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Is the Collapse of the Respiratory Center in the Brain Responsible for Respiratory Breakdown in COVID-19 Patients?
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  • Sonu Gandhi
    Sonu Gandhi
    DBT-National Institute of Animal Biotechnology (DBT-NIAB), Hyderabad 500032, India
    More by Sonu Gandhi
  • Amit Kumar Srivastava
    Amit Kumar Srivastava
    CSIR-Indian Institute of Chemical Biology (CSIR-IICB), Kolkata 700032, India
    IICB-Translational Research Unit of Excellence (IICB-TRUE), Kolkata 700091, India
    More by Amit Kumar Srivastava
  • Upasana Ray
    Upasana Ray
    CSIR-Indian Institute of Chemical Biology (CSIR-IICB), Kolkata 700032, India
    IICB-Translational Research Unit of Excellence (IICB-TRUE), Kolkata 700091, India
    More by Upasana Ray
  • Prem Prakash Tripathi*
    Prem Prakash Tripathi
    CSIR-Indian Institute of Chemical Biology (CSIR-IICB), Kolkata 700032, India
    IICB-Translational Research Unit of Excellence (IICB-TRUE), Kolkata 700091, India
    *Email: [email protected]
    More by Prem Prakash Tripathi
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ACS Chemical Neuroscience

Cite this: ACS Chem. Neurosci. 2020, 11, 10, 1379–1381
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https://doi.org/10.1021/acschemneuro.0c00217
Published April 29, 2020
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Abstract

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Following the identification of severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, we are now again facing a global highly pathogenic novel coronavirus (SARS-CoV-2) epidemic. Although the lungs are one of the most critically affected organs, several other organs, including the brain may also get infected. Here, we have highlighted that SARS-CoV-2 might infect the central nervous system (CNS) through the olfactory bulb. From the olfactory bulb, SARS-CoV-2 may target the deeper parts of the brain including the thalamus and brainstem by trans-synaptic transfer described for many other viral diseases. Following this, the virus might infect the respiratory center of brain, which could be accountable for the respiratory breakdown of COVID-19 patients. Therefore, it is important to screen the COVID-19 patients for neurological symptoms as well as possibility of the collapse of the respiratory center in the brainstem should be investigated in depth.

Copyright © 2020 American Chemical Society

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This article is made available via the ACS COVID-19 subset for unrestricted RESEARCH re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

We are facing a global highly pathogenic novel coronavirus (SARS-CoV-2) that has already infected more than 2.5 million people and caused more than 180 000 death worldwide. Coronaviruses (CoV) are large enveloped RNA viruses that cause respiratory disease in animals and humans, ranging from the common cold to life threatening pneumonia. There are total seven types of human CoVs reported to date. Four out of seven CoVs cause mild upper respiratory tract infections, while two human CoVs named SARS-CoV and MERS-CoV have caused major outbreaks. The recent outbreak of a novel coronavirus, named as SARS-CoV-2/2019-nCoV/COVID-19, has been recently declared as a pandemic by the World Health Organization, as it has spread to more than 200 countries and territories. Not only do SARS-CoV-2 and SARS-CoV share a high level of DNA sequence similarities, but also both of them exploit the same angiotensin-converting enzyme 2 (ACE2) receptor, binding to which facilitate the virus entry target cells. Due to the presence of similar proteins on the surface of the virus and exploitation of the same host cell receptor, it was anticipated that the mechanism through which SARS-CoV infects the host cell could also be same for SARS-CoV-2. SARS-CoV virus not only was found inside brain cells but also was capable of infecting it, highlighting the neurotropic properties of this virus. (1) Neuroinvasive and neurotropism properties of CoVs were demonstrated for other CoVs such as MERS-CoV, hCoV-OC43, HCoV-229E, and hepatitis virus. However, given the high genetic sequence similarity between SARS-CoV and SARS-CoV-2, as well as respiratory syndrome in other CoVs, it remains to be determined if respiratory failure seen in COVID-19 patients is due to potential neuroinvasion of SARS-CoV-2.

Contrary to popular notion, the presence of ACE2 is not sufficient enough for host cell susceptibility towards infection by CoV. For instance, intestinal cells and endothelial cells are not infected despite expression of ACE-2 while hepatocytes with undetectable levels could be infected by SARS-CoV. On the contrary, SARS-CoV and MERS-CoV infection was observed in the brain despite very low expression of ACE-2. Transgenic mice harboring hACE-2 have demonstrated that SARS-CoV enters the brain possibly via the olfactory bulb, and then from there it spreads to other specific parts of brain such as the thalamus and brainstem through olfactory nerves. Similarly, transgenic mice expressing hDPP4 were used to show that MERS-CoV enters the brain through the same route and affects the thalamus and brainstem. Importantly, at low dose, MERS-CoV was infectious only in the brain but not in the lung and this infection in the brain was correlated with high mortality observed in a mouse model of MARS-CoV. All these studies indicate that the brainstem is one of the highly infected areas of the brain by SARS-CoV or MERS-CoV.

Interestingly, two sets of neuronal networks are present within the brainstem that are crucial for generation of respiratory rhythm. (2) The pre-Bötzinger complex (PBC) functions as the primary respiratory oscillator, and it has been proposed as a kernel of respiration, while the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG) is a secondary oscillator. We have shown that disruption of the PBC in the existence of a normal RTN/pFRG cause lethality due to respiratory failure. (3) Overall, the PBC plays a central role in rhythmogenesis along with possible other respiratory networks present in the brainstem. It is possible that SARS-CoV-2 may shut down the PBC and in turn breathing by infecting and destroying the PBC in the brainstem. A destroyed respiratory center in the brainstem could be accountable for respiratory breakdown in COVID-19 patients. Therefore, respiratory failure related death might be due to the collapse of the respiratory center in the brainstem, which is usually not very apparent during diagnosis. Although this underlined hypothesis needs to be validated for SARS-CoV-2, a recent study has found that almost 50% of COVID-19 patients also had many neurological problems including epilepsy, stroke, and hemorrhage.

SARS-CoV-2 might target the central nervous system (CNS) through the olfactory bulb and infect the olfactory nerve. From there, it would spread to various parts of the brain by a synapse connected route and trans-synaptic transfer and infects the PBC in the brainstem, the respiratory center of the brain that controls the lungs, shutting down breathing and causing potential death in a similar manner what has been proposed by SARS-CoV. (4,5) In fact, from the appearance of first symptoms of infection with SARS-CoV-2 to hospitalization, usually it takes a week, which is enough for this virus to enter the brain and attack the PBC to collapse the respiratory center of patients. Transgenic mice expressing hACE-2 have also shown that SARS-CoV enters the brains through neurons present in the nose and from there it spreads to other parts of brain. They highlighted the dysfunctional neurons that serve as the breathing center could be the major cause of death. MERS virus expressing hACE2 has also indicated parallel results. Interestingly, a significant number of asymptomatic COVID-19 patients in Korea, China, Italy, and Spain have complained of loss of smell. If SARS-CoV-2 uses the same pathway, then it will target the olfactory mucosa and olfactory axons, making an opening in the cribiform plate for it enter the subarachnoid space and project towards olfactory epithelium and outer layer of the olfactory bulb. (6) This is a continuation of a previous report demonstrating the entry of Nipah virus into the CNS via the cribriform plate and olfactory bulb. Importantly, Nipas virus entry into the CNS occurs concurrently with respiratory disease, rather than as a result of secondary infection in the lungs. Once SARS-CoV-2 reaches the olfactory bulb, it may target the deeper parts of the brain including the thalamus and brainstem by trans-synaptic transfer as described for many viral diseases (Figure 1). Infection in the respiratory center of the brainstem can trigger changes that affect involuntary respiration controlled by the CNS. Thus, it is not only important to screen COVID-19 patients for neurological symptoms but also further segregate them when the symptoms appear. At present, the brain is not considered as a primary or secondary cause of death from COVID-19. It is important that we really focus our attention also toward the respiratory center of the CNS. In the future, cerebrospinal fluid of patients at different time points of infection and postmortem brains tissue of COVID-19 patients should also be assessed to understand the route of entry, transneuronal spread, neuronal damage, and affected areas, including a detailed assessment of the respiratory center of the brain.

Figure 1

Figure 1. Schematic representation showing how SARS-CoV-2 may infect the respiratory center of the brain. SARS-CoV-2 may enter the brain through the olfactory mucosa present in the upper nasal cavity. From there, through olfactory axons, it makes an opening in the cribriform plate and projects to the olfactory epithelium and olfactory bulb. SARS-CoV-2 further migrates to deeper parts of the brain such as the thalamus and brainstem by trans-synaptic migration and targets the pre-Bötzinger complex, thus possibly causing the collapse of the respiratory center of the brain.

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  • Corresponding Author
    • Prem Prakash Tripathi - CSIR-Indian Institute of Chemical Biology (CSIR-IICB), Kolkata 700032, India;  IICB-Translational Research Unit of Excellence (IICB-TRUE), Kolkata 700091, India;  Email: [email protected]
  • Authors
    • Sonu Gandhi - DBT-National Institute of Animal Biotechnology (DBT-NIAB), Hyderabad 500032, India
    • Amit Kumar Srivastava - CSIR-Indian Institute of Chemical Biology (CSIR-IICB), Kolkata 700032, India;  IICB-Translational Research Unit of Excellence (IICB-TRUE), Kolkata 700091, India
    • Upasana Ray - CSIR-Indian Institute of Chemical Biology (CSIR-IICB), Kolkata 700032, India;  IICB-Translational Research Unit of Excellence (IICB-TRUE), Kolkata 700091, India
  • Notes
    The authors declare no competing financial interest.

    * Corresponding author.

Acknowledgments

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P.P.T. originated the concept and wrote the manuscript. S.G., A.K.S. and U.R. helped in the discussion and editing during writing of the manuscript. P.P.T. kindly acknowledges SERB India (ECR/2017/000466) for the financial support and CSIR-IICB Kolkata for grant and infrastructure.

References

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  • Figure 1

    Figure 1. Schematic representation showing how SARS-CoV-2 may infect the respiratory center of the brain. SARS-CoV-2 may enter the brain through the olfactory mucosa present in the upper nasal cavity. From there, through olfactory axons, it makes an opening in the cribriform plate and projects to the olfactory epithelium and olfactory bulb. SARS-CoV-2 further migrates to deeper parts of the brain such as the thalamus and brainstem by trans-synaptic migration and targets the pre-Bötzinger complex, thus possibly causing the collapse of the respiratory center of the brain.

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  • References

    This article references 6 other publications.

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      3
      The H3K27 demethylase JMJD3 is required for maintenance of the embryonic respiratory neuronal network, neonatal breathing, and survival
      Burgold, Thomas; Voituron, Nicolas; Caganova, Marieta; Tripathi, Prem Prakash; Menuet, Clement; Tusi, Betsabeh Khoramian; Spreafico, Fabio; Bevengut, Michelle; Gestreau, Christian; Buontempo, Serena; Simeone, Antonio; Kruidenier, Laurens; Natoli, Gioacchino; Casola, Stefano; Hilaire, Gerard; Testa, Giuseppe
      Cell Reports (2012), 2 (5), 1244-1258CODEN: CREED8; ISSN:2211-1247. (Cell Press)
      JMJD3 (KDM6B) antagonizes Polycomb silencing by demethylating lysine 27 on histone H3. The interplay of methyltransferases and demethylases at this residue is thought to underlie crit. cell fate transitions, and the dynamics of H3K27me3 during neurogenesis posited for JMJD3 a crit. role in the acquisition of neural fate. Despite evidence of its involvement in early neural commitment, however, its role in the emergence and maturation of the mammalian CNS remains unknown. Here, we inactivated Jmjd3 in the mouse and found that its loss causes perinatal lethality with the complete and selective disruption of the pre-Botzinger complex (PBC), the pacemaker of the respiratory rhythm generator. Through genetic and electrophysiol. approaches, we show that the enzymic activity of JMJD3 is selectively required for the maintenance of the PBC and controls crit. regulators of PBC activity, uncovering an unanticipated role of this enzyme in the late structuring and function of neuronal networks.
    4. 4
      Netland, J., Meyerholz, D. K., Moore, S., Cassell, M., and Perlman, S. (2008) Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2. J. Virol. 82, 7264– 7275,  DOI: 10.1128/JVI.00737-08
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      Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2
      Netland, Jason; Meyerholz, David K.; Moore, Steven; Cassell, Martin; Perlman, Stanley
      Journal of Virology (2008), 82 (15), 7264-7275CODEN: JOVIAM; ISSN:0022-538X. (American Society for Microbiology)
      Infection of humans with the severe acute respiratory syndrome coronavirus (SARS-CoV) results in substantial morbidity and mortality, with death resulting primarily from respiratory failure. While the lungs are the major site of infection, the brain is also infected in some patients. Brain infection may result in long-term neurol. sequelae, but little is known about the pathogenesis of SARS-CoV in this organ. We previously showed that the brain was a major target organ for infection in mice that are transgenic for the SARS-CoV receptor (human angiotensin-converting enzyme 2). Herein, we use these mice to show that virus enters the brain primarily via the olfactory bulb, and infection results in rapid, transneuronal spread to connected areas of the brain. This extensive neuronal infection is the main cause of death because intracranial inoculation with low doses of virus results in a uniformly lethal disease even though little infection is detected in the lungs. Death of the animal likely results from dysfunction and/or death of infected neurons, esp. those located in cardiorespiratory centers in the medulla. Remarkably, the virus induces minimal cellular infiltration in the brain. Our results show that neurons are a highly susceptible target for SARS-CoV and that only the absence of the host cell receptor prevents severe murine brain disease.
    5. 5
      Li, Y. C., Bai, W. Z., and Hashikawa, T. (2020) The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients. J. Med. Virol. 92, 552,  DOI: 10.1002/jmv.25728
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      The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients
      Li, Yan-Chao; Bai, Wan-Zhu; Hashikawa, Tsutomu
      Journal of Medical Virology (2020), 92 (6), 552-555CODEN: JMVIDB; ISSN:0146-6615. (Wiley-Blackwell)
      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 Dec. 2019 in Wuhan, China, and rapidly spreads around the world. This virus shares highly homol. sequence with SARS-CoV, and causes acute, highly lethal pneumonia coronavirus disease 2019 (COVID-19) with clin. 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. Addnl., some patients with COVID-19 also showed neurol. 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 neurol. diseases. The infection of SARS-CoV has been reported in the brains from both patients and exptl. 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.
    6. 6
      Dando, S. J., Mackay-Sim, A., Norton, R., Currie, B. J., St. John, J. A., Ekberg, J. A., Batzloff, M., Ulett, G. C., and Beacham, I. R. (2014) Pathogens penetrating the central nervous system: infection pathways and the cellular and molecular mechanisms of invasion. Clin. Microbiol. Rev. 27 (4), 691– 726,  DOI: 10.1128/CMR.00118-13
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      Pathogens penetrating the central nervous system: infection pathways and the cellular and molecular mechanisms of invasion
      Dando, Samantha J.; Mackay-Sim, Alan; Norton, Robert; Currie, Bart J.; St. John, James A.; Ekberg, Jenny A. K.; Batzloff, Michael; Ulett, Glen C.; Beacham, Ifor R.
      Clinical Microbiology Reviews (2014), 27 (4), 691-726, 37 pp.CODEN: CMIREX; ISSN:1098-6618. (American Society for Microbiology)
      The brain is well protected against microbial invasion by cellular barriers, such as the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB). In addn., cells within the central nervous system (CNS) are capable of producing an immune response against invading pathogens. Nonetheless, a range of pathogenic microbes make their way to the CNS, and the resulting infections can cause significant morbidity and mortality. Bacteria, amoebae, fungi, and viruses are capable of CNS invasion, with the latter using axonal transport as a common route of infection. In this review, we compare the mechanisms by which bacterial pathogens reach the CNS and infect the brain. In particular, we focus on recent data regarding mechanisms of bacterial translocation from the nasal mucosa to the brain, which represents a little explored pathway of bacterial invasion but has been proposed as being particularly important in explaining how infection with Burkholderia pseudomallei can result in melioidosis encephalomyelitis.