Infection | Brain

Decoding Virus Reactivation: Insights for COVID-19

What can be learned from HCoV, HSV-1, and the Nipah virus?

An Emerging Concern

Cases of COVID-19 reactivations are rising. South Korea has reported more than 200 cases of recovered patients who were later tested positive for SARS-CoV-2 again. But the reactivated virus seems to have “little or no infectivity,” says the Korea Centres for Disease Control and Prevention (KCDC).

In an April letter to the American Journal of Infection Control, Chinese physicians reported, “Seven discharged patients turning positive again for SARS-CoV-2 on quantitative RT-PCR.” Common reactivated symptoms were cough and fever, and diseases were milder than the first-time infection.

Similarly, in a small China study in the Journal of Infection with 55 discharged patients, 9% returned to the hospital with fever, fatigue, cough, sore throat, abnormal white blood cell count, and tested positive again for SARS-CoV-2. “There is currently evidence to suggest that a proportion of recovered COVID-19 patients could reactivate,” the study authors wrote.

“Re-infection appears unlikely since COVID-19 infection rates were low in the region of our hospital and the trend of new infections declining at the time the patients were treated,” Switzerland researchers wrote in a May-printed study after analyzing two patients who were re-admitted to the hospital.

“Few researchers think that this is actually a case of reinfection or an issue of accuracy in test kits,” said the epidemiologist, Hwang Seung-sik, MD, PhD at the Seoul National University. “Many are looking at this more as a virus reactivation.” Not to mention that South Korea has more stringent criteria for defining COVID-19 recovery than other countries.

“There is currently evidence to suggest that a proportion of recovered COVID-19 patients could reactivate.”

Remembering the Nipah Virus

In a letter to Transboundary and Emerging Diseases, Kevin Roe, a semi-retired researcher at San Jose State University, detailed the “Explanation for COVID-19 infection neurological damage and reactivations.”

In this published paper, he provided new insights into COVID-19 reactivation by drawing connections to another bat-derived virus called the Nipah virus — known for its outbreaks in Asia — that causes respiratory and neurological symptoms.

Roe mentioned that SARS-CoV-2 and Nipah virus are both RNA enveloped viruses of bats origin. These two viruses cause similar neurological symptoms such as headache, convulsions, seizures, muscle twitches, disorientation, and brain inflammation (encephalitis).

For the Nipah virus, these signs are known to re-appear in about 8% of survivors “months and even years after exposure,” the CDC reported, as a result of virus reactivation in neurons. That’s why scientists have started cautioning on the neurological repercussions of COVID-19 over the coming years:

Why Neurons?

“There is a very good reason for viruses, such as COVID-19 and Nipah virus, to selectively infect neurons,” Roe wrote. This is because neurons lack MHC proteins required for presenting a foreign molecule — like virus proteins — to alert T-cells to destroy infected cells.

So virus replication in neurons often goes undetected by the host immune system — hence, a perfect hiding place.

That’s why other neuroinvasive viruses like herpes simplex virus type 1 (HSV-1) also establish latency in neurons to evade the host immune system. “And by this means, they can create life-long infections that can be reactivated whenever some stress weakens the host immune system,” Roe remarked.

Data from animal and human brain autopsy studies also suggest that “human coronaviruses (HCoV) can be added to the growing list of viruses that persist in the central nervous system, a viral flora of the brain that could have pathological consequences in some individuals but remain subclinical…,” said researchers at the laboratory of neuroimmunovirology at the University of Quebec. And, indeed, a Lancet paper has shown that SARS-CoV-2 can replicate in neuronal cell lines.

HCoV persists in neurons with potential subclinical effects “whenever some stress weakens the immune system.”

What Causes Virus Reactivations?

This is best understood from HSV-1 that reactivate in response to external immunosuppressive stimuli. The best-known one is psychological stress that releases cortisol that, when prolonged, undermines the immune system. Prolonged or excessive cortisol also serves as a cue for HSV-1 to enter the lytic (infectious; opposite of latent) phase of its life cycle.

“In most cases, reactivation does not lead to serious disease.”

This explains why psychologically stressed people have a reappearance of cold sores — a sign of reactivated HSV-1. Other stressors for HSV-1 reactivation include fever, fatigue, hormonal changes, prolonged exposure to UV radiation, surgical resection, organ transplants, immunosuppressive drugs, and aging of the immune system, said a Norwegian doctorate specializing in genetics and evolution, Bjørn Grinde.

“In most cases, reactivation does not lead to serious disease,” Grinde wrote. Fortunately, the same seems to apply to COVID-19 reactivations that have been milder than the first-time infection, as observed in Korean and Chinese cases detailed above.

To Wrap Up

In essence, the moment COVID-19 shows neurological symptoms, it provides a clear indication that SARS-CoV-2 can infect neurons and possibly becomes latent therein, which may reactivate in later life with milder symptoms.

Inferences from other related viruses — like the Nipah virus, HSV-1, and HCoV — supports this contention. Reported cases of COVID-19 reactivation could very well be the smoking gun. But whether COVID-19 infection is life-long still remains to be confirmed over the coming years, Roe closed.

Fortunately, there’re ways to suppress or prevents a latent virus reaction. Physical fitness has also been shown to prevent herpes virus reactivation in astronauts experiencing long periods of social isolation. Minimizing or coping with psychological stress, immunological ageing, or other immunosuppressive stimuli aforementioned would certainly help too.