blueprint’ may reveal potential therapeutic targets for progressive MS.

“We identified a set of cells that appear to be driving some of the chronic inflammation seen in progressive MS,” said Dr. Daniel Reich, senior investigator at NINDS. “These results give us a way to test new therapies that might speed up the brain’s healing process and prevent brain damage that occurs over time.”

Chronic active lesions are characterized by a slowly expanding rim of immune cells called microglia, which normally help protect the brain. In MS, they can become overactive and secrete toxic molecules that damage nerve cells. Astrocytes and lymphocytes found near the lesions may also contribute to ongoing tissue damage, however, prior research suggests that microglia are primarily responsible for lesion expansion.

To gain a better understanding of the MS lesions, Dr. Reich’s team used single-cell RNA sequencing to analyze the gene activity profiles of more than 66,000 human brain tissue cells, post-mortem from MS patients along with healthy controls. The team found a large diversity of cell types in the tissue surrounding chronic active lesions compared to normal tissue, and a high proportion of immune cells and astrocytes at the active edges of those lesions. Microglia comprised 25% of all immune cells present at the lesion edges.

Further analysis revealed that the gene for complement component 1q (C1q), an important and evolutionarily ancient protein of the immune system, was expressed mainly by a subgroup of microglia responsible for driving inflammation, suggesting that it may contribute to lesion progression. According to the authors, it’s possible that targeting C1q in human microglia could halt MS lesions and related neurodegenerative diseases in their tracks and supports the use of chronically inflamed rim lesions as an MRI biomarker for disease progression.

NIDA study finds Methamphetamine-involved overdose deaths nearly tripled between 2015 to 2019

In a new study by the National Institute on Drug Abuse (NIDA), researchers have found that methamphetamine related overdose deaths among people ages 18-64 from 2015 to 2019 in the United States. The number of people who reported using methamphetamine during this time did not increase as steeply, but the analysis found that populations with methamphetamine use disorder have become more diverse. Increases in higher-risk patterns of methamphetamine use, such as methamphetamine use disorder, frequent use, and combined drug use, may be contributing to the rise in overdose deaths.

“We are in the midst of an overdose crisis in the United States, and this tragic trajectory goes far beyond an opioid epidemic. In addition to heroin, methamphetamine and cocaine are becoming more dangerous due to contamination with highly potent fentanyl, and increases in higher risk use patterns such as multiple substance use and regular use,” said Dr. Nora Volkow, NIDA Director and one of the authors of the study. “Public health approaches must be tailored to address methamphetamine use across the diverse communities at risk, and particularly for American Indian and Alaska Native communities, who have the highest risk for methamphetamine misuse and are too often underserved.”

The CDC reported an unprecedented 30% increase in overdose deaths in 2020 in the US, primarily driven by fentanyl and other synthetic opioids. Overdose deaths involving psychostimulants, and particularly methamphetamine, have also risen steeply in recent years, and many of these deaths involved use of an opioid at the same time. However, questions remain on how trends in methamphetamine use contribute to greater risk for overdose deaths.

The researchers found that from 2015 to 2019, the number of overdose deaths involving psychostimulant drugs other than cocaine, (largely methamphetamine), rose from 5,526 to 15,489, a 180% increase. However, the number of people who reported using methamphetamine only increased by 43% over the same period, indicating that riskier use patterns may have contributed to the increased numbers of methamphetamine-involved overdose deaths during this time period.

The team also noted significant shifts in the populations using methamphetamine between 2015 and 2019. Historically, methamphetamine has been most commonly used by middle-aged white persons. In this new study, it was determined that American Indians and Alaskan Natives had the highest prevalence of methamphetamine use, as well as methamphetamine use disorder and methamphetamine injection. Previous studies have found that American Indians and Alaskan Natives also had the largest increases in methamphetamine overdose deaths in recent years.

The study also determined the prevalence of methamphetamine use disorder among those who did not inject the drug increased 10-fold among Black people from 2015 to 2019, a much steeper increase than among white or Hispanic people. Methamphetamine use disorder without injection quadrupled in young adults ages 18 to 23, a substantially greater increase than in older age groups. This is of particular concern, as young adulthood is a critical period of continued brain, social, and academic maturation, and could have long-lasting consequences from methamphetamine use disorder during this vulnerable period.

Currently, there are no approved medications for the treatment of methamphetamine use disorder. The research team at NIDA is working to develop safe and effective medications aimed at slowing this sharp increase in methamphetamine use, overdoses, and related deaths.

NIH study provides insights into the origins of lung cancer in never smokers

A recent collaborative international study, led by scientists at the National Cancer Institute (NCI) has provided insights that will help unlock the mystery of how lung cancer arises in people who have no history of smoking and may guide the development of more precise clinical treatments.

A genomic analysis of lung cancer in people with no prior history of smoking has found that the majority of these tumors arise from the accumulation of mutations caused by natural processes in the body. It describes for the first time three molecular subtypes of lung cancer in people who have never smoked.

“What we’re seeing is that there are different subtypes of lung cancer in never smokers that have distinct molecular characteristics and evolutionary processes,” says Dr. Maria Teresa Landi, senior investigator at NCI’s Integrative Tumor Epidemiology Branch and study leader. “In the future we may be able to have different treatments based on these subtypes.”

The research team is starting to distinguish subtypes that could potentially have different approaches for prevention and treatment. Dr. Landi noted that a slow-growing piano subtype could give clinicians a window of opportunity to detect these tumors earlier when they are less difficult to treat. The mezzo-forte and forte subtypes have only a few major driver mutations which could enable tumors to be identified by a single biopsy and could benefit from targeted treatments.

Lung cancer is the leading cause of cancer-related deaths worldwide, with a global estimate of more than 2 million people annually diagnosed with the disease. Most people who develop lung cancer have a history of tobacco smoking, however, between 10% and 20% of people who develop lung cancer have never smoked. Lung cancer in never smokers occurs more frequently in women and at an earlier age than lung cancer in smokers. Environmental risk factors, such as exposure to secondhand tobacco smoke, radon, air pollution, and asbestos, or prior lung diseases, may explain some lung cancers among never smokers, but scientists still are not certain what causes the majority of these cancers.

Upcoming Events

Advancing NIH Research on the Health of Women

Wednesday, October 20, 2021, 8:30 am to 5:00 pm (registration required)

Macrophage Infection by HIV: Implications for Pathogenesis and Cure

Wednesday, October 13, 2021 to Thursday, October 14, 2021 (registration required)

NIH Behavioral and Social Sciences Research Festival

Friday, November 19, 2021, 9:00 am to 5:00 pm