Sunday, April 03, 2022

Nat. Comms: Neuropathology and Virus in Brain of SARS-CoV-2 Infected Non-human Primates



In the opening months of the pandemic, SARS-CoV-2 was billed as an influenza-like virus; mostly mild but capable of producing severe, and sometimes fatal pneumonia.  Rather quickly, however, we began to see signs of extrapulmonary impacts as well. 

Just shy of 2 years ago, in April of 2020, we looked at the first major report (see JAMA: Neurologic Manifestations Of Patients With Severe Coronavirus Disease) on the neurological impact of COVID infection; one which found more than 1/3rd of a study group (n=214) hospitalized in Wuhan, China showing signs of neurological involvement.

Neurological manifestations ranged from relatively mild (headaches, dizziness, anosmia, mild confusion, etc.) to more profound (seizures, stupor, loss of consciousness, etc.) to potentially fatal (ischemic stroke, cerebral hemorrhage, muscle injury (rhabdomyolysis), etc.). 

Other studies around that that time found that COVID caused viremia (see Severe Acute Respiratory Syndrome Coronavirus 2 RNA Detected in Blood Donations), was linked to gastrointestinal issues (see NEJM Journal Watch Gastrointestinal Aspects of COVID-19), and even cardiac injuries (see COVID-19 linked to cardiac injury).

Over that first summer additional studies have appeared in the medical literature describing neurological manifestations in COVID patients - with some warning of potential long-term sequelae - including an enhanced risk of Parkinson's disease.

Additionally, a growing number of `recovered' COVID cases have reported a wide spectrum of chronic, and often debilitating symptoms - often dubbed `Long COVID' (such as fatigue, recurrent fevers, `brain fog', myalgias, etc. ),  that are highly reminiscent of ME/CFS - which has disabled and traumatized well over a million Americans over the past 3 decades (see NIH About CFS/ME).

Since then, the evidence that COVID is more than just a severe `flu' has continued to emerge, including:

Diabetologia: Incidence of Newly Diagnosed Diabetes After Covid-19

American Heart Assoc: Stroke Risk Among Older Adults Highest in First 3 Days After COVID-19 Diagnosis

Nature: Long-term Cardiovascular Outcomes of COVID-19

Preprint: Results of the Danish AFTER-COVID Survey

While many point to the relatively high survival rate (98%+) for COVID infection, and call it `mild', infection with COVID can often leave an indelible mark, even when it doesn't kill its host.  And, as we are learning, significant sequelae can occur even after a mild or moderate course of illness

All of which brings us to a new study, published on Friday in Nature Communications, that describes the neurological damage observed in non-human primates after they were infected with SARS-CoV-2. 

 Serious damage that occured even in mildly symptomatic animals. 

We've a link and some excerpts from the detailed study, followed by a press release from Tulane University on the results.  You'll want to follow the links to read them in their entirety.

Neuropathology and virus in brain of SARS-CoV-2 infected non-human primates

Nature Communications volume 13, Article number: 1745 (2022)


Neurological manifestations are a significant complication of coronavirus disease (COVID-19), but underlying mechanisms aren’t well understood. The development of animal models that recapitulate the neuropathological findings of autopsied brain tissue from patients who died from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are critical for elucidating the neuropathogenesis of infection and disease. Here, we show neuroinflammation, microhemorrhages, brain hypoxia, and neuropathology that is consistent with hypoxic-ischemic injury in SARS-CoV-2 infected non-human primates (NHPs), including evidence of neuron degeneration and apoptosis. Importantly, this is seen among infected animals that do not develop severe respiratory disease, which may provide insight into neurological symptoms associated with “long COVID”. Sparse virus is detected in brain endothelial cells but does not associate with the severity of central nervous system (CNS) injury. We anticipate our findings will advance our current understanding of the neuropathogenesis of SARS-CoV-2 infection and demonstrate SARS-CoV-2 infected NHPs are a highly relevant animal model for investigating COVID-19 neuropathogenesis among human subjects.


Here, we show substantial pathological changes in brain of SARS-CoV-2 infected NHPs that are compatible with autopsy and imaging reports of infected human subjects. Additionally, our pathological investigation suggests a significant role for brain hypoxia in the neuropathogenesis of COVID-19, including animals without severe disease. It is reasonable to anticipate that similar findings may occur among human subjects, particularly those with continuing neurological symptoms after recovery from infection 39,40,41. For example, an increasing number of retrospective neuroimaging reports have reported cerebral microhemorrhages in critically ill patients with COVID-1942,43,44.

Many patients, however, including those who do not require hospitalization, report comparatively milder neurological symptoms that are not evaluated through neuroimaging. As such, neuropathology among these individuals remains unclear but likely contributes to lingering neurocognitive difficulties reported by a number of convalesced/convalescing patients45 and warrants further investigation. This further increases the significance of NHPs as a viable model for elucidating the mechanisms that underlie SARS-CoV-2-associated neuropathology that are translatable to human disease, as neuropathogenesis can be more closely examined in animals that do not experience mortal disease. Additionally, neuropathological complications may contribute to worsening disease among infected patients. For example, damage to the brainstem, which modulates the respiratory cycle by regulating inspiratory and expiratory muscle activity, may contribute to worsening respiratory distress and failure in patients with COVID-19. Additional studies, employing relevant animal models, are warranted and likely to reveal important insight into human disease.

While SARS-CoV-2 neuropathogenic processes are poorly understood, this work reveals infected NHPs are a viable animal model for understanding the neuropathogenesis and potential long-term consequences of infection. We also provide important insight into the mechanisms underlying CNS disease, which was seen even in the absence of severe respiratory disease and may suggest that vascular leakage and hypoxic brain injury is a common complication of SARS-CoV-2 infection and COVID-19. Neuronal degeneration and activation of caspase 3 observed in this study supports this notion and indicates non-reversible neuronal injury may be significant to individuals suffering from PASC. Finally, our findings and conclusions presented herein suggest the need for long-term neurological follow-up of persistently symptomatic convalescent patients.

Tulane study shows COVID-19’s lingering impacts on the brain
April 01, 2022 7:00 AM

Leslie Tate
COVID-19 patients commonly report having headaches, confusion and other neurological symptoms, but doctors don’t fully understand how the disease targets the brain during infection.

Now, researchers at Tulane University have shown in detail how COVID-19 affects the central nervous system, according to a new study published in Nature Communications. The findings are the first comprehensive assessment of neuropathology associated with SARS-CoV-2 infection in a nonhuman primate model.

The research team found severe brain inflammation and injury consistent with reduced blood flow or oxygen to the brain, including neuron damage and death. Microhemorrhages, or small bleeds in the brain, were also present.

Surprisingly, these findings were seen in subjects that did not experience severe respiratory disease from the virus.

Tracy Fischer, Ph.D., lead investigator and associate professor of microbiology and immunology at the Tulane National Primate Research Center, has studied brains for decades. Soon after the primate center launched its COVID-19 pilot program in the spring of 2020, Fischer began studying the brain tissue of several subjects that had been infected.

Fischer’s initial findings documenting the extent of damage seen in the brain due to SARS-CoV-2 infection were so striking that she spent the next year further refining the study controls to ensure that the results she reported were clearly attributable to the infection.

          (Continue . . . )

During, and for the 10 years following the 1918 pandemic, the world saw a second epidemic of a  neurological illness called Encephalitis Lethargica (EL). The NIH describes the disease as:

Encephalitis lethargica is a disease characterized by high fever, headache, double vision, delayed physical and mental response, and lethargy. In acute cases, patients may enter coma. Patients may also experience abnormal eye movements, upper body weakness, muscular pains, tremors, neck rigidity, and behavioral changes including psychosis. The cause of encephalitis lethargica is unknown.
Between 1917 to 1928, an epidemic of encephalitis lethargica spread throughout the world, but no recurrence of the epidemic has since been reported. Postencephalitic Parkinson's disease may develop after a bout of encephalitis-sometimes as long as a year after the illness.

There are some scientists who suspect this disease to be a rare sequelae of the 1918 pandemic virus, while a 2012 study made a case for the EL epidemic having been caused by an enterovirus (see Evidence for an enterovirus as the cause of encephalitis lethargica). 

It has been estimated that between 1 and 5 million people were afflicted with EL between 1917 and 1927 - and while roughly 1/3rd died during the acute phase of the illness - many of the survivors would go on to develop Parkinsonian features and other profound neurological sequelae.

Its aftermath was depicted in the 1990 fictionalized movie Awakenings, which was based on Oliver Sacks' 1973 memoir. In it, he described patients who had been comatose for 40 years who were treated with L-DOPA in the 1960s, and briefly recovered, only to slip back into a catatonic state.
Throughout history, there have been reports of similar outbreaks, resulting in severe neurological disease, including febris comatosa which sparked a severe epidemic in London between 1673 and 1675, and in 1890 in Italy, in the wake of the 1889–1890 influenza (?) pandemic, a severe wave of somnolent illnesses (nicknamed the "Nona") appeared.

While hopefully we aren't in for a repeat with COVID, we probably won't have a good handle on the long-term impacts of COVID infection for several more years.  

A good reason not to get infected if you can avoid it, even if COVID is `milder' now. 

For more on the EL epidemic of 100 years ago, you may wish to revisit The Lancet: COVID-19: Can We Learn From Encephalitis Lethargica?