Coming Together to Solve COVID-19 Mysteries

As the COVID-19 pandemic began to be felt, scientists at Penn started work todevelop a vaccineandassess possible treatments. But the scope of COVID-19 studies at the University goes much broader. Scientists whose typical work finds them investigating autoimmune disease, influenza, HIV/AIDS, Ebola, cancer, hemophilia and more, are now applying their deep understanding of biology to confront a novel threat.

What Does SARS COVID-19 Do To Our Lungs? Another respiratory infection, influenza, has been a focus of research led by Andrew Vaughan, Penn Vet assistant professor of biomedical sciences. But Dr. Vaughan didnt hesitate to begin studies of the novel coronavirus once its eventual impact became apparent. Now, graduate students and research specialists in his labworking no more than two together at a time to maximize social distancingare conducting new experiments focused more specifically on the biology of SARS-CoV-2, alongside parallel efforts by Edward Morrissey from PSOM. Knowing that the ACE2 receptor on lung cells is the gateway for the virus into the human body, theyre genetically manipulating alveolar type-two lung cells, which are particularly essential for continuing oxygen exchange deep in the lungs, to alter or block ACE2 gene expression to try to prevent viral entry.

Why are Men Worse Off Than Women? In a separate project, Dr. Vaughan is partnering with Montserrat Anguera, Penn Vet associate professor of biomedical sciences, to explore a curious feature of COVID-19 disease: the fact that more men than women become severely ill and die. A number of hypotheses have been put forward to explain the disparity, but the two labs are investigating one particular possibility.

Dr. Anguera had posted something on Twitter saying that the ACE2 gene happens to be on the X chromosome, meaning that women have two copies of it, said Dr. Vaughan. I immediately texted her and said, I think theres something to that.

Hormone expression levels are another factor that may influence sex differences in disease. Together, Drs. Anguera and Vaughans groups are both studying ACE2 expression and exposing alveolar type-two cells to various hormones to see how expression of viral receptors, ACE2 and others, changes. Ultimately wed like to see if this changes susceptibility to infection, working withSusan Weissand others, said Dr. Vaughan.

Do Genetics Influence Susceptibility? Individual differences in how people respond to infection may be influenced by their unique genomic sequences. PIK Professor Sarah Tishkoff of PSOM and SAS is probing the rich sources of genomic data her group already had in hand to look for patterns that could explain differences in disease susceptibility. Using genomic data from 2,500 Africans collected for another project, Dr. Tishkoffs team is looking for patterns of genetic diversity. Early findings suggest that natural selection may have acted upon on a version of the ACE2 gene, making it more common in some African populations with high exposure to animal viruses.

She is also collaborating withAnurag Vermaand Giorgio Sirugo of Penn Medicine to analyze genetic variation in samples from thePenn Medicine Biobank, looking in particular at people of African descent.

How is the Immune System Reacting? The immune system is what eliminates the virus, saidE. John Wherry, chair of Systems Pharmacology and Translational Therapeutics at PSOM. The immune system is what we need to activate with a good vaccine. But also, especially in many respiratory infections, the immune system is what also causes damage. A healthy outcome means your immune system is striking a balance between killing off the virus and not doing so much damage that it kills you.

Dr. Wherry and Michael Betts, professor of microbiology, have embarked on a study to discern both the magnitude of patients immune responses as well as their flavor, that is, what components in the immune system are being activated by the coronavirus. They are doing so by working with clinicians at HUP and, soon, atPenn Presbyterian Medical Center, to collect blood samples from patients with severe and more mild infections, as well as patients who have recovered from illness, to profile their immune reactions. Variety across patients strongly suggests that the treatments that work for one patient may not for another, Drs. Wherry and Betts note. They are speaking daily with their colleagues on the front lines of COVID-19 care, relaying what theyre finding out in the lab.

The PSOMs Ronald Collman, professor of medicine, andFrederic Bushman, William Maul Measey Professor in Microbiology, have been devoting attention to how the community of bacteria, viruses, fungi and parasites that dwell in the respiratory tract affect health and disease risk. They are now addressing that question in the context of COVID-19. According to Dr. Collman, The microbiome can help set the tone for the immune response to infections, influencing whether a patient ends up with mild or severe disease. And second, the microbiome is where infectious agents that can cause infection can arise from. So if a patient dies of an eventual pneumonia, the pathogen that caused that pneumonia may have been part of that individuals respiratory tract microbiome.

Working with nurses at HUP to collect samples, Drs. Collman and Bushman are analyzing the microbiome of both the upper and lower portions of the respiratory tract of COVID-19 patients. Their labs are using these samples to identify the types and quantities of organisms that compose the microbiome to find patterns in how they correlate with disease.

What Drugs Might Make An Impact? Absent a vaccine, researchers are looking to existing drugssome already approved by the US FDA for other maladiesto help patients recover once infected. Throughout his career,Ronald Harty, Penn Vet professor of pathobiology and microbiology, has worked to develop antivirals for other infections, such as Ebola, Marburg and Lassa Fever.

Though many of the biological details of how SARS-CoV-2 interacts with the human body are distinct from the other diseases Dr. Harty has studied, his group noticed a similarity: A sequence hes targeted in other virusesa motif called PPxYis also present in the spike protein of SARS-CoV-2, which the coronavirus uses to enter cells.

This caught our eye, said Dr. Harty, and piqued our interest in the very intriguing possibility that this PPxY motif could play a role in the severity of this particular virus. He is testing antivirals he has helped identify that block the replication of Ebola, Marburg and other viruses to see if they make a dent on the activity of SARS-CoV-2. Those experiments will be done in collaboration with colleagues whose labs can work in BSL-III or -IV laboratories.

Also of interest is the speculation that the coronavirus might disrupt cell-cell junctions in the human body, making them more permeable for virus spread.

Another faculty member is assessing whether a drug developed for a very different conditionpulmonary arterial hypertension(PAH)could serve coronavirus patients. Henry Daniell, vice-chair and W.D. Miller Professor in Penn Dentals department of basic and translational sciences, shared news that a drug grown in a plant-based platform to boost levels of ACE2 and its protein product, angiotensin (1-7), was progressing to the clinic to treat PAH. Dr. Daniell is now working withKenneth Margulies, PSOM professor of medicine and physiology and research and fellowship director of the Heart Failure and Transplant Program, to explore whether this novel oral therapy can improve the clinical course of patients with symptomatic COVID-19 infection.

Reduced ACE2 expression has been linked to acute respiratory distress, severe lung injury, multi-organ failure and death, especially in older patients. The earlier preclinical studies in PAH animal models showed that orally delivered ACE2 made in plant cells accumulated ten times higher in the lungs than in the blood and safely treated PAH. Now, new clinical studies have been developed to explore whether oral supplementation of ACE2 and angiotensin-1-7 can help mitigate complications of COVID-19 disease. The fact that freeze-dried plant cells can be stored at room temperature for as long as a year and can be taken at home by COVID-19 patients make this novel approach an attractive potential option.

This trial has been given a high priority by the Penn Clinical Trial Working Group, said Dr. Daniell. Im pleased that this looks to be on the cusp of moving forward to help the growing number of COVID-19 patients.

As the coronavirus began to spread in the US, Joshua Plotkin, Walter H. and Leonore C. Annenberg Professor of the Natural Sciences, began to raise alarms about Philadelphias St. Patricks Day parade. His studies of the 1918 flu pandemic had explored disease incidence and spread, and it was hard to avoid noticingthe role of the Liberty Loan paradedown Broad Street in triggering a rampant spread of flu back then. Now, with work conducted with two graduate students and faculty member Simon Levin fromPrinceton University, Dr. Plotkin has mathematically sound advice for policymakers hoping to effectively stem the spread of a pandemic. In apreprint on arXiv.org, they share optimal, near-optimal, and robust strategies.

Their analysis makes the realistic assumption that policymakers can only enforce social distancing for a limited amount of time and aims to minimize the peak incidence of disease. The optimal strategy, they found, is to start by introducing moderate social distancing measures to keep the incidence rate the same for a period of time. This would mean that every person with COVID-19 would infect one additional person. Then the intervention should switch over to a full suppressionthe strongest possible quarantinefor the rest of the period. At the end of that period, all restrictions would be lifted.

This works because you dont want to fully suppress disease spread right off the bat, said Dr. Plotkin, because then at the end, after you remove restrictions, there will be a second peak that is just as large as the first. By employing a moderate suppression at the beginning, youre building up a population of people who are going to recover and become immune, without letting the epidemic get out of control.

Dr. Plotkin and colleagues are hoping to share the findings widely to help navigate a likely second wave of COVID-19.

Adapted from a story by Katie Baillie, Penn TodayVisithttps://tinyurl.com/pennandcovid for the full story.

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