Summary
After severe acute respiratory syndrome coronavirus (SARS - CoV) and Middle East respiratory syndrome coronavirus (MERS - CoV), another highly pathogenic coronavirus called SARS - CoV - 2 (previously known as 2019 - nCoV) emerged in December 2019 in Wuhan, China, and rapidly spreading around the world.
This virus shares a highly homologous sequence with SARS-CoV and causes the highly lethal acute pneumonia coronavirus disease 2019 (COVID-19) with clinical symptoms similar to those reported for SARS-CoV and MERS-CoV.
The most characteristic symptom of COVID-19 patients is respiratory distress , and most patients admitted to intensive care were unable to breathe spontaneously. Additionally, some COVID-19 patients also showed neurological signs , such as headache, nausea, and vomiting.
Growing evidence shows that coronaviruses are not always limited to the respiratory tract and can also invade the central nervous system inducing neurological diseases.
SARS-CoV infection has been reported in the brains of patients and experimental animals, where the brainstem was heavily infected. Furthermore, it has been shown that some coronaviruses can spread through a route connected to the synapse to the medullary cardiorespiratory center from mechanoreceptors and chemoreceptors in the lung and lower respiratory tract.
Taking into account the high similarity between SARS-CoV and SARS-CoV2, it remains to be clarified whether the possible invasion of SARS-CoV2 is partially responsible for the acute respiratory failure of COVID-19 patients. Knowledge of this may have guiding importance for the prevention and treatment of respiratory failure induced by SARS-CoV-2.
Highlights
|
Coronaviruses (CoV), which are large-enveloped, non-segmented, positive-sense RNA viruses, generally cause enteric and respiratory diseases in animals and humans. Most human CoVs, such as hCoV - 229E, OC43, NL63 and HKU1 cause mild respiratory diseases, but the global spread of two previously unrecognized CoVs, severe acute respiratory syndrome CoV (SARS - CoV) and SARS-CoV Middle East respiratory tract infection (MERS - CoV) have drawn global attention to the lethal potential of human CoVs.
While MERS - CoV is still not eliminated from the world, another highly pathogenic CoV, currently called SARS-CoV-2 (previously known as 2019-nCoV), emerged in December 2019 in Wuhan, China. This new CoV has caused a nationwide outbreak of severe pneumonia (coronavirus disease 2019 [COVID - 19]) in China, and is spreading rapidly around the world.
Genomic analysis shows that SARS-CoV-2 is in the same beta-coronavirus (βCoV) clade as MERS-CoV and SARS-CoV, and shares a highly homologous sequence with SARS-CoV. Public evidence shows that COVID-19 shares similar pathogenesis with pneumonia induced by SARS-CoV or MERS-CoV. Furthermore, the entry of SARS-CoV-2 into human host cells has been identified to use the same receptor as SARS-CoV.
Most CoVs share a similar viral structure and infection pathway, and therefore infection mechanisms previously found for other CoVs may also be applicable for SARS-CoV-2.
A growing body of evidence shows that neurotropism is a common characteristic of CoVs.
Therefore, it is urgent to clarify whether SARS-CoV-2 can gain access to the central nervous system (CNS) and induce neuronal lesions. to acute respiratory distress.
Clinical features
SARS-CoV-2 causes acute and highly lethal pneumonia with clinical symptoms similar to those reported for SARS-CoV and MERS-CoV.2. Imaging examination revealed that most patients with fever, dry cough, and dyspnea showed bilateral ground-glass opacities on chest CT scans.
However, unlike patients with SARS-CoV infection, patients with SARS-CoV-2 infection rarely showed prominent upper respiratory tract signs and symptoms, indicating that SARS-CoV-2 target cells They may be located in the lower part of the airway .
According to first-hand evidence from local hospitals in Wuhan, the common symptoms of COVID-19 were fever (83%-99%) and dry cough (59.4%-82%) at the onset of the disease. However, the most characteristic symptom of patients is respiratory distress (~55%).
Among patients with dyspnea, more than half required intensive care . About 46% to 65% of patients in intensive care worsened in a short period of time and died due to respiratory failure. Among the 36 intensive care cases reported by Wang et al. 1% received high-flow oxygen therapy, 41.7% received non-invasive ventilation, and 47.2% received invasive ventilation. These data suggest that the majority (approximately 89% ) of patients requiring intensive care were unable to breathe spontaneously.
It is now known that CoVs are not always limited to the respiratory tract and can also cause CNS-inducing neurological diseases.
Regarding the high similarity between SARS-CoV and SARS-CoV2, it remains to be known whether the potential neuroinvasion of SARS-CoV-2 plays a role in the acute respiratory failure of COVID-19 patients.
The neuroinvasive potential of SARS-CoV2
The tissue distributions of host receptors are thought to be generally consistent with the tropisms of viruses. The entry of SARS-CoV into human host cells is mainly mediated by the cellular receptor for angiotensin-converting enzyme 2 (ACE2), which is expressed in human airway epithelia, lung parenchyma, vascular endothelia, kidney cells and small intestine cells.
Unlike SARS-CoV, MERS-CoV enters human host cells primarily through dipeptidyl peptidase 4 (DPP4), which is present in the lower respiratory tract, kidney, small intestine, liver, and immune system cells. .
However, the presence of ACE2 or DPP4 alone is not sufficient to make host cells susceptible to infection. For example, some ACE2-expressing endothelial cells and human intestinal cell lines could not be infected by SARS-CoV, while some cells without a detectable expression level of ACE2, such as hepatocytes , could also be infected by SARS-CoV.
Likewise, SARS-CoV or MERS-CoV infection has also been reported in the CNS, where the expression level of ACE230 or DDP430 is very low under normal conditions.
In early 2002 and 2003, studies on samples from SARS patients have shown the presence of SARS-CoV particles in the brain , where they were located almost exclusively in neurons. -CoV34 or MERS - COV, when administered intranasally, could enter the brain, possibly through the olfactory nerves , and then spread rapidly to some specific areas of the brain, such as the thalamus and brainstem.
Of note, in mice infected with low-dose inoculum, MERS-CoV virus particles were detected only in the brain, but not in the lung, indicating that infection in the CNS was more important for the high mortality observed. in infected mice. Among the brain areas involved, the brainstem has been shown to be highly infected by SARS-CoV34, 35 or MERS-CoV.13
The exact route by which SARS-CoV or MERS-COV enters the CNS is not yet reported. However, the hematogenous or lymphatic route seems impossible, especially in the early stage of infection, since almost no viral particles were detected in non-neuronal cells in the infected brain areas.
On the other hand, growing evidence shows that CoVs can first invade peripheral nerve terminals , and then access the CNS through a route connected to the synapse. Trans-synaptic transfer has been well documented for other CoVs and avian bronchitis viruses.
HEV 67N is the first CoV to invade the porcine brain, and shares more than 91% homology with HCoV-OC43. HEV first orally infects the nasal mucosa, tonsils, lungs, and small intestine in suckling piglets, and is then delivered retrogradely via peripheral nerves to medullary neurons in charge of the peristaltic function of the digestive tract, which results in so-called vomiting diseases . The transfer of HEV 67N between neurons has been demonstrated by our previous ultrastructural studies to utilize the clathrin coating-mediated endocytotic/exocytotic pathway.
Similarly, trans-synaptic transfer was reported for avian bronchitis virus. Intranasal inoculation of mice with avian influenza virus was reported to cause neural infection in addition to bronchitis or pneumonia.
Of interest, viral antigens have been detected in the brainstem, where infected regions included the nucleus tractus solitarius and nucleus ambiguus. The nucleus tractus solitarius receives sensory input from mechanoreceptors and chemoreceptors in the pulmonary and respiratory tracts, while efferent fibers from the nucleus ambiguus and nucleus tractus solitarius provide innervation to the smooth muscle, glands, and blood vessels of the airways. . Such neuroanatomical interconnections indicate that the death of infected animals or patients may be due to dysfunction of the cardiorespiratory center in the brainstem.
Taken together, neuroinvasive propensity has been demonstrated as a common characteristic of CoVs. In light of the high similarity between SARS-CoV and SARS-CoV2, it is quite likely that SARS-CoV-2 also possesses similar potential.
According to an epidemiological survey on COVID - 19, the median time from the first symptom to dyspnea was 5.0 days, to hospital admission was 7.0 days, and to intensive care was 8.0 days. Therefore, the latency period may be sufficient for viruses to enter and destroy spinal neurons. In fact, the previous studies mentioned above have reported that some patients infected with SARS-CoV-2 showed neurological signs such as headache (about 8%), nausea and vomiting (1%).
More recently, a study on 214 patients with COVID - 19 by Mao et al. further found that about 88% (78/88) among severely ill patients showed neurological manifestations , including acute cerebrovascular diseases and impaired consciousness.
Therefore, awareness of potential neuroinvasion may have guiding importance for the prevention and treatment of SARS-CoV-2-induced respiratory failure.
