In response to the pandemic, many Einstein scientists have pivoted from their ongoing research to tackle the novel coronavirus and the COVID-19 disease it causes. Here we describe three such projects that are now underway.
Seeking a Broad-Spectrum Viral “Antibiotic”
A compound isolated from an Asian shrub that protects human cells from Zika virus infection also may work against the novel coronavirus, according to new laboratory research.
“COVID-19 is the third pandemic in recent decades to be caused by a coronavirus,” said lead researcher Felipe Diaz-Griffero, Ph.D., professor of microbiology & immunology and the Elsie Wachtel Faculty Scholar at Einstein. “To be prepared for the fourth outbreak, we’ll need a broad-spectrum anti-viral compound like the one we’re evaluating now. Like an antibiotic that inhibits several types of bacteria, a broad-spectrum antiviral will target different viruses and prepare us for future outbreaks.”
The anti-viral compound—6-deoxyglucose-diphyllin, or DGP—was originally tested as a treatment for Zika, which is caused by a mosquito-borne flavivirus. DGP was found to prevent Zika virus from infecting mice as well as a variety of human cell lines, according to a study that Dr. Diaz-Griffero published last year in the journal EBioMedicine. “DGP potently inhibited Zika virus infection at very low concentrations,” he said, “and we couldn’t detect any toxic effects in mice or in human cells.”
The compound also showed activity against other disease-causing viruses, including two coronaviruses (SARS-CoV-1 and MERS-CoV), several flaviviruses (Dengue and West Nile), and Ebola virus. Now, in a new experiment, Dr. Diaz-Griffero has found that DGP can protect human cells in tissue culture from infection with SARS-CoV-2, the coronavirus that causes COVID-19. He is now searching for opportunities to evaluate the compound in preparation for a phase 1 clinical trial.
Zika and many other viruses enter cells via a process in which a portion of the cell membrane surrounds and entraps viruses and other material attached to the cell. That membrane segment buds off within the cell to form structures called endosomes, which transport their cargo elsewhere in the cell for destruction. But the endosomes’ acidic environment is hospitable to viruses, allowing them to survive and ultimately escape into the cell body to replicate. In his Zika study, Dr. Diaz-Griffero showed that DGP inactivates viruses by lowering the acidity within endosomes.
Breath Test May Improve Diagnosis of Coronavirus Infections
Einstein researchers are developing a breath test for coronavirus that could improve the detection of active infections.
In the nasal swab PCR test—the standard test for active coronavirus infection—a healthcare worker uses a long cotton swab to obtain secretions from deep within the nasopharynx, the first part of the body the virus infects. But the test’s accuracy depends heavily on testing at the right time and the worker’s skill at obtaining a valid secretion sample—which may explain why the swab test misses an estimated 30 percent of active infections.
“With so many ‘false negative’ tests, we’re left with a lot of people who think they’re disease-free but are actually shedding virus,” said Simon Spivack, M.D., M.P.H., professor of medicine, of epidemiology & population health, and of genetics at Einstein. “Even if just 20 percent of active COVID-19 cases are missed, that’s more than enough to sustain the pandemic.”
As the pandemic began to unfold, Dr. Spivack realized a breath test that he’s developing to detect lung cancer could be adapted for COVID-19 diagnosis. “If you breathe outside on a cold January day, you’ll see the water portion of your breath appear in the form of a mist,” he explained. “That moisture, or exhaled breath condensate, contains lots of microRNAs and other biological material.” MicroRNAs—small bits of RNA that regulate gene expression—vary from one cell type to another and from healthy to diseased cells.
Dr. Spivack is a pulmonary medicine specialist who has been treating COVID-19 patients at Montefiore. His previous research found that people predisposed to lung cancer exhale a different microRNA signature than those with healthy lung tissue. It stands to reason, he said, that lungs actively infected with coronavirus will also have a unique microRNA signature that could be detected in exhaled breath condensate. He is planning to test this hypothesis as part of an ongoing NIH-funded study of age-related changes in the human lung.
Since the standard nasal swab test also measures microRNAs, Dr. Spivack’s test of breath condensate would have some of the same limitations. “I’m not sure this will be a better mousetrap than the nasal swab PCR test for COVID-19 diagnosis,” he said, “but it would probably pick up some of the cases now missed by nasal swab testing alone. Using the two tests together might be better than using either of them alone.”
Dr. Spivack hopes to begin collecting exhaled breath samples from people in a few weeks. He is teaming up with Einstein scientists Irwin Kurland, M.D., Ph.D., associate professor of medicine, and Simone Sidoli, Ph.D., assistant professor of biochemistry, to measure metabolites and small peptides in exhaled breath. “We expect that those molecules along with exhaled microRNAs will comprise unique signatures of the virus itself or of the human response to the virus,” said Dr. Spivack.
The breath test would also allow for noninvasive access to samples deep within the lungs, which could help reveal why older COVID-19 patients experience higher rates of respiratory failure and death compared to younger ones. “It’s very challenging to study the lung complications of COVID-19 without having biospecimens from the deep lung,” said Dr. Spivack. “Concerns over the risks faced by healthcare workers have virtually shut down bronchoscopies and thoracic surgeries across the country, greatly limiting our access to lung tissue samples. We’re proposing exhaled breath as an alternative approach that could be more widely used on a population level.”
A Long-Term Strategy Against a Pandemic
Most infectious disease researchers are understandably focused on the here and now of the COVID-19 pandemic, seeking therapies or vaccines against it. But many Einstein researchers are taking the long view—looking for factors that put people at risk for coronavirus infection or help protect against it. Such knowledge could help prevent future outbreaks or minimize their impact.
“We’ve never had an exposure quite like this, with so many things we don’t know about the disease,” said Robert Burk, M.D., professor of pediatrics, of microbiology & immunology, and of epidemiology & population health at Einstein and an attending physician at Montefiore. “Why do some people get infected but not others? Why do some people remain symptom free while others become seriously ill? Genetics? Pre-existing conditions? Diet? The home environment? We can gain answers through large-scale population studies that collect detailed health data before and after exposure to a disease like COVID-19.”
Epidemiologists Carmen R. Isasi, M.D., Ph.D., and Robert C. Kaplan, Ph.D., are conducting just such a study: the longstanding Hispanic Community Health Study /Study of Latinos (HCHS/SOL), the most comprehensive analysis of Latino/Hispanic health and disease in the United States. Some 16,000 Hispanics/Latinos—the fastest-growing segment of the population—are enrolled in this multicenter, NIH-funded study. Dr. Isasi is associate professor of epidemiology & population health and of pediatrics. Dr. Kaplan is professor of epidemiology & population health and the Dorothy and William Manealoff Foundation and Molly Rosen Chair in Social Medicine.
“We have already begun collecting data on the study participants’ COVID-19-related diagnoses and hospitalizations, including how the pandemic has affected them personally from a health, emotional and employment standpoint,” said Dr. Isasi, who was responsible for rapidly re-designing the project to encompass the COVID-19 pandemic.
Their study is also investigating whether the gut microbiome (the collection of microorganisms live in the intestinal tract) influences the body’s response to SARS-CoV-2, the coronavirus that causes COVID-19. “We know from many studies that the gut microbiome has important immunological functions,” said Dr. Burk. “The microbiome could be contributing to the immune system’s overreaction to the virus—the so-called cytokine storm that overwhelms the lungs and is the main cause of death in patients with COVID-19.”
Analyses of the gut microbiome before and after people’s coronavirus exposure, Dr. Burk said, could help predict which patients with the infection are likely to experience a cytokine storm and lead to strategies to prevent it from happening.
The Einstein teams also plan to look at the long-term effects of coronavirus infection—not only on the lungs but also on the heart, liver, and neurological system. Most patients sickened by SARS-CoV-2 appear to make a complete recovery, but history shows the full effects of viral infections may not become apparent for years.
Viruses all too often “revisit” people in one way or another. Polio survivors, for example, can experience post-polio syndrome decades after recovery from an initial acute attack. People who had chicken pox as children are susceptible to shingles, caused when the varicella zoster virus reactivates after lurking for decades in nerve cells. And after recovering from severe acute respiratory syndrome (SARS)—also caused by a coronavirus—some people experienced long-term effects including depression, cough, shortness of breath, and chronic lung disease or kidney disease.
“We could quite possibly be dealing with the effects of COVID-19 long after this pandemic is over,” said Dr. Kaplan. “We’re hopeful that our ongoing HCHS/SOL can shed light on risk factors that can lead to long-term complications and on what can be done to prevent those complications.”
Posted on: Friday, June 05, 2020