key: cord-0749903-ygwos7cb authors: Mao, Xiao-Yuan; Jin, Wei-Lin title: The COVID-19 pandemic: consideration for brain infection date: 2020-05-04 journal: Neuroscience DOI: 10.1016/j.neuroscience.2020.04.044 sha: 70905c224d9a270807f0a827337f1ab796c23608 doc_id: 749903 cord_uid: ygwos7cb • The entry of SARS-CoV-2 to brain via olfactory nerves. • The entry of SARS-CoV-2 to brain via ACE-2. • The entry of SARS-CoV-2 via cytokine storms. As of Apr 21st, 2020, a total of 2,397,217 confirmed cases and 162,956 deaths have been announced. Nowadays, it has been declared as a global public health threat by WHO due to a high rate of morbidity and mortality worldwide. COVID-19 is produced by a new virus which belongs to the Group 2 of beta-coronavirus that contains Severe Acute Respiratory Syndrome Coronavirus, namely, SARS-CoV-2. In parallel with this knowledge, COVID-19 patients commonly manifest respiratory complications, such as cough, respiratory insufficiency and fiber. Recently, increasing evidence shows that the novel coronavirus not only attacks respiratory system, but also likely invades the central nervous system (CNS), developing neurological symptoms. In a retrospective analysis, it was documented that 36.4% (78/214) of SARS-CoV-2-infected patients possessed neurological manifestations including acute cerebrovascular diseases, disturbed consciousness and paresthesia (Mao et al., 2020) . Severely infected patients are particularly more vulnerable to occurrence of neurological symptoms than patients who succumb to mild disease. The evidence supporting neuroinfection also arises from a case of viral encephalitis caused by SARS-CoV-2 in Beijing Ditan Hospital on Mar 4th, 2020 (Moriguchi et al., 2020) . The researchers firstly reported that the cerebrospinal fluid tested positive for SARS-CoV-2 virus RNA by genome sequencing (Moriguchi et al., 2020) , suggesting the neuroinvasive potential for the virus. Mechanistically, SARS-CoV-2 virus has developed an ability to enter host cells through interacting directly with angiotensin-converting enzyme-2 (ACE-2), which is widely expressed in various tissues including brain (Gheblawi et al., 2020) . In this case, we consider the virus infects central nervous system due to the abundant expression of ACE-2 target throughout the brain. Indeed, SARS-CoV-2 virus could interact with ACE-2 in the capillary endothelium and caused blood-brain-barrier destruction, finally promoting virus entry into CNS. Besides, there is compelling evidence showing that the presence of mRNA from closely related SARS virus including SARS-CoV, which also interacts with ACE-2, is present in the brain of infected patients (Inoue et al., 2007) . In light of the high similarity between SARS-CoV and SARS-CoV-2 virus, it is quite likely that ACE-2 abundance in brain tissues promotes the entry of SARS-CoV-2 virus into CNS and subsequently causes neuroinfection. Additionally, it is also noteworthy that SARS-CoV-2 virus may enter the brain via the olfactory nerves through the nasal cavity and infect neurons that control breathing. This evidence arises from a recent investigation showing that nearly 89% of SARS-CoV-2-infected patients in need of intensive care could not breathe spontaneously and many had neurological manifestations including headache, nausea, and vomiting . Almost half of the patients became seriously sick in a short period of time and died as a result of respiratory failure. It is although not definitively demonstrated that neurons controlling breathing are likely to be infected. Another, under-investigated pathogenic factor that possibly triggers infection in the brain involves a cytokines storm. It is likely that proinflammatory factors released in large quantities promote neuroinflammation following viral infection. Further investigation is essential to clarify this issue. The mechanistic explanations are summarized in Figure 1 . We propose three possible patterns about the entry of SARS-CoV-2 virus into brain, namely, via the olfactory nerves in the nasal cavity ( ① ), interaction with angiotensin-converting enzyme-2 (ACE-2) in the brain (②) and a cytokine storm-induced blood brain barrier disruption (③). Angiotensin Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System Clathrin-dependent entry of severe acute respiratory syndrome coronavirus into target cells expressing ACE2 with the cytoplasmic tail deleted The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease A first case of meningitis/encephalitis associated with SARS-Coronavirus-2 The entry of SARS-CoV-2 to brain via olfactory nerves The entry of SARS-CoV-2 to brain via ACE-2 The entry of SARS-CoV-2 via cytokine storms The authors apologize to all the investigators whose work cannot cite in this paper due to space constraint. The authors declare no potential competing interests.