What we know about nervous system disorders due to COVID-19

Neurological symptoms can have many causes, but is it possible for the new coronavirus to penetrate neurons?

Many of the symptoms seen in people infected with SARS-CoV-2 reside in the nervous system. Weeks and even months after infection, they experience headaches, muscle and joint pain, fatigue, drowsiness, or loss of taste (ageusia) and smell (anosmia). In severe cases, COVID-19 also causes encephalitis or stroke. Although the virus has undeniable neurological effects, how it affects neurons remains a mystery. Are symptoms caused by the mere activation of the immune system? Or does the new coronavirus directly attack the nervous system?

Some studies, including a recent prepublication studying mouse and human brain tissue, offer evidence that SARS-CoV-2 manages to enter neurons and the brain. We still do not know if it always does it or only in the most serious cases. Once the immune system is put into overdrive, the effects can be far-reaching, even with an invasion of immune cells into the brain, where they wreak havoc.

Some neurological symptoms are less severe than they appear, but perhaps more disconcerting. One symptom (or a set of them) that illustrates this puzzle, and which is receiving increasing attention, is the imprecise diagnosis called “clouding.” Even after the main symptoms disappear, it is not uncommon for COVID-19 patients to have a poor memory, feel confused, and do not reason clearly. The fundamentals of these sensations remain surrounded by uncertainty, although they could be due to the generalized inflammation that usually accompanies this disease. However, many people feel tired and clouded for months, even after a mild case in which the immune system has not gone haywire.

Another common symptom is anosmia, which could also be due to changes not directly related to infection of the nerves. The olfactory neurons, which transmit odors to the brain, do not have the main receptor where SARS-CoV-2 attaches, so they appear to be immune to it. It is still being studied whether loss of smell could be caused by an interaction between the virus and another receptor on olfactory neurons, or by contact with the non-neural cells that line the nasal cavity.

Experts say it is not necessary for the virus to enter neurons to cause some of the mysterious neurological symptoms that surface in some cases. Many pain-related effects could arise from attack on sensory neurons, the nerves that extend from the spinal cord throughout the body to gather information from outside or from internal processes in the body. Researchers are now focusing on how SARS-CoV-2 appropriates pain-sensing neurons, classified as nociceptors, to produce some symptoms of COVID-19.

Chronic pain from nerve injuries

Neuroscientist Theodore Price, who studies pain at the University of Texas at Dallas, took note of the symptoms described in the first articles and those explained by the patients of his wife, a telecare nurse for people with COVID-19. He found a sore throat, headaches, general muscle pain, and a severe cough (the cough is triggered, in part, by sensory neurons in the lungs).

Interestingly, some patients report that they lose a specific sense, the so-called chemosesthesia, which prevents them from detecting hot peppers or mint, perceptions that are transmitted by nociceptor neurons, not taste cells. Although many of these effects are typical of viral infections, the prevalence and persistence of pain-related symptoms, as well as their presence even in mild cases of COVID-19, suggest that sensory neurons could be affected by something more than the normal inflammatory response against infection. In other words, the effects would be directly linked to the virus itself. Price notes: “It is surprising, affected patients suffer from headaches and some appear to have pain problems similar to neuropathies.” That is, chronic pain due to nerve injuries.

The main criterion used to determine whether SARS-CoV-2 will infect a cell in the body is the presence of angiotensin-converting enzyme type 2 (ACE2) that is embedded in the surface of cells. ACE2 acts as a receptor that transmits signals into the cell to regulate blood pressure, but it is also an entry point for SARS-CoV-2. That is why Price set out to look for it in human neurons, as reported in a study published in the journal PAIN .

Nociceptor neurons and other sensory neurons are found outside the spinal cord, in distinct clusters called dorsal root ganglia (DRG). Price and his team obtained the nerve cells from post-mortem donations and cancer surgeries. They sequenced the RNA to determine which proteins were about to be synthesized in a cell; they also used antibodies against ACE2. They found that a subset of neurons in the DRGs contained ACE2, which would allow the virus to access them.

Sensory neurons send long extensions (axons), the ends of which perceive specific stimuli from the organism that they transmit to the brain in the form of electrochemical signals. The ACE2 neurons in the DRGs also had the genetic instructions, the mRNA, for a sensitive protein called MRGPRD. Their presence defines a subset of neurons whose endings are concentrated on the surfaces of the body (skin and internal organs, such as the lungs) where they would be ready to “grab” the virus.

Price argues that the acute symptoms, as well as the long-lasting ones, of COVID-19 could be due to infection of the nerves. As he explains: “In the most likely scenario, the autonomic and sensory nerves would be affected by the virus. We know that viral infection of sensory neurons has long-term consequences, ‘even if the virus is no longer in cells. And he adds: “It is not necessary for neurons to be infected.” In another study compared nucleotide sequence data from lung cells from COVID-19 patients and healthy participants (control group) to look for interactions with neurons from non-infected DRGs. His team found many cytokines (immune system signaling molecules) in infected patients that could interact with receptors on the surface of neurons. “It’s basically a lot of things that we know are involved in neuropathic pain.” This observation suggests that nerves, without being directly infected by the virus, suffered lasting damage from immune molecules.

Neurologist Anne Louise Oaklander of Massachusetts General Hospital wrote a commentary accompanying Price’s PAIN article, arguing that the study “was exceptionally good,” in a way, for using human cells. Although he adds that while “there is no evidence that the main mechanism of [neuronal] damage is direct entry of the virus into these [nerve] cells,” the new findings do not rule out such a possibility. For Oaklander, it is “very possible” that the inflammatory conditions surrounding neurons alter their activity or cause permanent damage to them. Another possibility would be that viral particles that interact with neurons promote an autoimmune attack against nerves.

It is widely accepted that ACE2 is the main entry point for the new coronavirus. But neuroscientist Rajesh Khanna, who researches pain at the University of Arizona, emphasizes: “ACE2 is not the only route of entry for SARS-CoV-2 into cells.” Another protein, neuropilin-1 (NRP1), “could serve as an alternative gateway” for the virus to enter. NRP1 plays an important role in angiogenesis (the formation of new blood vessels) and in the growth of the long axons of neurons.

The idea comes from cell and mouse studies where NRP1 was found to interact with the notorious spike protein of the virus, which helps it enter cells. “We showed that it binds to neuropilin, which could act as a receptor for infection,” explains virologist Giuseppe Balistreri, from the University of Helsinki, co-author of the mouse study that was published in Science along with another study with cells. It seems more likely that NRP1 acts as a cofactor with ACE2 rather than that it alone is sufficient for the virus to enter. “We know that there is more infection when the two receptors are present: together they are more powerful,” adds Balistreri.https://e1bc59c597f2feaa5c9170329ed0f8a9.safeframe.googlesyndication.com/safeframe/1-0-38/html/container.html

Possible anesthetic effect?

These findings piqued the interest of Khanna, who was studying vascular endothelial growth factor (VEGF), a very important molecule for pain signaling that also binds to NRP1. He wondered if the virus would disturb the pain signal through NRP1, so he investigated it with rats in a study that was also published in PAIN.. Khanna explains: “We put the VEGF into the animal [in its paw] and, look where, we observed powerful pain for 24 hours. Then came the really amazing experiment, in which we introduced VEGF and spicule at the same time. The result was incredible: the pain was gone. The study showed “what happens to the signaling of neurons when the virus plays with the NRP1 receptor. The results are firm ”, says Balistreri. As he adds, they show that neuronal activity was altered “by the contact of the virus spike with NRP1.”

In an experiment with rats that were damaged a nerve to use as a model of chronic pain, it was enough to administer spike protein to attenuate the animals’ pain behavior. This finding suggests that we would be facing a possible new anesthetic: a drug that simulates the spicule and that binds to NRP1. Such molecules are already in development against cancer.

Khanna offers us a more provocative hypothesis yet to be tested: the spicule could act on NRP1 to silence people’s nociceptive neurons, perhaps masking pain-related symptoms from the onset of infection. The idea is that the protein provides an anesthetic effect as the SARS-CoV-2 infection begins, making the virus more easily spread. Balistreri does not rule it out: “It is possible that viruses have an arsenal of tools never seen before. What they do best is to silence our defenses.

It remains to be determined whether a SARS-CoV-2 infection would produce analgesia in people. Balistreri notes: ‘High doses of a piece of the virus have been used in a laboratory system with rats, but not in a human. The magnitude of the effects that are being seen [could be due to] the large amount of viral protein that he used. We will have to see if the virus by itself can [dull the pain] of a person.

The experience of patient Rave Pretorius, a 49-year-old South African, suggests that this line of research is worth pursuing. In a car accident in 2011, Pretorius fractured several vertebrae in his neck and suffered numerous nerve injuries. As he explains, he lives with a constant burning in his limbs that wakes him up every night at three or four in the morning: “I feel like someone is pouring hot water over my legs non-stop.” But this changed dramatically in July 2020, when he contracted COVID-19 at his workplace. “I was very surprised that the pain was bearable when I had COVID-19. At times, it felt like he was gone. I could’nt believe it.” He was able to sleep soundly for the first time since the accident: “My quality of life improved when I was ill, because the pain had disappeared. This, despite feeling tired and disabling headaches. Once recovered from COVID-19, he suffered neuropathic pain again.

For better or for worse, it appears that COVID-19 affects the nervous system. It is still unknown if the nerves are infected, like many other things that are not known about SARS-CoV-2. Although the virus seems, in principle, capable of infecting some neurons, this does not seem necessary, because it can cause a lot of damage from outside them.