The findings, published in the November 3, 2022 issue of PLOS Biology, also report that the antiviral drug sofosbuvir, already an approved treatment for hepatitis C, effectively inhibited SARS-CoV-2 replication and reversed neuronal alterations in infected brain organoids.

“Vaccines and emerging treatments have reduced the health consequences of COVID-19 in most patients,” said senior study author Alysson R. Muotri, PhD, professor in departments of Pediatrics and Cellular and Molecular at UC San Diego School of Medicine. “But the phenomenon of Long COVID, characterized by persisting symptoms that include neurological impairment, remains poorly understood and without any specific remedy.

“This work helps explain some of the neurological symptoms of COVID-19 and, more importantly, it suggests that an FDA-approved antiviral drug might be repurposed to restore infected brain cells to health and address long-term neurological outcomes of COVID-19.”

Though primarily considered to be a respiratory disease, COVID-19 can cause temporary or long-lasting neurological symptoms in some patients, ranging from loss of taste and smell, impaired concentration (brain fog), and psychological effects such as depression to stroke, epilepsy, and encephalopathy (a change in brain function or structure).

With evidence accumulating that the SARS-CoV-2 virus can infect and alter brain cells (including in developing fetuses), the research team focused on using organoids — self-organizing, three-dimensional tissues derived from cultured stem cells that can mimic some organ functions.

Researchers exposed the brain organoids to SARS-CoV-2, observed viral infection and replication and noted that the virus rapidly decreased the number of excitatory synapses in neurons within seven days post-infection. Excitatory synapses increase the firing action potential of a neuron, while their counterparts, called inhibitory synapses, decrease that potential.

However, when infected organoids were treated with sofosbuvir, viral replication was inhibited, and observed neurological impairments rescued or restored. The findings echo earlier computational models that suggested sofosbuvir could be a treatment and previous research by Muotri and colleagues that found sofosbuvir effectively protected and rescued neural cells infected by the Zika virus.

“The bottom line is that sofosbuvir appears to have the potential to arrest or prevent the development of neurological symptoms in COVID-19 patients,” Muotri said. “And because it has been shown to present no safety concerns in pregnant women, it might also be an option for preventing SARS-CoV-2 transmission to their unborn children.

“Further studies and clinical trials are needed, of course, but these findings offer a path forward for treating a condition (Long COVID) that has so far stymied remedy for millions of people wordwide.”

Co-authors include: Pinar Mesci, Janaina S. de Souza, Angela Macia, Aurian Saleh, Cedric Snethlage, Jason W. Adams, Angels Almenar-Queralt, Ryan A. Szeto, Gabriela Goldberg and Patrick T. Bruck, all at UC San Diego and Rady Children’s Hospital-San Diego; Laura Martin-Sancho, Yuan Pu and Sumit K. Chandra, Sanford Burnham Prebys Medical Discovery Institute; Simoni H. Avansini and Fabio Papes, UC San Diego and University of Campinas, Brazil; and Roberto H. Herai, Pontificia Universidade Catolica do Parana, Brazil and Lico Kaesemodel Institute, Brazil.

“This discovery is the first demonstration in primates that maternal unhealthy diet and obesity disrupt the immune system in the developing fetus,” says Oleg Varlamov of the Oregon National Primate Research Center. “The main implication of this study is that maternal obesity may influence the development of the fetal bone marrow and fetal immune system.”

Pre-pregnancy obesity is associated with an increased risk of infection and aberrant inflammatory responses in the offspring, but the underlying mechanisms remain largely unknown. In particular, very little is known about the effect of a Western-style diet on fetal hematopoiesis — the formation of blood cellular components — in animal models that resemble human development.

During late development, the fetal bone marrow becomes the major site where immune cells called macrophages and B-lymphocytes are produced via differentiation of hematopoietic stem and progenitor cells (HSPCs). In the new study, Varlamov and his collaborators analyzed the transcriptional landscape of fetal bone marrow HSPCs at single-cell resolution in fetal macaques exposed to a maternal high-fat, Western-style diet or a low-fat control diet.

“We were motivated to investigate how maternal obesity impacts the fetal immune system during pregnancy in nonhuman primates, representing the most relevant animal model for studying human development,” Varlamov says.

The results demonstrated that a Western-style diet induced a hyperinflammatory response in HSPCs and fetal macrophages and suppressed the expression of B-cell development genes. Moreover, the unhealthy diet led to poor engraftment of fetal HSPCs in immunodeficient mice.

“Maternal obesity greatly impacted the ability of fetal blood stem cells to produce B-lymphocytes — immune cells that make antibodies in response to infection — and made fetal blood stem cells more inflamed,” Varlamov says.

Study limitations included the small sample size, which might limit the ability to detect weaker effects of maternal diet on fetal outcomes. In addition, the researchers didn’t explore the effects of maternal obesity on postnatal development and only focused on prenatal development. Further studies are also needed to test whether maternal obesity disrupts offspring responses to infection and inflammation.

“This study sets the stage for understanding the link between maternal obesity, prenatal nutrition, and diseases involving immune progeny of the HSPC compartment in children and highlights the need to better understand the susceptibility of the developing hematopoietic system to metabolic dysregulation over the lifetime,” Varlamov says.

This study was supported by the National Institutes of Health.

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Materials provided by Cell Press. Note: Content may be edited for style and length.

As of October 2022, more than 630 million COVID-19 cases and over 6.5 million deaths were reported (although the real death toll has been estimated to be upwards of 20 million). In addition, millions of patients with cancer and chronic disease have experienced dangerous healthcare delays, and Long COVID continues to elude definitive treatment, posing an ongoing threat to survivors. In addition, the virus also continues to accumulate mutations that can make it better at evading previous immunity. This is why many public health leaders, including the authors of this study, continue to regard COVID-19 as a persistent and dangerous global health threat.

Despite notable scientific and medical advances, the world’s response to COVID-19 has been hindered by broader political, social, and behavioural factors such as false information, vaccine hesitancy, inconsistent global coordination, and the inequitable distribution of equipment, vaccines and treatments. “Each country has responded differently, and often inadequately, which is partly due to a serious lack of coordination and clear goals,” says Jeffrey V Lazarus, head of the Health Systems Research Group and co-director of the Viral and Bacterial Infections Programme at ISGlobal, Associate Professor at the University of Barcelona, and coordinator of the study.

To develop global consensus on how to address these issues going forward, Lazarus and colleagues carried out a Delphi study, a well-established research methodology that challenges experts to garner consensus on answers to complex research questions. A multidisciplinary panel of 386 academic, health, NGO, government and other experts from 112 countries and territories took part in three rounds of structured consultation. The result is a set of 41 statements and 57 recommendations across six major areas: communication; health systems; vaccination; prevention; treatment and care; and inequities.

Three of the highest-ranked recommendations are: i) adopt a whole-of-society strategy that involves multiple disciplines, sectors and actors to avoid fragmented efforts; ii) whole-of-government approaches (e.g. coordination between ministries) to identify, review, and address resilience in health systems and make them more responsive to people’s needs; and iii) maintain a vaccines-plus approach, which includes a combination of COVID-19 vaccination, other structural and behavioural prevention measures, treatment, and financial support measures. The panellists also prioritised recommendations for developing technologies (vaccines, therapies and services) that can reach target populations.

Other recommendations with at least 99% agreement were: communicating effectively with the public, rebuilding public trust, and engaging communities in managing the pandemic response.

Only six recommendations had more than 5% disagreement, including that which considers further economic incentives to address vaccine hesitancy or a symptoms approach to diagnose COVID-19 in settings with low access to testing.

The 57 recommendations are directed at governments, health systems, industry, and other key stakeholders. “To the greatest degree possible, our results place emphasis on health and social policy recommendations that can be implemented in months, not years, to help bring this public health threat to an end,” says Quique Bassat, ICREA professor at ISGlobal, co-author of the study and member of the University of Barcelona.

“Our study does echo some earlier recommendations, such as the Independent Panel for Pandemic Preparedness and Response and WHO’s 2022 plan on Strategic Preparedness,” says Lazarus, “but what makes this work unique is the very large number of experts consulted, the wide geographical representation, and the study design, which emphasises consensus building and identifies areas of disagreement. It may prove to be a model for developing responses to future global health emergencies.”