Lung, immune function in kids could protect from severe COVID-19

July 8, 2020

Science Daily/University of Texas Health Science Center at Houston

Differences in lung physiology and immune function in children could be why they are more often spared from severe illness associated with COVID-19 than adults, according to pediatric and adult physicians at The University of Texas Health Science Center at Houston (UTHealth) and Baylor College of Medicine, who teamed up to investigate the disparity.

The perspectives paper was recently published in American Journal of Physiology-Lung Cellular and Molecular Physiology.

According to the paper, only about 1.7% of the first 149,082 cases in the U.S. were infants, children, and adolescents younger than 18 years old. Authors noted that children under 18 make up 22% of the U.S. population. Only three pediatric deaths were identified by the Centers for Disease Control and Prevention (CDC) as of April 2020.

"These profoundly decreased rates of symptomatic infection, hospitalization, and death are well beyond statistical significance, require further examination, and may hold the key to identifying therapeutic agents," the authors wrote.

Angiotensin-converting enzyme 2s, called ACE2, are the doors that allow SARS-CoV-2, the novel coronavirus that causes COVID-19, to enter the body's cells. Children naturally have less ACE2 in the lungs than adults.

"ACE2 are important for viral entry and there seems to be less of them in children, because they increase with age," said Matthew Harting, MD, MS, assistant professor in the Department of Pediatric Surgery at McGovern Medical School at UTHealth, pediatric surgeon with UT Physicians, and senior author of the paper. Harting is also director of the pediatric ECMO program providing advanced cardiac and respiratory support at Children's Memorial Hermann Hospital.

In addition to fewer ACE2 receptors, the authors note the immune system in children responds to viruses differently than that of adults, leaving less opportunity for severe illness in pediatric patients. There are several different mechanisms behind the differences, including the retention of T-cells in children, which are able to fight off or limit inflammation.

"T-cells have a viral response and also an immune modulator response. In severe cases of adult COVID-19 patients, we've seen that those T-cells are reduced, so the ability to fight the virus is also reduced. In kids, those T-cells seem to be maintained, so they are still able to prevent the virus," said Harry Karmouty-Quintana, PhD, an assistant professor in the Department of Biochemistry and Molecular Biology at McGovern Medical School, and a co-author of the paper.

Lung tissue in children naturally has a higher concentration of regulator T-cells. Patients with higher levels of T-cells also have higher levels of Interleukin 10 (IL-10), also known as human cytokine synthesis inhibitory factor, an anti-inflammatory cytokine.

"IL-10 inhibits the inflammation of other components like IL-6 that are detrimental. Adults tend to experience hyperinflammatory state, where kids do not," Karmouty-Quintana said. "In preclinical studies in mice, IL-10 has also shown to decrease with age."

The paper's findings were made possible through collaboration in a multidisciplinary group made up of pediatric and adult physicians and scientists in pediatric surgery, adult critical care, neonatology, and molecular biology.

"We, as physicians, have been challenged with the question of how to treat COVID-19 and we're learning in real time," said Bindu Akkanti, MD, associate professor of critical care medicine with McGovern Medical School, attending physician in critical care with Memorial Hermann-Texas Medical Center, and a study co-author. "I knew that to figure out the best way to treat adults, we needed to get a team together to get to the bottom of why children were being spared from severe illness related to the virus. So, I reached out to Dr. Karmouty-Quintana and we teamed up with Dr. Harting and two other physicians in the Texas Medical Center to start investigating." Akkanti also sees pulmonary patients at UT Physicians.

"Collaborations like this between adult and pediatric providers are really important and this disease highlights where we can learn a lot when we compare the way it behaves in younger kids with older people," Harting said. "Even now as we're learning about effective treatments, we're seeing younger people handle this disease better than older people. Moving forward, physicians and scientists need multidisciplinary collaboration to continue learning -- this is just another step in the right direction to attack this virus."

Krithika Lingappan, MBBS, was the first author of the paper and Jonathan Davies, MD, was a co-author. Both Lingappan and Davies are assistant professors of pediatrics at Baylor College of Medicine and neonatologists with Texas Children's Hospital.

As a result of the collaboration, the team has begun a new study using blood samples from patients in different stages of COVID-19 to continue to understand how to treat the virus and the disparities in disease progression between children and adults.

https://www.sciencedaily.com/releases/2020/07/200708155528.htm

COVID-19: Study shows virus can infect heart cells in lab dish

Research uses stem cell technology to learn how coronavirus may directly attack heart muscle

June 30, 2020

Science Daily/Cedars-Sinai Medical Center

A new study shows that SARS-CoV-2, the virus that causes COVID-19 (coronavirus), can infect heart cells in a lab dish, indicating it may be possible for heart cells in COVID-19 patients to be directly infected by the virus. The discovery, published today in the journal Cell Reports Medicine, was made using heart muscle cells that were produced by stem cell technology.

Although many COVID-19 patients experience heart problems, the reasons are not entirely clear. Pre-existing cardiac conditions or inflammation and oxygen deprivation that result from the infection have all been implicated. But until now, there has been only limited evidence that the SARS-CoV-2 virus directly infects the individual muscle cells of the heart.

"We not only uncovered that these stem cell-derived heart cells are susceptible to infection by novel coronavirus, but that the virus can also quickly divide within the heart muscle cells," said Arun Sharma, PhD, a research fellow at the Cedars-Sinai Board of Governors Regenerative Medicine Institute and first and co-corresponding author of the study. "Even more significant, the infected heart cells showed changes in their ability to beat after 72 hours of infection."

The study also demonstrated that human stem cell-derived heart cells infected by SARS-CoV-2 change their gene expression profile, further confirming that the cells can be actively infected by the virus and activate innate cellular "defense mechanisms" in an effort to help clear out the virus.

While these findings are not a perfect replicate of what is happening in the human body, this knowledge may help investigators use stem cell-derived heart cells as a screening platform to identify new antiviral compounds that could alleviate viral infection of the heart, according to senior and co-corresponding author Clive Svendsen, PhD.

"This viral pandemic is predominately defined by respiratory symptoms, but there are also cardiac complications, including arrhythmias, heart failure and viral myocarditis," said Svendsen, director of the Regenerative Medicine Institute and professor of Biomedical Sciences and Medicine. "While this could be the result of massive inflammation in response to the virus, our data suggest that the heart could also be directly affected by the virus in COVID-19."

Researchers also found that treatment with an ACE2 antibody was able to blunt viral replication on stem cell-derived heart cells, suggesting that the ACE2 receptor could be used by SARS-CoV-2 to enter human heart muscle cells.

"By blocking the ACE2 protein with an antibody, the virus is not as easily able to bind to the ACE2 protein, and thus cannot easily enter the cell," said Sharma. "This not only helps us understand the mechanisms of how this virus functions, but also suggests therapeutic approaches that could be used as a potential treatment for SARS-CoV-2 infection."

The study used human induced pluripotent stem cells (iPSCs), a type of stem cell that is created in the lab from a person's blood or skin cells. IPSCs can make any cell type found in the body, each one carrying the DNA of the individual. Tissue-specific cells created in this way are used for research and for creating and testing potential disease treatments.

"This work illustrates the power of being able to study human tissue in a dish," said Eduardo Marbán, MD, PhD, executive director of the Smidt Heart Institute, who collaborated with Sharma and Svendsen on the study. "It is plausible that direct infection of cardiac muscle cells may contribute to COVID-related heart disease."

The investigators also collaborated with co-corresponding author Vaithilingaraja Arumugaswami, DVM, PhD, an associate professor of molecular and medical pharmacology at the David Geffen School of Medicine at UCLA and member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research. Arumugaswami provided the novel coronavirus that was added to the heart cells, and UCLA researcher Gustavo Garcia Jr. contributed essential heart cell infection experiments.

"This key experimental system could be useful to understand the differences in disease processes of related coronaviral pathogens, SARS and MERS," Arumugaswami said.

https://www.sciencedaily.com/releases/2020/06/200630155745.htm