Title: Neurotropism of SARS-CoV 2: Mechanisms and manifestations
Abstract: SARS-Cov-2 is a beta-coronavirus that shares similarities with SARS-CoV. So far, it is proposed that it binds by glycoproteins expressed on its surface to the receptor of the angiotensin-converting enzyme 2, which is distributed in the respiratory tract epithelium, the lung parenchyma and other areas such as the gastrointestinal tract, endothelial cells, among others [[1]Li Y.C. Bai W.Z. Hashikawa T. The neuroinvasive potential of SARS-CoV2 may be at least partially responsible for the respiratory failure of COVID-19 patients.J. Med. Virol. 2020; 2: 0-2Google Scholar]. Respiratory involvement is the most common in patients confirmed with Covid-19, however there are already reports of neurological manifestations [[2]Filatov A. Sharma P. Hindi F. Espinosa P.S. Neurological complications of Coronavirus disease ( COVID-19 ).Encephalopathy. 2020; 12Google Scholar,[3]Mao L. Wang M. Chen S. He Q. Chang J. Hong C. et al.Neurological Manifestations of Hospitalized Patients with COVID-19 in Wuhan, China: a retrospective case series study.medRxiv. 2020; (Jan;2020.02.22.20026500)Google Scholar]. It should be mencioned that the central nervous system (CNS) involvement was also reported in other coronaviruses [[4]Hwang C.S. Olfactory neuropathy in severe acute respiratory syndrome: report of a case.Acta Neurol. Taiwanica. 2006; 15: 26-28PubMed Google Scholar] and studies in humans and experimental models revealed a possible neural pathway given by the olfactory nerve [5St-Jean J.R. Jacomy H. Desforges M. Vabret A. Freymuth F. Talbot P.J. Human respiratory coronavirus OC43: genetic stability and neuroinvasion.J. Virol. 2004; 78: 8824-8834Crossref PubMed Scopus (137) Google Scholar, 6Gu J. Gong E. Zhang B. Zheng J. Gao Z. Zhong Y. et al.Multiple organ infection and the pathogenesis of SARS.J. Exp. Med. 2005; 202: 415-424Crossref PubMed Scopus (1054) Google Scholar, 7Perlman S. Evans G. Afifi A. Effect of olfactory bulb ablation on spread of a neurotropic coronavirus into the mouse brain.J. Exp. Med. 1990; 172: 1127-1132Crossref PubMed Scopus (96) Google Scholar]. Viruses can reach the CNS through hematogenous or neural propagation [[8]Desforges M. Le Coupanec A. Stodola J.K. Meessen-Pinard M. Talbot P.J. Human coronaviruses: viral and cellular factors involved in neuroinvasiveness and neuropathogenesis.Virus Res. 2014; 194: 145-158Crossref PubMed Scopus (196) Google Scholar]. Nerve dissemination is possible by the polarization of neurons, this property gives them the ability to receive and transfer information. This transport can be retrograde or antegrade and is facilitated by proteins called dinein and kinesin, which can be targets of viruses [[9]Bohmwald K. Gálvez N.M.S. Ríos M. Kalergis A.M. Neurologic alterations due to respiratory virus infections.Front. Cell. Neurosci. 2018; 12: 1-15PubMed Google Scholar]. Once entered the CNS, viruses can generate alterations in neurons, as evidenced by a study carried out by Gu et al., who detected in 8 autopsies of victims of SARS, neuronal histopathological changes in the cortex and hypothalamus [[6]Gu J. Gong E. Zhang B. Zheng J. Gao Z. Zhong Y. et al.Multiple organ infection and the pathogenesis of SARS.J. Exp. Med. 2005; 202: 415-424Crossref PubMed Scopus (1054) Google Scholar]. The olfactory pathway begins in bipolar cells located in the olfactory epithelium, from there its axons and dendrites extend to the olfactory bulb, where they make synapses with the cells present in this structure. Subsequently, this cranial pair is divided into two branches and is directed towards the olfactory nucleus present in the pyriform cortex [[10]Galindo H. Ramos Y. Mendoza M.J. Quintana Pájaro L. Moscote L.R. Núcleos de los nervios craneales, conexiones.in: Neuroanatomia: Conceptos Esenciales Para El Estudiante de Medicina. 2019: 171-184Google Scholar] . This nerve route has been used by some coronaviruses in rodent models exposed to nasal inoculation [[11]Netland J. Meyerholz D.K. Moore S. Cassell M. Perlman S. Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2.J. Virol. 2008; 82: 7264-7275Crossref PubMed Scopus (935) Google Scholar,[12]Dubé M. Le Coupanec A. Wong A.H.M. Rini J.M. Desforges M. Talbot P.J. Axonal transport enables neuron-to-neuron propagation of human coronavirus OC43.J. Virol. 2018; 92Crossref PubMed Scopus (331) Google Scholar]. For example, after exposure to SARS-CoV by inhalation, Netland et al. detected the coronavirus after 60 h in the olfactory bulb and after four days its dissemination to the pyriform cortex and dorsal nucleus of the rafe was confirmed, the latter located on the brain stem [[11]Netland J. Meyerholz D.K. Moore S. Cassell M. Perlman S. Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2.J. Virol. 2008; 82: 7264-7275Crossref PubMed Scopus (935) Google Scholar]. Similar results were found in a Canadian study with another coronavirus, HCoV-OC43. In this case, by the fourth day of inoculation, the virus had already spread to the piriformis cortex, brain stem, and spinal cord [[12]Dubé M. Le Coupanec A. Wong A.H.M. Rini J.M. Desforges M. Talbot P.J. Axonal transport enables neuron-to-neuron propagation of human coronavirus OC43.J. Virol. 2018; 92Crossref PubMed Scopus (331) Google Scholar]. On the other hand, a study from the 1990s showed that interruption by ablation in the olfactory pathway did not allow the neural spread of the MHV coronavirus in an animal model [[7]Perlman S. Evans G. Afifi A. Effect of olfactory bulb ablation on spread of a neurotropic coronavirus into the mouse brain.J. Exp. Med. 1990; 172: 1127-1132Crossref PubMed Scopus (96) Google Scholar]. The interesting thing about this possible propagation mechanism is the presence of the virus in areas of the brain stem [[11]Netland J. Meyerholz D.K. Moore S. Cassell M. Perlman S. Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2.J. Virol. 2008; 82: 7264-7275Crossref PubMed Scopus (935) Google Scholar,[12]Dubé M. Le Coupanec A. Wong A.H.M. Rini J.M. Desforges M. Talbot P.J. Axonal transport enables neuron-to-neuron propagation of human coronavirus OC43.J. Virol. 2018; 92Crossref PubMed Scopus (331) Google Scholar], because this structure contains nuclei that regulate the respiratory rhythm. Breathing has central control given by the regulation of a number of neural groups. Through the nucleus of the solitary fascicle, the CNS receives information from the chemoreceptors that detect changes in the concentrations of CO2 and O2, alterations in these components lead to an increase or decrease in respiratory effort [[13]Nogués M.A. Benarroch E. Respiratory control disorders and respiratory motor unit.Neurol. Argent. 2011; 3: 167-175Crossref Scopus (4) Google Scholar]. In this way, stem nuclei have connections with the respiratory system [[1]Li Y.C. Bai W.Z. Hashikawa T. The neuroinvasive potential of SARS-CoV2 may be at least partially responsible for the respiratory failure of COVID-19 patients.J. Med. Virol. 2020; 2: 0-2Google Scholar,[13]Nogués M.A. Benarroch E. Respiratory control disorders and respiratory motor unit.Neurol. Argent. 2011; 3: 167-175Crossref Scopus (4) Google Scholar], and the entry of the coronavirus into this structure could trigger death by alteration of these neuronal groups [[1]Li Y.C. Bai W.Z. Hashikawa T. The neuroinvasive potential of SARS-CoV2 may be at least partially responsible for the respiratory failure of COVID-19 patients.J. Med. Virol. 2020; 2: 0-2Google Scholar]. In January 2020, Chen et al. published a retrospective analysis based on 99 patients diagnosed with SARS-COV-2 pneumonia at a hospital in Wuhan, China. In order to describe the epidemiological, demographic, clinical and radiological characteristics of these patients. The neurological symptoms presented were confusion and headache in 9% and 8%, respectively [[14]Chen N. Zhou M. Dong X. Qu J. Gong F. Han Y. et al.Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.Lancet. 2020 Feb; 395: 507-513Abstract Full Text Full Text PDF PubMed Scopus (13936) Google Scholar]. Months later, Mao et al. published a retrospective case series at 3 hospital centers in Wuhan, China. This included 214 patients with a molecular diagnosis of SARS-CoV-2 acute respiratory distress syndrome. The presence of neurological symptoms was evaluated in 3 categories: central, peripheral and musculoskeletal symptoms. In their analysis they found that 36.4% of the patients had neurological symptoms, these being directly related to the severity of the patient (severe cases VS non-severe: 40 [45.5%] vs. 38 [30.2%], P < .05). In patients with central symptoms (24.8%), 16.8% and 13.1% presented dizziness and headache, respectively. Among the peripheral symptoms (8.9%), the most common were hypogeusia and hyposmia with 5.6 and 5.1%. On the other hand, significant differences were found when comparing the presence of stroke (5 [5.7%] vs. 1 [0.8%], P < .05), alteration of the state of consciousness, severity (13 [14.8%] vs 3 [2.4%], P < .001) and muscle damage (17 [19.3%] vs 6 [4.8%], P < .001), according to the level of severity of the cases [[3]Mao L. Wang M. Chen S. He Q. Chang J. Hong C. et al.Neurological Manifestations of Hospitalized Patients with COVID-19 in Wuhan, China: a retrospective case series study.medRxiv. 2020; (Jan;2020.02.22.20026500)Google Scholar]. In addition to this, case reports have shown neurological alterations in patients with COVID-19, so far, we have found 4 cases; one is that of a 79-year-old patient, who enters with altered state of consciousness and a febrile history associated with coughs of several days of evolution. Imaging and laboratory studies showed massive intracerebral bleeding from the right hemisphere and RT - PCR positive for SARS-CoV-2, this event can be explained by the presence of receptors of the angiotensin-converting enzyme 2 in the cerebral vascular endothelium and its self-regulatory function that when invaded by the virus reduces its functionality causing elevation of cerebral blood pressure and as a consequence, the blood vessel rupture [[15]Karimi N. Rouhani N. COVID 19 and intra cerebral hemorrhage: causative or coincidental.New Microb. New Infect. [Internet]. 2020; (Available from): 100669https://doi.org/10.1016/j.nmni.2020.100669Google Scholar]. On the other hand, Filatov et al. report a case of an older adult patient with multiple cardiovascular and pulmonary pathological antecedents, in addition to Parkinson's disease, which consults the emergency department due to increased respiratory distress, persistence of fever, headache and altered mental status. Cranial tomography without acute alterations, electroencephalogram with findings of focal dysfunction of the left temporal lobe and focus of epileptogenicity, study of the cerebrospinal fluid (CSF) reported within normal limits, without detection of the virus. Based on these findings, it was considered that in addition to respiratory symptoms, the patient had encephalopathy [[2]Filatov A. Sharma P. Hindi F. Espinosa P.S. Neurological complications of Coronavirus disease ( COVID-19 ).Encephalopathy. 2020; 12Google Scholar]. In contrast, Zhou et al., detected the presence of the virus genome in the CSF of a 59-year-old patient with COVID-19 pneumonia, diagnosing viral encephalitis, demonstrating the direct damage that the virus produces in the CNS [[16]Zhou L. Zhang M. Gao J. Wang J. Sars-Cov-2: underestimated damage to nervous system.Travel. Med. Infect. Dis. [Internet]. 2020; (Available from): 101642https://doi.org/10.1016/j.tmaid.2020.101642Crossref PubMed Scopus (206) Google Scholar].Finally, Poyiadji et al., report the case of a patient with acute necrotizing encephalopathy diagnosed by images, associated with COVID-19, probably related to the cytokine storm that it produces within the CNS [[17]Poyiadji N. Shahin G. Noujaim D. Stone M. Patel S. Griffith B. COVID-19–associated acute hemorrhagic necrotizing encephalopathy: CT and MRI features.Radiology [Internet]. 2020 Mar; 31 (Available from:): 201187https://doi.org/10.1148/radiol.2020201187Crossref Scopus (1038) Google Scholar]. The aforementioned makes us think that respiratory distress is not only the result of pulmonary inflammatory structural damage, but also due to the damage caused by the virus in the respiratory centers of the brain, making it more difficult to manage these patients.