Infection routes, invasion mechanisms, and drug inhibition pathways of human coronaviruses on the nervous system

Abstract

So far, numerous studies have reported on how coronaviruses affect the human nervous system. However, these studies mainly focused on the impact of a single coronavirus on the nervous system, and failed to fully report the invasion mechanisms and the rules of symptoms of the seven human coronaviruses. This research can assist medical professionals in identifying the regularity of coronavirus invasion into the nervous system by examining the impacts of human coronaviruses on the nervous system. Meanwhile, the discovery also helps humans to prevent the damage to the human nervous system caused by the more novel coronavirus in advance, thus reducing the rate of disease transmission and fatality caused by such viruses. In addition to describing the structures, routes of infection, and symptomatic manifestations of human coronaviruses, this review also finds that the structures of human coronaviruses correlate with virulence, pathways of infection, and blocking mechanisms of drugs. This review can provide a theoretical basis for the research and development of related drugs, promote the prevention and treatment of coronavirus infectious diseases, and contribute to global epidemic prevention.

Keywords: central nervous system; coronavirus; drug; peripheral nervous system; prevention and treatment.

FIGURE 1

Routes of coronaviruses infection. Coronavirus entry routes into the central nervous system (CNS). ➀ Olfactory pathway: Coronaviruses enter from the mouth and bind to the surface receptors of the olfactory nerve. It is transmitted by the olfactory nerve to the olfactory bulb and thence to the nerve center. ➁ Receptor binding: Coronaviruses bind to the host cell receptors by the surface proteins with the assistance of TMPRSS2. On the one hand, coronaviruses enter the host cells through endocytosis and use Cat L to clear S2. Thus coronaviruses can use plasma membrane fusion so that nucleic acid is released. On the other hand, coronaviruses fuse with the host cell membrane through the viral outer membrane, allowing the nucleic acid to enter the host cell. ➂ Trojan horse mechanism: Coronavirus-mediated cytokine storm. After attachment and entry into the epithelial cells through the ACE-2 receptor, the virus may activate the pro-inflammatory pathway through NF-κB signaling, followed by the formation of an inflammasome. Various pro-inflammatory cytokines and chemokines are released, including CCL-2, CCL-4, and CXCL-10. These proteins attract different immune cells in the circulation, like the monocytes, macrophages, and T cells at the site of infection. Additionally, the T lymphocytes release substances (e.g., TNF-β, IL-6, IL-4, IL-12, and IL-23) that in turn affect macrophages and accumulate in the body, creating a pro-inflammatory feedback loop. These cytokines may damage the BBB and activate astrocytes and microglia. In response, the activated microglia and astrocytes produce IL-1β, IL-6, TNF-α, and IL-8. Elevated levels of these inflammatory cytokines can impart neurotoxic effects leading. ➃ Neurons retrograde: After infection of peripheral neurons, coronaviruses spread through retro-transsynaptic neurons (from postsynaptic neurons to presynaptic neurons in reverse), and infect synaptic connected central neurons or other peripheral neuron cell bodies. The solid line shows the process of virus infection, and the dashed line shows the possible route of virus infection.

FIGURE 2

Pathways of drug inhibition. Some drugs are listed for their role in inhibiting the entry of coronaviruses. The gray arrows represent the invasion route and replication process of the coronavirus, and the blue boxes represent the name of the invasion link. The red arrows and “(–)” indicate the drug’s resistance to coronavirus invasion, and the yellow boxes indicate the name of the drug. Ceftazidime, VHHs, and MARCH 8 can inhibit the binding of coronaviruses to receptors. Analogs of arbidol, Camostat, and nafamostat can impact how well TMPRSS2 clears S2. Chloroquine can prevent Cat L from clearing S2. The coronavirus nucleic acids can’t replicate when treated with Remdesivir and Masitinib. The purple boxes show interleukin and interferon secreted by immune cells. Interferon, IL-6, and IL-8 actions can be inhibited by chloroquine, Remdesivir, and Masitinib, which will lessen the inflammatory response.