Neuropathies and neurological dysfunction induced by coronaviruses

Abstract

During the recent years, viral epidemic due to coronaviruses, such as SARS (Severe Acute Respiratory Syndrome), Middle East Respiratory Coronavirus Syndrome (MERS), and COVID-19 (coronavirus disese-19), has become a global problem. In addition to causing cardiovascular and respiratory lethal dysfunction, these viruses can cause neurodegeneration leading to neurological disorders. Review of the current scientific literature reveals the multiple neuropathies and neuronal dysfunction associated with these viruses. Here, we review the major findings of these studies and discuss the main neurological sequels and outcomes of coronavirus infections with SARS, MERS, and COVID-19. This article analyzes and discusses the main mechanisms of coronavirus-induced neurodegeneration according to the current experimental and clinical studies. Coronaviruses can damage the nerves directly through endovascular dysfunctions thereby affecting nerve structures and synaptic connections. Coronaviruses can also induce neural cell degeneration indirectly via mitochondrial dysfunction inducing oxidative stress, inflammation, and apoptosis. Thus, coronaviruses can cause neurological disorders by inducing neurovascular dysfunction affecting nerve structures and synaptic connections, and by inducing inflammation, oxidative stress, and apoptosis. While some of these mechanisms are similar to other RNA viruses, the neurotoxic mechanisms of COVID-19, MERS, and SARS-CoV viruses are unknown and need detailed clinical and experimental studies.

Keywords: Coronavirus; Neurodegeneration.

Fig. 1

The life cycle of coronavirus: At the beginning, S protein binds to the ACE2 receptor in host cells. Then, the conformation of S protein is changed and causes the virus envelope to merge with the cell membrane via the endosomal pathway. Next coronavirus releases its RNA into the host cell. Genome RNA is translated to viral replicas polyproteins pp1a and 1ab. That polyproteins disparted to small proteins by proteinases. Polymerase makes some of subgenomic mRNAs by discontinuous transcription and finally translated to viral proteins. Viral proteins and genome RNA are assembled to the ER and Golgi. After that, it transported via vesicles and released out of the cell. ACE2, angiotensin-converting enzyme 2; ER, endoplasmic reticulum; ERGIC, ER–Golgi intermediate compartment

Fig. 2

Multiple effects of infection with Coronaviruses Family, such as SARS (Severe Acute Respiratory Syndrome), Middle East Respiratory Coronavirus Syndrome (MERS) and COVID-19 (coronavirus disese-19), on body organs and systems

Fig. 3

Mechanisms of coronavirus-induced neurological dysfunction via directly damaging the virus particle to the nerve or microvascular system and indirectly activating of pathological mechanisms such as inflammation of the nerve, oxidative stress and apoptosis was indicated. Each of these two pathways was effect on the neural system via downstream specific mechanisms which mentioned and described in diagram

Fig. 4

Coronaviruses induced neural neuro-inflammation was mediated via production of some cytokine and chemokine such as Interleukin (IL)-1,6,12,18,36 and Tumor Necrosis Factor alpha(TNF-α) and Interferon alpha(IFN-α) and Tumor Growth Factor beta(TGF-β) and some proteins such as chemokine chemoattractant protein-1 (CCL2) such as activation, monocyte chemoattractant protein-1(MCP-1). All this biomarkers cause initiation of inflammatory signaling in astrocyte and neuron which led to activation of extrinsic pathway of apoptosis in neuronal cell and lead neurodegeneration

Fig. 5

Coronaviruses induced neural oxidative stress which was mediated via some parameters such as activation of NADH oxidase, induction of blood barriers barrier damage, induction of damage to neural structure, induction of hypoxia, induction of disturbances in neurotrophic factor, and activation of nitric oxide synthase enzyme (NOS).This parameters causes mitochondrial dysfunction which lead to production of Reactive oxygens specie(ROS) and Nitrogen Oxygen Species (NOS) and cause disturbances in glutathione pathway and antioxidant enzymes such as superoxide dismutase(SOD), Glutathione peroxidase(GPx) and Glutathione Reductase(GR), also causes occurrences of apoptosis and secretion of lactate dehydrogenases(LDH) and cytochrome C enzyme which all this event causes neurodegeneration

Fig. 6

Coronaviruses causes apoptosis in both intrinsic and in-extrinsic pathways. In the extrinsic pathway of apoptosis, death ligand such as TRAIL and FAS causes activation of death receptor, which lead to the activation of pro-caspase and caspase 8 and 10, which consequently activated caspase 3 and 7 and lead to apoptosis in the intrinsic pathway of apoptosis. This family viruses causes mitochondrial damage via activation of NADH oxidase, induction of blood barriers barrier damage, induction of damage to neural structure, induction of hypoxia, induction of disturbances in neurotrophic factor, and activation of nitric oxide synthase enzyme (NOS).Which lead to release of cytochrome C and production of apoptosome and therefore causes activation of caspasce-9, caspase 3 and 7 and, finally, apoptosis. Some proteins such as BCL-2 cause inhibition of Bax, which has led to the stability and mitochondrial survival and inhibited the process of apoptosis. FADD: Fas-associated protein with death domain, TRAIL: TNF-related apoptosis-inducing ligand,, Bcl-2: B-cell lymphoma 2, mitochondrial outer membrane permeabilization

Fig. 7

The angiotensin-converting enzyme 2(ACE2) induces angiotensin (1–7) [Ang-(1–7)] development of angiotensin-2(AngII). Ang(1–7) causes AT2R, which is the angiotensin receptor type-2.On the other hand, it has been shown that ACE-2/Ang(1–7)/Mas causes Bcl-2/Beclin1 or Bcl-2/Bax complex stability and inhibits autophagy and apoptosis in the cardio-respiratory system respectively. Ang(1–7) can inhibit phosphorylation by the c-Jun N-terminal kinase(JNK). Apoptosis and autophagy are regulated by the complexes Bcl-2/Beclin1 and Bcl-2/Bax. Bcl-2 is an anti-apoptotic protein that interacts with Beclin1 (the key protein involved in autophagy) and Bax(the main protein involved in autophagy) in an unphosphorylated form. Induction of Bcl-2 phosphorylation after indications of autophagy or apoptosis such as dysfunction in the signaling pathway of ACE-2/Mas / Ang (1–7), which occurred in patient with underlying cardio-respiratory disease, activating JNK which led to phosphorylation (inactivation) of Bcl-2 and dissociation of this protein from Beclin1 or Bax and thus causes autophagy or apoptosis in respiratory and cardiac tissue of patients and increased their mortality rate. Some indirect evidence indicates that one of the key causes of increased mortality rates in high-risk patients with COVID-19 virus infection is lower expression and inactivation of ACE-2/Mas / Ang (1–7) in the cardiovascular system, resulting in activation of JNC / Bcl-2-Beclin1 or JNC / Bcl-2-bax signaling pathway and initiation of autophagy or apoptosis and thus death signal