Studies since the start of the pandemic have noted that pigs can be infected by the virus if exposed to high doses, but the infection is self-limited and pigs don’t show clinical signs of disease nor do they transmit the virus to other animals. So Rahul Nelli, a research assistant professor of veterinary diagnostic and production animal medicine, and Luis Gimenez-Lirola, an associate professor of veterinary diagnostic and production animal medicine, set out to find out why in a newly published study in the academic journal Cell Death Discovery. What they found could lead to new ways to treat humans who contract COVID-19, the disease that results from infection by the virus SARS-CoV-2, said Nelli and Gimenez-Lirola.

Nelli and Gimenez-Lirola have studied how coronaviruses affect pigs for years. They’ve developed models that allow them to study in detail how viruses infect pigs and pig cells and how the cells respond to fight the infection. For the latest experiments, they introduced the virus to cultured porcine and human respiratory epithelial cells, which line most of the respiratory tract. They found the pig cells underwent apoptosis, or controlled cell death, in response to infection at a higher rate than human epithelial cells.

“When we looked under the microscope there was an interesting phenomenon going on inside the cells,” Nelli said. “The nuclei of the infected pig cells were starting to shred into fragments but not uninfected pig cells.”

That shredding of the nucleus is a telltale sign of apoptosis, which may be a key in helping pigs avoid symptoms after exposure to SARS-CoV-2. Triggering apoptosis early in the infection essentially causes minimal tissue damage and confines viral replication, thus limiting severe illness. Human cells can undergo apoptosis in response to coronavirus infection as well, but the study found human cells do so much less frequently than porcine cells. Pig cells are roughly 100 times more likely to undergo apoptosis than human cells, according to the study.

Human cells are more likely to go through necrosis, another form of cell death that’s less controlled than apoptosis. During necrosis, the contents of a cell release into the surrounding space, provoking a strong hyperimmune response that isn’t triggered during apoptosis.

The researchers surmise that a wide-scale apoptosis response is helpful for avoiding disease because it disposes of infected cells quickly without the immune system overreacting, while wide-scale necrosis and the resulting hyperimmune response is less favorable to host cells.

“We don’t want to over-conclude, but this response is probably something intrinsic to the pig immune system that is innate and not acquired,” Giminez-Lirola said. “The idea is to kill the virus subtly but fast enough so there’s not an excessive immune response triggered.”

The researchers said further study could lead to therapies designed to trigger apoptosis in human cells, allowing people infected with the coronavirus to avoid severe symptoms.

The next step for the ISU research team is to identify all the genes activated during the infectious process and compare them with other animal species in which those genes are present. That could give them further clues about how and why other animals, such as deer, can carry the virus without suffering symptoms of disease.

In addition to Nelli and Gimenez-Lirola, the research team included Kruttika Phadke, Gino Castillo, Lu Yen and Bryan Bellaire at Iowa State. Amy Saunders, Rolf Rauh and William Nelson of Maryland-based Tetracore, Inc., are also listed as co-authors of the study.

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“It is important for patients with cancer who are receiving chemotherapy to receive a COVID-19 vaccine,” says Saranya Chumsri, M.D., a Mayo Clinic hematologist and oncologist, and author of the paper. Dr. Chumsri says this advice also applies to patients with cancer who are taking a CDK 4/6 inhibitors. These inhibitors are a newer class of medicines used to treat hormone-receptor-positive and HER2-negative breast cancers.

Dr. Chumsri says that while CDK 4/6 inhibitors are not conventionally considered to be as immunosuppressive as chemotherapy, her research on patients with breast cancer who take these drugs found that they exhibited less optimal neutralizing antibody activity. Dr. Chumsri recommends that antibody levels be tested in these patients after vaccination, and they should consider receiving booster vaccinations for COVID-19.

Dr. Chumsri anticipates having additional data later this year regarding broader immune responses to COVID-19 vaccinations, including cellular and antibody responses in patients receiving chemotherapy and targeted therapies with booster vaccinations.

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“Our study suggests that maintaining and improving social connections may benefit the oral health of older adults,” said Xiang Qi, a PhD student at NYU Meyers and the study’s first author. “The findings align with previous studies demonstrating that structural indicators of social disconnection can have powerful effects on indicators of health and well-being.”

Social isolation and loneliness in older adults are major public health concerns around the world and are risk factors for heart disease, mental health disorders, cognitive decline, and premature death. In some countries, including the United States and China, up to one in three older adults are lonely, according to the World Health Organization. The COVID-19 pandemic has exacerbated these issues among older adults, as many in-person interactions have been interrupted to protect older adults from infection.

Social isolation and loneliness are related but different. Social isolation is an objective measure defined as having few social relationships or infrequent social contact with others, while loneliness is the feeling created by a lack of social connection.

“While social isolation and loneliness often go hand in hand, it’s possible to live alone and be socially isolated but to not feel lonely, or to be surrounded by people but still feel lonely,” said Bei Wu, Dean’s Professor in Global Health at NYU Meyers and the study’s senior author.

Older adults are also at risk for another health concern: losing teeth. In China, older adults aged 65 to 74 have fewer than 23 teeth on average (adults typically have 32 teeth, or 28 if wisdom teeth have been removed) and 4.5% of this age group has lost all of their teeth. Gum disease, smoking, lack of access to dental care, and chronic illnesses like diabetes and heart disease increase the risks of tooth loss. Missing teeth can have a significant impact on one’s quality of life, affecting nutrition, speech, and self-esteem.

To understand the relationship between social isolation, loneliness, and tooth loss in older adults in China, the researchers used the Chinese Longitudinal Healthy Longevity Survey to analyze data from 4,268 adults aged 65 and up. The participants completed surveys at three different timepoints (2011-12, 2014, and 2018), which captured measures of social isolation and loneliness, how many teeth people had and lost over the 7-year study, and other factors. More than a quarter (27.5%) of the study participants were socially isolated, and 26.5% reported feeling lonely.

The researchers found that higher levels of social isolation were associated with having fewer teeth and losing teeth more quickly over time, even when controlling for other factors such as oral hygiene, health status, smoking and drinking, and loneliness. Older adults who were socially isolated had, on average, 2.1 fewer natural teeth and 1.4 times the rate of losing their teeth than those with stronger social ties.

“Socially isolated older adults tend to be less engaged in social and health-promoting behaviors like physical activity, which could have a negative impact on their overall functioning and oral hygiene, as well as increase their risk for systemic inflammation,” said Wu. “This functional impairment seems to be a major pathway linking social isolation to tooth loss.”

Surprisingly, loneliness was not associated with the number of remaining teeth, nor with the rate of tooth loss.

“While social isolation can result in a lack of support that can affect health behaviors, for older adults who feel lonely, it’s possible that their social networks are still in place and can help them to keep up healthy behaviors,” said Qi.

The findings — which are relevant to countries beyond China, given that social isolation and tooth loss are global issues — highlight the importance of developing interventions to reduce social isolation. Programs could aim to foster intergenerational support within families and improve older adults’ peer and social connections within their local communities.

Additional study authors include Yaolin Pei of NYU Meyers, Katherine Wang of Duke University, and Shuyu Han of Fudan University in China. The research was supported by the National Institute on Aging (1R56AG067619) and the National Institute of Dental and Craniofacial Research (U01DE027512).

Among African children admitted to 25 hospitals with COVID-19 between March and December 2020, infants younger than 1 year had nearly five times the risk of death than adolescents aged 15 to 19 years. Children of all ages with comorbidities, including high blood pressure, chronic lung diseases, hematological disorders and cancer, also were at higher risk of dying.

“Although our study looked at data from earlier in the pandemic, the situation hasn’t changed much for the children of Africa — if anything, it is expected to be worsening with the global emergence of the highly contagious Omicron variant,” said lead author Jean B. Nachega, M.D., Ph.D., M.P.H., associate professor of infectious diseases and microbiology and epidemiology at Pitt’s Graduate School of Public Health. “Vaccines are not yet widely available, and pediatric intensive care is not easily accessible.”

The study examined outcomes in 469 children who ranged in age from 3 months to 19 years and were hospitalized in one of six countries: the Democratic Republic of the Congo, Ghana, Kenya, Nigeria, South Africa and Uganda. A quarter of the children had pre-existing conditions. Eighteen had confirmed or suspected multisystem inflammatory syndrome, a serious complication of COVID-19 where different parts of the body become inflamed.

The study, which included investigators across all six of the African countries that provided data, found that 34.6% of hospitalized children were admitted to an intensive care unit (ICU) or required supplemental oxygen, and 21.2% of those admitted to the ICU required invasive mechanical ventilation. During the time frame studied, 39 — over 8% — of the children died. This compares with rates between 1% and 5% that have been reported in high-income countries.

“The high morbidity and mortality associated with hospitalized children with COVID-19 in our study challenge the existing understanding of COVID-19 as a mild disease in this population,” said Nachega, also a professor extraordinary of medicine at Stellenbosch University’s Faculty of Medicine and Health Sciences in Cape Town, South Africa. “But if a child has a comorbidity, is very young and is in a place where there are limited or no specialized doctors, facilities or equipment for pediatric intensive care, then that child faces a very real possibility of dying.”

“Our findings call for an urgent scale-up of COVID-19 vaccination and therapeutic interventions among at-risk eligible children and adolescents in Africa,” Nachega continued. “They also raise further the acute need for capacity-building and support for pediatric intensive care in these settings.”

Nachega noted recent progress on increasing the COVID-19 vaccine supply in Africa but emphasized that those vaccines are not yet widely available and only about 5% of the continent’s population has been fully vaccinated.

“COVID-19 vaccine hesitancy is a global issue, and Africa is no exception,” he said. “It is imperative that evidence-based public health campaigns address concerns in accessible, trustworthy ways so that there is high vaccine uptake as soon as it is available.”

Additional investigators of this study are members of the African Forum for Research and Education in Health COVID-19 Research Collaboration on Children and Adolescents and are listed in the JAMA Pediatrics article.

This research was supported by National Institutes of Health Fogarty International Center grant 1R25TW011217-01.

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The study, which examined zebrafish embryos, discovered a type of astrocyte glial cell that is new to science, and have been named estrogen responsive olfactory bulb (EROB) cells.

estrogens are known for their roles as signalling hormones in the development of sex, but the study shows that prior to sexual differentiation (when the sex of an individual becomes fixed), a small group of cells in the region of the brain where the sense of smell develops, the olfactory bulb, are responsive to estrogen.

The research, led by Dr Aya Takesono of the University of Exeter, employed a genetically engineered (transgenic) zebrafish, developed in the laboratories of Professor Tyler and Dr Kudoh at Exeter, that enables cells and tissues responding to estrogen to be seen via microscopy imaging for this work.

Using this transgenic zebrafish, together with chemical and genetic methods to manipulate these estrogen responding cells, has revealed a new function of estrogens during embryonic brain development.

Dr Takesono said: “Previous studies in mice have shown that estrogen is important for development of the somatosensory cortex of the brain and for establishing sexual dimorphic brain tissues that mediate reproductive functions and behaviour in later life.

“In this study, however, we show that the olfactory bulb is the one of earliest parts of the developing brain that is responsive to estrogens in the zebrafish embryo.

“We further show that our newly discovered EROB cells mediate the estrogen driven instruction for development of olfactory sensory system in the embryonic brain.”

Tracing the development of these EROBs using various cellular and imaging methods showed they interact with olfactory sensory neurons and their loss — or disturbance of their interactions with the surrounding neurons — disrupts establishing inhibitory neural connections in the olfactory glomeruli.

Using another transgenic zebrafish, this time one that detects both neural activity (via the detection of calcium produced when nerve cells fire) and estrogen responses, the study shows that estrogen signalling alters neuronal activity in the olfactory bulb through these newly identified EROBs which in turn affects odorant-response behaviour.

This study provides evidence that estrogens act on EROB glia to regulate olfactory circuits with important consequences for the sense of smell in later life.

Professor Tyler, senior author in the work, said: “This work identifying new embryonic brain cells involved in the development of the sense of smell in fish opens up a major new research area for us.

“Surface waters receive many human-made chemicals that mimic estrogens and an intriguing question we wish to now address is whether these chemicals affect the function of the EROB glia in embryogenesis and thus alter the sense of smell, as this could have major fitness consequences for fish.”

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