CoVID-19が経シナプス的脳幹侵入によって呼吸不全を起こす

重症急性呼吸器症候群コロナウイルス（SARS-CoV）および中東呼吸器症候群コロナウイルス（MERS-CoV）に続いて、中国武漢で2019年12月にSARS-CoV-2（以前は2019-nCoVと呼ばれていた）という名前の別の高病原性コロナウイルスが出現しました、そして世界中に急速に広がっています。

このウイルスはSARS-CoVと非常に相同的な配列を共有し、SARS-CoVおよびMERS-CoVで報告されているものと同様の臨床症状を伴う急性の非常に致命的な肺炎コロナウイルス病2019（COVID-19）を引き起こします。

COVID-19患者の最も特徴的な症状は呼吸困難であり、集中治療室に入院した患者のほとんどは自発呼吸ができませんでした。

さらに、COVID-19の一部の患者は、頭痛、吐き気、嘔吐などの神経症状も示しました。

増加する証拠は、コロナウイルスが常に気道に限定されるわけではなく、神経疾患を誘発する中枢神経系にも侵入する可能性があることを示しています。

SARS‐CoVの感染は、脳幹が重度に感染した患者と実験動物の両方の脳で報告されています。

さらに、一部のコロナウイルスは、シナプス接続経路を介して、肺および下気道の機械受容器および化学受容器から髄質心肺中枢に広がることが実証されています。

SARS-CoVとSARS-CoV2の類似性が高いことを考慮すると、SARS-CoV2の潜在的な浸潤がCOVID-19患者の急性呼吸不全の原因の一部であるかどうかを明確にする必要があります。

これを知ることは、SARS‐CoV‐2誘発性呼吸不全の予防と治療にとって重要な意味を持つかもしれません。

宿主受容体の組織分布は、一般にウイルスの向性と一致すると考えられています。

ヒト宿主細胞へのSARS-CoVの侵入は、主に細胞受容体アンジオテンシン変換酵素2（ACE2）によって媒介され、これはヒト気道上皮、肺実質、血管内皮、腎臓細胞、および小腸細胞で発現します。

SARS-CoVとは異なり、MERS-CoVは、主に下気道、腎臓、小腸、肝臓、および免疫系の細胞に存在するジペプチジルペプチダーゼ4（DPP4）を介してヒト宿主細胞に入ります。

ただし、ACE2またはDPP4の存在だけでは、宿主細胞が感染しやすくなりません。

たとえば、一部のACE2発現内皮細胞およびヒト腸細胞株はSARS-CoVに感染できませんでしたが、肝細胞などの検出可能なACE2発現レベルを持たない一部の細胞もSARS-CoVに感染する可能性があります。

同様に、CNSでもSARS-CoVまたはMERS-CoVの感染が報告されており、通常の状態ではACE2またはDDP4の発現レベルが非常に低くなっています。

2002年と2003年の初期に、SARS患者のサンプルの研究により、SARS-CoV粒子が脳に存在することが実証されました。

トランスジェニックマウスを使用した実験研究により、SARS-CoVまたはMERS-COVのいずれかも、

鼻腔内投与すると、おそらく嗅神経を介して脳に入り、その後、視床や脳幹を含む特定の脳領域に急速に広がる可能性があります。

低接種量のMERS-CoVウイルス粒子に感染したマウスでは、脳でのみ検出されたことは注目に値します。

肺ではなく、CNSの感染が感染マウスで観察される高い死亡率にとってより重要であることを示します。

関与する脳の領域の中で、脳幹はSARS-CoVまたはMERS-CoVにひどく感染していることが実証されています。

SARS-CoVまたはMERS-COVがCNSに入る正確な経路はまだ報告されていません。

しかし、感染した脳領域の非神経細胞ではウイルス粒子がほとんど検出されなかったため、特に感染の初期段階では、血行性またはリンパ性の経路は不可能と思われます。

一方で、CoVが最初に末梢神経終末に侵入し、次にシナプス接続経路を介してCNSにアクセスできることを示す証拠が増えています。

HEV67、および鳥類気管支炎ウイルスなど、他のCoVのシナプス間伝達は十分に実証されています。

HEV 67Nはブタの脳に侵入した最初のCoVであり、HCoV-OC43と91％以上の相同性を共有しています。

HEVはまず、子豚の鼻粘膜、扁桃腺、肺、および小腸に感染し、その後、末梢神経を介して消化管のper動機能を担当する髄質ニューロンに逆行して送達され、いわゆる嘔吐性疾患を引き起こします。

ニューロン間のHEV 67Nの移動は、クラスリンコーティングを介したエンドサイトーシス/エキソサイトーシス経路を使用する以前の超微細構造研究で実証されています。

同様に、鳥類気管支炎ウイルスのシナプス間伝達も報告されています。

鳥インフルエンザウイルスのマウスへの鼻腔内接種は、気管支炎または肺炎に加えて神経感染を引き起こすことが報告されています。

興味深いことに、ウイルス性抗原は脳幹で検出されており、感染部位には孤独核と疑核が含まれていました。孤束核は、肺および気道の機械受容器および化学受容器から感覚情報を受け取り、

一方、疑核と孤束核からの遠心性線維は、気道平滑筋、腺、および血管の神経を支配します。

このような神経解剖学的相互接続は、感染した動物または患者の死が脳幹の心肺中枢の機能不全による可能性があることを示しています。

まとめると、神経侵襲性はCoVの共通の特徴として実証されています。

SARS-CoVとSARS-CoV2の類似性が高いことを考えると、SARS-CoV-2も同様の可能性が高いです。 COVID-19の疫学的調査に基づくと、最初の症状から呼吸困難までの時間の中央値は5.0日、入院までの期間は7.0日、集中治療室までの期間は8.0日でした。

したがって潜伏期間は、ウイルスが髄質ニューロンに侵入して破壊するのに十分な時間があります。

実際、以前の研究では、SARS-CoV-2に感染した一部の患者は、頭痛（約8％）、吐き気、嘔吐（1％）などの神経症状を示したことが報告されています。

より最近では、Maoらによる COVID-19患者に関する1つの研究もあります。

さらに、重度の患者の約88％（=78/88）が急性脳血管疾患や意識障害を含む神経症状を示しました。

したがって、起こりうる神経浸潤の認識は、SARS‐CoV‐2誘発性呼吸不全の予防と治療にとって重要な意味を持つ可能性があります。

The neuroinvasive potential of SARS‐CoV2 may play a role in the respiratory failure of COVID‐19 patients

J Med Virol. 2020 Feb 27 [Online ahead of print]

Yan‐Chao Li , Wan‐Zhu Bai , Tsutomu Hashikawa

First published: 27 February 2020

https://doi.org/10.1002/jmv.25728

[Correction added on March 17, 2020 after first online publication: Manuscript has been revised with author's latest changes]

PubMed ID: 32104915

Abstract

Following the severe acute respiratory syndrome coronavirus (SARS‐CoV) and Middle East respiratory syndrome coronavirus (MERS‐CoV), another highly pathogenic coronavirus named SARS‐CoV‐2 (previously known as 2019‐nCoV) emerged in December 2019 in Wuhan, China, and rapidly spreads around the world. This virus shares highly homological sequence with SARS‐CoV, and causes acute, highly lethal pneumonia coronavirus disease 2019 (COVID‐19) with clinical symptoms similar to those reported for SARS‐CoV and MERS‐CoV. The most characteristic symptom of patients with COVID‐19 is respiratory distress, and most of the patients admitted to the intensive care could not breathe spontaneously. Additionally, some patients with COVID‐19 also showed neurologic signs, such as headache, nausea, and vomiting. Increasing evidence shows that coronaviruses are not always confined to the respiratory tract and that they may also invade the central nervous system inducing neurological diseases. The infection of SARS‐CoV has been reported in the brains from both patients and experimental animals, where the brainstem was heavily infected. Furthermore, some coronaviruses have been demonstrated able to spread via a synapse‐connected route to the medullary cardiorespiratory center from the mechanoreceptors and chemoreceptors in the lung and lower respiratory airways. Considering the high similarity between SARS‐CoV and SARS‐CoV2, it remains to make clear whether the potential invasion of SARS‐CoV2 is partially responsible for the acute respiratory failure of patients with COVID‐19. Awareness of this may have a guiding significance for the prevention and treatment of the SARS‐CoV‐2‐induced respiratory failure.

Research Highlights

• SARS‐CoV2 causes epidemic pneumonia characterized by acute respiratory distress.

• This novel coronavirus is similar to SARS‐CoV in sequence, pathogenesis, and cellular entry.

• Some coronaviruses can invade brainstem via a synapse‐connected route from the lung and airways.

• The potential invasion of SARS‐CoV2 may be one reason for the acute respiratory failure.

• Awareness of this will have guiding significance for the prevention and treatment.

1 INTRODUCTION

Coronaviruses (CoVs), which are large enveloped non‐segmented positive‐sense RNA viruses, generally cause enteric and respiratory diseases in animals and humans.1 Most human CoVs, such as hCoV‐229E, OC43, NL63, and HKU1 cause mild respiratory diseases, but the worldwide spread of two previously unrecognized CoVs, the severe acute respiratory syndrome CoV (SARS‐CoV) and Middle East respiratory syndrome CoV (MERS‐CoV) have called global attention to the lethal potential of human CoVs.2 While MERS‐CoV is still not eliminated from the world, another highly pathogenic CoV, currently named SARS‐CoV‐2 (previously known as 2019‐nCoV), emerged in December 2019 in Wuhan, China. This novel CoV has caused a national outbreak of severe pneumonia (coronavirus disease 2019 [COVID‐19]) in China, and rapidly spreads around the world.

Genomic analysis shows that SARS‐CoV‐2 is in the same betacoronavirus (βCoV) clade as MERS‐CoV and SARS‐CoV, and shares highly homological sequence with SARS‐CoV.3 The public evidence shows that COVID‐19 shares similar pathogenesis with the pneumonia induced by SARS‐CoV or MERS‐CoV.4 Moreover, the entry of SARS‐CoV‐2 into human host cells has been identified to use the same receptor as SARS‐CoV.5, 6

Most CoVs share a similar viral structure and infection pathway,7, 8 and therefore the infection mechanisms previously found for other CoVs may also be applicable for SARS‐CoV‐2. A growing body of evidence shows that neurotropism is one common feature of CoVs.1,9-12 Therefore, it is urgent to make clear whether SARS‐CoV‐2 can gain access to the central nervous system (CNS) and induce neuronal injury leading to the acute respiratory distress.

2 THE CLINICAL FEATURES OF SARS‐CoV‐2 INFECTION

SARS‐CoV‐2 causes acute, highly lethal pneumonia with clinical symptoms similar to those reported for SARS‐CoV and MERS‐CoV.2, 11 Imaging examination revealed that most patients with fever, dry cough, and dyspnea showed bilateral ground‐glass opacities on chest computerized tomography scans.12 However, different from SARS‐CoV, SARS‐CoV‐2‐infected patients rarely showed prominent upper respiratory tract signs and symptoms, indicating that the target cells of SARS‐CoV‐2 may be located in the lower airway.2

Based upon the first‐hand evidence from Wuhan local hospitals,2, 10, 12 the common symptoms of COVID‐19 were fever (83%‐99%) and dry cough (59.4%‐82%) at the onset of illness. However, the most characteristic symptom of patients is respiratory distress (~55%). Among the patients with dyspnea, more than half needed intensive care. About 46% to 65% of the patients in the intensive care worsened in a short period of time and died due to respiratory failure. Among the 36 cases in the intensive care reported by Wang et al,10 11.1% received high‐flow oxygen therapy, 41.7% received noninvasive ventilation, and 47.2% received invasive ventilation. These data suggest that most (about 89%) of the patients in need of intensive care could not breathe spontaneously.

It is now known that CoVs are not always confined to the respiratory tract and that they may also invade the CNS inducing neurological diseases. Such neuroinvasive propensity of CoVs has been documented almost for all the βCoVs, including SARS‐CoV,1 MERS‐CoV,13 HCoV‐229E,14 HCoV‐OC43,15 mouse hepatitis virus,16 and porcine hemagglutinating encephalomyelitis coronavirus (HEV).9, 17-19

With respect to the high similarity between SARS‐CoV and SARS‐CoV2, it remains to know whether the potential neuroinvasion of SARS‐CoV‐2 plays a role in the acute respiratory failure of patients with COVID‐19.

3 THE NEUROINVASIVE POTENTIAL OF SARS‐CoV‐2

It is believed that the tissue distributions of host receptors are generally consistent with the tropisms of viruses.20-22 The entry of SARS‐CoV into human host cells is mediated mainly by a cellular receptor angiotensin‐converting enzyme 2 (ACE2), which is expressed in human airway epithelia, lung parenchyma, vascular endothelia, kidney cells, and small intestine cells.23-25 Different from SARS‐CoV, MERS‐CoV enters human host cells mainly via dipeptidyl peptidase 4 (DPP4), which is present in the lower respiratory tract, kidney, small intestine, liver, and the cells of the immune system.26, 27

However, the presence of ACE2 or DPP4 solely is not sufficient to make host cells susceptible to infection. For example, some ACE2‐expressing endothelial cells and human intestinal cell lines failed to be infected by SARS‐CoV,28, 29 while some cells without a detectable expression level of ACE2, such as hepatocytes could also be infected by SARS‐CoV.20 Likewise, the infection of SARS‐CoV or MERS‐CoV was also reported in the CNS, where the expression level of ACE230 or DDP430 is very low under normal conditions.

Early in 2002 and 2003, studies on the samples from patients with SARS have demonstrated the presence of SARS‐CoV particles in the brain, where they were located almost exclusively in the neurons.31-33 Experimental studies using transgenic mice further revealed that either SARS‐CoV34 or MERS‐COV,13 when given intranasally, could enter the brain, possibly via the olfactory nerves, and thereafter rapidly spread to some specific brain areas including thalamus and brainstem. It is noteworthy that in the mice infected with low inoculum doses of MERS‐CoV virus particles were detected only in the brain, but not in the lung, which indicates that the infection in the CNS was more important for the high mortality observed in the infected mice.13 Among the involved brain areas, the brainstem has been demonstrated to be heavily infected by SARS‐CoV34, 35 or MERS‐CoV.13

The exact route by which SARS‐CoV or MERS‐COV enters the CNS is still not reported. However, hematogenous or lymphatic route seems impossible, especially in the early stage of infection, since almost no virus particle was detected in the nonneuronal cells in the infected brain areas.31-33 On the other hand, increasing evidence shows that CoVs may first invade peripheral nerve terminals, and then gain access to the CNS via a synapse‐connected route.9, 17, 19, 36 The trans‐synaptic transfer has been well documented for other CoVs, such as HEV679‐10, 18‐19 and avian bronchitis virus.36, 37

HEV 67N is the first CoV found to invade the porcine brain, and it shares more than 91% homology with HCoV‐OC43.38, 39 HEV first oronasally infects the nasal mucosa, tonsil, lung, and small intestine in suckling piglets, and then is delivered retrogradely via peripheral nerves to the medullary neurons in charge of peristaltic function of the digestive tract, resulting in the so‐called vomiting diseases.18, 19 The transfer of HEV 67N between neurons has been demonstrated by our previous ultrastructural studies to use the clathrin‐coating‐mediated endocytotic/exocytotic pathway.17

Similarly, the trans‐synaptic transfer has been reported for avian bronchitis virus.36, 37 Intranasal inoculation in mice with avian influenza virus was reported to cause neural infection besides bronchitis or pneumonia.36 Of interest, viral antigens have been detected in the brainstem, where the infected regions included the nucleus of the solitary tract and nucleus ambiguus. The nucleus of the solitary tract receives sensory information from the mechanoreceptors and chemoreceptors in the lung and respiratory tracts,40-42 while the efferent fibers from the nucleus ambiguus and the nucleus of the solitary tract provide innervation to airway smooth muscle, glands, and blood vessels. Such neuroanatomic interconnections indicate that the death of infected animals or patients may be due to the dysfunction of the cardiorespiratory center in the brainstem.11, 30, 36

Taken together, the neuroinvasive propensity has been demonstrated as a common feature of CoVs. In light of the high similarity between SARS‐CoV and SARS‐CoV2, it is quite likely that SARS‐CoV‐2 also possesses a similar potential. Based on 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 the intensive care was 8.0 days.10 Therefore, the latency period may be enough for the virus to enter and destroy the medullary neurons. As a matter of fact, the previous studies214, 15 mentioned above has reported that some patients infected with SARS‐CoV‐2 did show neurologic signs such as headache (about 8%), nausea and vomiting (1%). More recently, one study on 214 COVID‐19 patients by Mao et al.43 further found that about 88% (78/88) among the severe patients displayed neurologic manifestations including acute cerebrovascular diseases and impaired consciousness. Therefore, awareness of the possible neuroinvasion may have a guiding significance for the prevention and treatment of the SARS‐CoV‐2‐induced respiratory failure.