20191220F Day -11: Human Coronaviruses and the Central Nervous System

20200520W Santa Cruz, CA: When I searched back 5 months to see what was going on related to the COVID-19 pandemic, I found a research paper published online on Dec. 20, 2019: Human Coronaviruses and Other Respiratory Viruses: Underestimated Opportunistic Pathogens of the Central Nervous System?

Since the effect of COVID-19 on the CNS has also been discussed lately, I thought it would be interesting to go through this paper and see what quotes leap out at me. So here goes.

First from the Abstract, some key points so you know what you’re getting into. This is the entire Abstract from the paper in bullet form so that I can easily refer back to it later, if needed.

1. Respiratory viruses infect the human upper respiratory tract, mostly causing mild diseases. However, in vulnerable populations, such as newborns, infants, the elderly and immune-compromised individuals, these opportunistic pathogens can also affect the lower respiratory tract, causing a more severe disease (e.g., pneumonia).
2. Respiratory viruses can also exacerbate asthma and lead to various types of respiratory distress syndromes.
3. Furthermore, as they can adapt fast and cross the species barrier, some of these pathogens, like influenza A and SARS-CoV, have occasionally caused epidemics or pandemics, and were associated with more serious clinical diseases and even mortality.
4. For a few decades now, data reported in the scientific literature has also demonstrated that several respiratory viruses have neuroinvasive capacities, since they can spread from the respiratory tract to the central nervous system (CNS). Viruses infecting human CNS cells could then cause different types of encephalopathy, including encephalitis, and long-term neurological diseases.
5. Like other well-recognized neuroinvasive human viruses, respiratory viruses may damage the CNS as a result of misdirected host immune responses that could be associated with autoimmunity in susceptible individuals (virus-induced neuro-immunopathology) and/or viral replication, which directly causes damage to CNS cells (virus-induced neuropathology).
6. The etiological agent of several neurological disorders remains unidentified. Opportunistic human respiratory pathogens could be associated with the triggering or the exacerbation of these disorders whose etiology remains poorly understood.
7. Herein, we present a global portrait of some of the most prevalent or emerging human respiratory viruses that have been associated with possible pathogenic processes in CNS infection, with a special emphasis on human coronaviruses.

Here are some interesting facts quoted from the Introduction:

1. Considering all types of viral infections, between 6000 and 20,000 cases of encephalitis that require hospitalization occur every year in the United States, representing about 6 cases per 100,000 infected persons every year.
2. Viruses represent the most prevalent pathogens present in the respiratory tract. Indeed, it is estimated that about 200 different viruses (including influenza viruses, coronaviruses, rhinoviruses, adenoviruses, metapneumoviruses, such as human metapneumovirus A1, as well as orthopneumoviruses, such as the human respiratory syncytial virus) can infect the human airway.
3. new respiratory viral agents emerge from time to time, causing viral epidemics or pandemics associated with more serious symptoms, such as neurologic disorders. These peculiar events usually take place when RNA viruses like influenza A, human coronaviruses, such as MERS-CoV and SARS-CoV, or henipaviruses, present in an animal reservoir, cross the species barrier as an opportunistic strategy to adapt to new environments and/or new hosts.

In the rest of the paper, I found these quotes of interest:

Respiratory viruses such as RSV, henipaviruses, influenza A and B, and enterovirus D68 are also sometimes found in the blood and, being neuroinvasive, they may therefore use the hematogenous route to reach the CNS.

 

Influenza viruses are classified in four types: A, B, C and D. All are endemic viruses with types A and B being the most prevalent and causing the flu syndrome, characterized by chills, fever, headache, sore throat and muscle pain. They are responsible for seasonal epidemics that affect 3 to 5 million humans, among which 500,000 to 1 million cases are lethal each year. Associated with all major pandemics since the beginning of the 20th century, circulating influenza A presents the greatest threat to human health.

 

Last but not least, human coronaviruses (HCoV) are another group of respiratory viruses that can naturally reach the CNS in humans and could potentially be associated with neurological symptoms. These ubiquitous human pathogens are molecularly related in structure and mode of replication with neuroinvasive animal coronaviruses.

Taken together, all these data bring us to consider a plausible involvement of HCoV in neurological diseases.

As I read the following, I’m struct by how it could be written about the current SARS-2 (COVID-19) pandemic. Even the CFR of 10% is not that far off if there is only limited testing. I’m curious now to know if serological testing of SARS-1 has been done in SARS-1 outbreak areas to determine the true infection spread in those areas.

The 2002–2003 SARS pandemic was caused by a coronavirus that emerged from bats (first reservoir) to infect palm civets (intermediary reservoir) and then humans . A total of 8096 probable cases were reported and almost 10% (774 cases in more than 30 countries) of these resulted in death. The clinical portrait was described as an initial flu-like syndrome, followed by a respiratory syndrome associated with cough and dyspnea, complicated with the “real” severe acute respiratory syndrome (SARS) in about 20% of the patients. In addition, multiple organ failure was observed in several SARS-CoV-infected patients .

And the following “inefficient human-to-human transmission” and “more efficient human-to-human transmission in S. Korea” mentioned below shows how both of these universes can exist.

Although possible, human-to-human MERS-CoV transmission appears inefficient as it requires extended close contact with an infected individual. Consequently, most transmission have occurred among patients’ families and healthcare workers (clusters of transmission). A more efficient human-to-human transmission was observed in South Korea, during the 2015 outbreak of MERS-CoV. Even though it has propagated to a few thousand people and possesses a high degree of virulence, MERS-CoV seems mostly restricted to the Arabic peninsula and is not currently considered an important pandemic threat. However, virus surveillance and better characterization are warranted, in order to be prompt to respond to any change in that matter.

As I read the following about SARS-1 and MERS, the same populations seem to be infected except that not much is reported about SARS-2/COVID-19 affecting infants.

As of October 8, 2019, the World Health Organization (WHO) reported that MERS-CoV had spread to at least 27 different countries, where 2468 laboratory-confirmed human cases have been identified with 851 being fatal (https://www.who.int/emergencies/mers-cov/en/). As observed for the four circulating strains of HCoV, both SARS-CoV and MERS-CoV usually induce more severe illnesses, and strike stronger in vulnerable populations such as the elderly, infants, immune-compromised individuals or patients with comorbidities.

A comparison between the endemic coronavirus, HCoV-OC43, and both SARS-CoV-1 and SARS-CoV-2 seems like it would be helpful in better understanding these coronaviruses.

After an intranasal infection, both HCoV-OC43 and SARS-CoV were shown to infect the respiratory tract in mice and to be neuroinvasive. Over the years, we and others have gathered data showing that HCoV-OC43 is naturally neuroinvasive in both mice and humans.

Here’s a mention of the viral glycoprotein (S):

Immune cell infiltration and cytokine production were observed in the mouse CNS after infection by HCoV-OC43. This immune response was significantly increased after infection by viral variants, which harbor mutations in the viral glycoprotein (S).

Virus–cell interactions are always important in the regulation of cell response to infection. For HCoV-OC43, we clearly showed that the viral S and E proteins are important factors of neurovirulence, neuropropagation and neurodegeneration of infected cells.

And this on Hemagglutinin-esterase (HE protein) seems of interest:

We have also demonstrated that the HE protein is important for the production of infectious HCoV-OC43 and for efficient spreading between neuronal cells, suggesting an attenuation of the eventual spread into the CNS of viruses made deficient in fully active HE protein, potentially associated with a reduced neurovirulence.

This final paragraph sums up the risk of chronic human neurological diseases tied to coronavirus infections.

Like for several other respiratory viruses, accumulating evidence now indicate that HCoV are neuroinvasive in humans and we hypothesize that these recognized respiratory pathogens are potentially neurovirulent as well, as they could participate in short- and long-term neurological disorders either as a result of inadequate host immune responses and/or viral propagation in the CNS, which directly induces damage to resident cells. With that in mind, one can envisage that, under the right circumstances, HCoV may successfully reach and colonize the CNS, an issue largely deserted and possibly underestimated by the scientific community that has impacted or will impact the life of several unknowing individuals. In acute encephalitis, viral replication occurs in the brain tissue itself, possibly causing destructive lesions of the nervous tissue with different outcomes depending on the infected regions. As previously mentioned, HCoV may persist in the human CNS as it does in mice and potentially be associated with different types of long-term sequelae and chronic human neurological diseases.

The conclusions specifically calls out human coronaviruses. It also states the belief that Koch’s postulates should be modified to account for cases where diseases result rarely from a prior infection. It also refers to Multiple Schlerosis.

Several human respiratory viruses are neuroinvasive and neurotropic, with potential neuropathological consequences in vulnerable populations. Understanding the underpinning mechanisms of neuroinvasion and interaction of respiratory viruses (including HCoV) with the nervous system is essential to evaluate potentially pathological short- and long-term consequences. However, viral infections related to diseases that are rare manifestations of an infection (like long term chronic neurological diseases), represent situations where Koch’s postulates [323] need to be modified. A series of new criteria, adapted from Sir Austin Bradford Hill, for causation [324,325] was elaborated by Giovannoni and collaborators concerning the plausible viral hypothesis in MS [326].

The feeling I’m having now is to understand the fear that anti-vaccine folks have when presented with the idea of giving everyone in the world a “limited” viral infection in order to provide everyone with protective antibodies.