Next Article in Journal
The Bronchoprotective Effects of Dual Pharmacology, Muscarinic Receptor Antagonist and β2 Adrenergic Receptor Agonist Navafenterol in Human Small Airways
Next Article in Special Issue
StressMatic: A Novel Automated System to Induce Depressive- and Anxiety-like Phenotype in Rats
Previous Article in Journal
The Roles of Bone Marrow-Derived Stem Cells in Coronary Collateral Growth Induced by Repetitive Ischemia
Previous Article in Special Issue
Vestibular Nuclei: A New Neural Stem Cell Niche?
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cells
Volume 12
Issue 2
10.3390/cells12020244
cells-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Influence of SARS-CoV-2 on Adult Human Neurogenesis

by
Tomasz Stępień
1,*,
Sylwia Tarka
2,
Natalia Chmura
3,
Michał Grzegorczyk
4,
Albert Acewicz
1,
Paulina Felczak
1 and
Teresa Wierzba-Bobrowicz
1
1
Department of Neuropathology, Institute of Psychiatry and Neurology, 02-957 Warsaw, Poland
2
Chair and Department of Forensic Medicine, Medical University of Warsaw, 02-007 Warsaw, Poland
3
Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Warsaw, 02-097 Warsaw, Poland
4
Department of Descriptive and Clinical Anatomy, Medical University of Warsaw, 00-001 Warsaw, Poland
*
Author to whom correspondence should be addressed.
Cells 2023, 12(2), 244; https://doi.org/10.3390/cells12020244
Submission received: 2 December 2022 / Revised: 28 December 2022 / Accepted: 4 January 2023 / Published: 6 January 2023
(This article belongs to the Special Issue Advances in Neurogenesis: 2nd Edition)
Browse Figures
Versions Notes

Abstract

:
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with the onset of neurological and psychiatric symptoms during and after the acute phase of illness. Inflammation and hypoxia induced by SARS-CoV-2 affect brain regions essential for fine motor function, learning, memory, and emotional responses. The mechanisms of these central nervous system symptoms remain largely unknown. While looking for the causes of neurological deficits, we conducted a study on how SARS-CoV-2 affects neurogenesis. In this study, we compared a control group with a group of patients diagnosed with COVID-19. Analysis of the expression of neurogenesis markers showed a decrease in the density of neuronal progenitor cells and newborn neurons in the SARS-CoV-2 group. Analysis of COVID-19 patients revealed increased microglial activation compared with the control group. The unfavorable effect of the inflammatory process in the brain associated with COVID-19 disease increases the concentration of cytokines that negatively affect adult human neurogenesis.

1. Introduction

For a few years, people have been struggling with the COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1]. Subsequent mutations have led to COVID-19 waves of infection with significantly varying symptoms, prognoses, and transmissibility levels. Reports to date are mainly associated with coronavirus structural proteins and, in particular, the receptor binding domains of spike (S)-proteins rather than other nonstructural and accessory proteins [2]. SARS-CoV-2 B.1.617.2, also termed the Delta variant, was classified as a variant of concern according to the World Health Organization (WHO), demonstrating both increased transmissibility and increased disease severity. In contrast, the Omicron (B.1.1.529) variant seemed more infectious than the Delta variant and more likely to lead to vaccine breakthrough infections; it has also been reported to induce milder symptoms in most patients [3].
WHO statistics show that more than 628 million people have been infected with SARS-CoV-2 and approximately 6.6 million have died; however, the true numbers are significantly higher (see https://covid19.who.int, https://ourworldindata.org, accessed on 2 December 2022). The coronavirus disease pandemic continues due to the spread of new variants of SARS-CoV-2 worldwide [4,5]. The typical symptoms of COVID-19 include anosmia and ageusia along with fever, dry cough, and shortness of breath [6,7]. COVID-19 is a neurotropic virus associated with neurological manifestations in up to 36% of patients [8], and the most commonly reported manifestations are cerebrovascular events, followed by altered mental status [9]. Neurological manifestations can range from a mild headache or “brain fog” [10] to more serious complications, such as Guillain-Barre syndrome [11], encephalitis [12], and arterial and venous strokes [13]. The SARS-CoV-2 vaccine is still under development, and there is no specific drug at present. Many antiviral drugs have been employed for the treatment of SARS-CoV-2 infection, but have not been effective yet. Prompt development of effective drugs for COVID-19 therapy is a difficult task as the conventional drug development process usually takes a long time and costs billions. A comparative genomics-based approach with earlier known human CoVs can provide a breakthrough in COVID-19 therapeutics [14,15,16].
SARS-CoV-2 enters the human body via the angiotensin-converting enzyme (ACE)-2 receptor, which has been found to be expressed by airway epithelia, lungs, choroid plexus and various brain cells, including endothelial cells of the cerebral microvascular system [17,18]. Angiotensin-converting enzyme 2 (ACE2)- and transmembrane serine protease 2 (TMPRSS2)-expressing ciliated cells of the nasal mucosa are the primary targets of initial SARS-CoV-2 infection [19]. Infection with SARS-CoV-2 primarily leads to respiratory tract infection, and its sequelae frequently dominate the clinical course [20]. The olfactory tract seems to be the principal entry route to the CNS in the initial phases of SARS-CoV-2 infection [21]. Moreover, a high fraction of patients, perhaps as high as 33%, continue to suffer neuropsychiatric symptoms posthospital discharge, including a dysexecutive syndrome consisting of inattention, disorientation, and poor movement coordination [22,23,24,25].
Postmortem human neuropathological findings in COVID-19 include hypoxic damage, microglial activation, astrogliosis, leukocytic infiltration, and microhemorrhages, suggesting that, at least in some cases, the CNS undergoes neuropathological sequelae associated with hypoxia and neuroinflammation [26,27]. This is supported by neuroimaging studies in postacute COVID-19 patients, showing disruption of fractional anisotropy and diffusivity, suggesting microstructural and functional alterations of the hippocampus, a brain region critical for memory formation, and part of a conserved subcortical network involved in anxiety and stress responses. Thus far, the neurobiological bases of COVID-19 neuropsychiatric symptoms remain largely unknown [28]. Disruption of the blood–brain barrier (BBB) and damage to tight junctions may occur during COVID-19 infection. The BBB is crucial in protecting the hemodynamic function of the brain. The interconnected nature of brain capillary endothelial cells, pericytes, neurons, astrocytes, and microglia in the BBB strongly suggests this to be a path of SARS-CoV-2 viral entry to the brain and a contribution to neuroinflammatory events [29]. Evidence from in vitro models has shown that isolated spike proteins can cross the BBB [30]. While all regions examined, including the olfactory bulb (OB), cortex, hippocampus, and medulla oblongata, showed some degree of BBB disruption, the hippocampus suffered the most significant changes [31,32]. Recent studies have shown that people with COVID-19 are at a significantly increased risk of a new diagnosis of Alzheimer’s disease within 360 days of the initial COVID-19 diagnosis, especially those aged ≥ 85 years [33].
The hippocampus is one of the two regions where new neurons are generated. In the adult human brain, two locations of adult human neurogenesis, the dentate gyrus (DG) and the subventricular zone (SVZ), have been identified. Therefore, we wanted to explore how SARS-CoV-2 influences adult human neurogenesis. Neurogenesis involves the proliferation and differentiation of progenitor cells, as well as the migration and maturation of newly formed neurons. The first direct evidence for the occurrence of neurogenic processes in the adult human brain was described in 1998 by Erickson [34]. He revealed the generation of new neurons in the dentate gyrus and subventricular zone [35]. Newborn neurons migrate from the SVZ toward the olfactory bulb (OB). The fate of newborn neurons in the DG is strictly determined topographically, and they do not show a tendency to migrate toward the brain’s neocortical areas. They only participate in the constant supplementation of the pool of new granule cells in the dentate. In the DG, three types of transcriptionally active cells were identified: neural stem cells glia-like (NSCs, type-I cells), cells without processes (NSCs, progenitor cells, type-II cells), and neuroblasts [36]. In the SVZ, three types of transcriptionally active cells have been distinguished, namely, GFAP-positive neural stem cells (NSCs, type-B1 cells), progenitor cells (NSCs, type-C cells), and neuroblasts (type-A cells) [37]. Markers of early adult human neurogenesis phases comprise DCX (microtubule-associated protein expressed during neuronal migration) and NeuN (neuronal nuclear antigen), which label migrating neuroblasts and immature neurons, as well as GFAP (glial fibrillary antigen protein), which labels astrocytic stem cells [38,39]. Phosphorylated histone H3Ser-10 (p-Histone H3Ser-10) is more precise, and contrary to DCX, its expression occurs only in newborn neurons (neuronal progenitor cells, NPCs) [40]. Phosphorylation of the N-terminal domain of histone H3 at position Ser-10 and/or Ser-28 destabilizes chromatin, directly preceding replication and transcription [41,42].
Adult human neurogenesis is regulated by endogenous and exogenous factors that influence the proliferation potential of progenitor cells and accelerate the rate of development of the dendritic connections of newly formed neurons. The factors influencing the dynamics of neurogenesis and the total number of neurons include stress, diet, physical activity, alcohol, drugs, and medications [43]. Increased levels of proinflammatory factors may contribute to the formation and development of newly formed neurons. Proneurogenic importance during inflammation is shown by proteins secreted by active microglia, mainly CD47 and CD55 and interleukins 4 and 10. Analysis of COVID-19 patients revealed increased microglial activation and IL-1β expression compared with the control group. Elevated expression of IL-6 was detected in neurons, suggesting neuronal cytokine production [44]. However, the brain inflammation associated with COVID-19 increases the concentration of cytokines that negatively affect adult human neurogenesis, e.g., IL-6, IL-1β, IL-1α, and TNF [45]. Among the factors that reduce neurogenesis, the factor that almost completely suppresses neurogenesis is Zika virus (ZIKV). The CNS developmental arrest observed in congenital Zika syndrome is beyond neuronal cell death. Interestingly, Zika virus, as one of the proapoptotic factors, is very similar to SARS-CoV-2 and belongs to the same group of nonsegmented positive-sense RNA. Some studies have reported a decrease in neurogenesis in patients with COVID-19, linking it with brain fog and other neurological symptoms [10].
We hypothesized that the inflammatory response present in COVID-19 changes adult human neurogenesis. The aim of our study was to identify neuronal progenitor cells (NPCs) and perform a quantitative analysis of neurogenesis cell density, as well as to compare the group of patients with SARS-CoV-2 and the control group.

2. Materials and Methods

The study material was derived from the Brain Bank at the Institute of Psychiatry and Neurology, Warsaw, Poland. It comprises two structures, the hippocampal dentate gyrus and the subventricular zone. All brains were fixed in buffered 4% formaldehyde and embedded in paraffin.
The whole study group consisted of 52 patients with many different comorbidities. The final study group was composed of brains derived from 14 patients (7 men, 7 women, mean age 62.5 ± 6.9 years) with a COVID-19 diagnosis. The criteria for inclusion in this study were a positive result for the nasopharyngeal swab for SARS-CoV-2 RNA (PCR), pathological/radiological diagnosis of pneumonia of SARS-CoV-2, and/or presence of SARS-CoV-2 nucleoprotein in pulmonary tissue confirmed by immunohistochemical examination (IHC). The exclusion criteria in this study were hemorrhage, ischemic stroke, and cancer. Half of the study group had no comorbidities, and the rest had hypertension, chronic obstructive pulmonary disease (COPD), ischemic heart disease, and diabetes. Brains from the control group had no significant neuropathological lesions. They were derived from 8 patients (6 men, 2 women, mean age 64 ± 10.95 years) whose deaths occurred sporadically (within less than 10 min) without comorbidities and did not meet the study inclusion criteria. The tissue samples embedded in paraffin were cut into 5 µm slices and stained with hematoxylin and eosin and Mallory trichrome. Moreover, the study material was analyzed by IHC with the p-Histone antibodies H3Ser-10 (Proteintech, 66863-1-IG,1:2200, Rosemont, IL, USA), LCA (Dako, 8B11-PD7/26, 1:75, Los Angeles, CA, USA), and NeuN (Millipore MAB377, 1:100, Darmstadt, Germany).

Quantitative Analysis

Neuronal progenitor cells were counted in the hippocampal dentate gyrus (DG) and subventricular zone (SVZ) of the lateral ventricles. The quantitative analysis was performed by CellSens software (Tokyo, Japan). The results were analyzed with STATISTICA 12 (TIBCO Software Inc., Poland) software.

3. Results

We analyzed the experimental material in terms of neuropathological changes due to COVID-19. In all patients who died in the course of COVID-19, we observed perivascular changes, microbleeding/petechial hemorrhages, and hemosiderophages (Figure 1).
We observed a positive immunohistochemical response in transcriptionally active nuclei of the neuronal progenitor cells in the hippocampal dentate gyrus (DG) (Figure 2) and subventricular zone (SVZ) of both experimental groups (Figure 3). In the study group of patients diagnosed with COVID-19, we observed a decreased density of neuronal progenitor cells in the DG and SVZ. Quantitative analysis of neuronal progenitor cells (NPCs) with p-H3Ser-10 expression in the subventricular zone (610.9 ± 164.7 NPCs/mm2) and dentate gyrus (2024.1 ± 190.9 NPCs/mm2) revealed decreased density in the group of patients with SARS-CoV-2 compared to the control group (DG 2295.5 ± 488.5 NPCs/mm2; SVZ 788.8 ± 318.5 NPCs/mm2) (Figure 4). The statistical analysis showed no significant differences between the group of patients with diagnosed COVID-19 and the control group.
In both experimental groups, we observed the presence of newborn, maturing neurons labeled with NeuN (Figure 5 and Figure 6). Maturing neurons were not quantified, while the analysis of selected cases showed a reduced density of newborn neurons in the group of patients with diagnosed COVID-19 in the hippocampal dentate gyrus.
To mechanistically dissect the reasons for the decreased density of neuronal progenitor cells, we performed labeling with LCA antibodies. We observed the presence of active, ramified microglia in the hippocampal dentate gyrus (Figure 7) and subventricular zone (Figure 8) only in the group of patients with diagnosed COVID-19.

4. Discussion

The neuropathological changes observed in the COVID-19 group included the subarachnoid space and around the blood vessels of the parenchyma, microbleeds/petechial hemorrhages, and hemosiderin deposits, suggesting previous petechial hemorrhage. Other neuropathological changes have also been described in the available literature. Postmortem human neuropathological findings in COVID-19 include hypoxic damage, microglial activation, astrogliosis, leukocytic infiltration, and microhemorrhages, suggesting that, at least in some cases, the CNS undergoes neuropathological sequelae associated with hypoxia and neuroinflammation [26,27,46].
The hippocampus and subventricular zone are key neurogenic areas of the adult brain that harbor neural stem cells. The hippocampus is one of the important functional regions of the limbic system of the brain that contributes to the neuroregenerative process, long-term potentiation, learning process, memory formation, and regulation of emotion. In the hippocampus of a healthy adult, approximately 700 new neurons are generated every day [47]. Defects in hippocampal structure and functions due to aging and neurological illnesses have been directly linked to emotional disorders and memory loss [28]. Impaired neurogenesis has been identified as a potential cause of cognitive decline and progressive memory loss in aging and neurodegenerative diseases, particularly Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease [48,49,50]. Various neurocognitive disturbances in COVID-19 patients suggest the localization of lesions within the hippocampus. This was confirmed by neuroimaging (magnetic resonance imaging (MRI)) in patients after acute COVID-19 and microstructural and clinical studies of hippocampal changes [28].
The results of our research showed that SARS-CoV-2 could disrupt the process of neurogenesis. We observed a decrease in the density of neural progenitor cells in the hippocampal dentate gyrus and subventricular zone in the group of patients diagnosed with COVID-19 compared to the control group. Our observations of some cases also suggested a lower density of newborn neurons in the dentate gyrus of the hippocampus. The exclusion criteria were restrictive to exclude the influence of other factors on neurogenesis. There is experimental evidence that SARS-CoV-2 is able to infect neural progenitor cells, leading to impaired neuroblast maturation and neuronal death [51,52,53].
One of the possible answers to the question of what causes the disturbance of neurogenesis may be proinflammatory cytokines and the presence of active microglia in the hippocampal dentate gyrus and subventricular zone. This was confirmed by our study. In the group of patients diagnosed with COVID-19, we observed the presence of active ramified microglia in both the DG of the hippocampus and SVZ.
Upon infection, SARS-CoV-2 replicates in tissues and organs and induces peripheral and local cytokine storms that potentially deteriorate the innate immune system. Based on the experimental data derived from immunological assays in the plasma samples of COVID-19 patients, elevated levels of key proinflammatory determinants, including different interleukins (ILs), fibroblast growth factor (FGF), interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and vascular endothelial growth factor (VEGF), have become evident. Among them, the surplus levels of IFN-γ, TNF-α, IL-1, and IL-6 have been known to be associated with the dysfunction of the blood–brain barrier (BBB) as a part of priming the neuroinflammatory process in the human brain during COVID-19 [32,54,55,56].
Moreover, neuropathological studies indicating vascular pathology and hypoxic neuronal damage in the hippocampus of COVID-19 patients correlate with emerging dementia [26]. Our results may explain the frequent presence of brain fog in the course of COVID-19, which is associated with increased hypoxia.
ZIKV, which is one of the few factors that almost completely silences neurogenesis, operates in a similar mechanism. ZIKV, such as SARS-CoV-2, is a positive-sense RNA virus. Zika virus has been shown to directly infect neuronal progenitor cells, leading to apoptosis [57]. Receptor NPC IL-1β is involved in reducing neurogenesis in murine models of brain inflammation [58,59].
Long COVID-19 and post-COVID-19 changes and their impact on adult human neurogenesis remain open questions. The increasing death rate from COVID-19 around the world is a serious problem, but a significant proportion of COVID-19 survivors appear to be at increased risk of various neurological deficits. Several studies have shown a decrease in the level of neurogenesis and the associated memory impairment caused by elevated levels of stress hormones and proinflammatory factors in the brain, which disrupt the neuroplasticity of the hippocampus and could be a potential cause of dementia in a significant proportion of patients with a history of COVID-19. It has been suggested that the probability of replenishing dysfunctional and degenerated neurons is then the lowest. We do not know how long elevated markers of inflammation persist in survivors. The persistence of neuropsychiatric symptoms in chronic COVID-19 suggests that neuronal damage may be prolonged. Animal model studies suggest that the inflammatory changes are transient, decreasing after removal of the virus from the nasal cavity [56].
The changes in neuronal progenitor cells induced by ZIKV are different from those induced by SARS-CoV-2, and their effects appear to be reversible in SARS-CoV-2. Due to the recurring waves of the pandemic, there is an urgent need for a detailed analysis of the misfire of hippocampal neurogenesis due to cognitive impairment in COVID-19.

5. Limitations

The present study’s strengths include a relatively large group of patients with a COVID-19 diagnosis. However, limitations should be acknowledged. Perhaps factors other than SARS-CoV-2, which we do not know, had an impact on the reduction of neurogenesis. However, patients in both groups were free of comorbidities or had comorbidities not affecting neurogenesis.

Author Contributions

Conceptualization, T.S.; methodology, T.S.; software, T.S.; validation, T.S., S.T., A.A. and P.F.; formal analysis, T.S. and A.A.; investigation, T.S.; resources, S.T., N.C. and M.G.; data curation, S.T., N.C. and M.G.; writing―original draft preparation, T.S.; writing―review and editing, A.A., P.F. and T.W.-B.; visualization T.S.; supervision, T.W.-B.; project administration, T.S. All authors have read and agreed to the published version of the manuscript.

Funding

The study was supported by the Institute of Psychiatry and Neurology statutory fund No. 501-42-071-19021.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

https://covid19.who.int (accessed on 2 December 2022). https://ourworldindata.org (accessed on 2 December 2022).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Feng, W.; Zong, W.; Wang, F.; Ju, S. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): A review. Mol. Cancer 2020, 1, 100. [Google Scholar] [CrossRef] [PubMed]
  2. Hebbani, A.V.; Pulakuntla, S.; Pannuru, P.; Aramgam, S.; Badri, K.R.; Reddy, V.D. COVID-19: Comprehensive review on mutations and current vaccines. Arch. Microbiol. 2021, 204, 8. [Google Scholar] [CrossRef] [PubMed]
  3. Aleem, A.; Akbar Samad, A.B.; Slenker, A.K. Emerging Variants of SARS-CoV-2 and Novel Therapeutics Against Coronavirus (COVID-19). In StatPearls; StatPearls Publsihing: Treasure Island, FL, USA, 2022. [Google Scholar]
  4. Bucuvalas, J.; Lai, J.C. Unforeseen consequences of the COVID pandemic. Am. J. Transplant. 2020, 20, 2973–2974. [Google Scholar] [CrossRef] [PubMed]
  5. Dayan, I.; Roth, H.R.; Zhong, A.; Harouni, A.; Gentili, A.; Abidin, A.Z.; Liu, A.; Costa, A.B.; Wood, B.J.; Tsai, C.-S.; et al. Federated learning for predicting clinical outcomes in patients with COVID-19. Nat. Med. 2021, 27, 1735–1743. [Google Scholar] [CrossRef]
  6. Ali, I.; Alharbi, O.M. COVID-19: Disease, management, treatment, and social impact. Sci. Total Environ. 2020, 728, 138861. [Google Scholar] [CrossRef]
  7. Almaghaslah, D.; Kandasamy, G.; Almanasef, M.; Vasudevan, R.; Chandramohan, S. Review on the coronavirus disease (COVID-19) pandemic: Its outbreak and current status. Int. J. Clin. Pract. 2020, 74, e13637. [Google Scholar] [CrossRef] [PubMed]
  8. Mao, L.; Jin, H.; Wang, M.; Hu, Y.; Chen, S.; He, Q.; Chang, J.; Hong, C.; Zhou, Y.; Wang, D.; et al. Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease 2019 in Wuhan, China. JAMA Neurol. 2020, 77, 683–690. [Google Scholar] [CrossRef] [Green Version]
  9. Varatharaj, A.; Thomas, N.; Ellul, M.A.; Davies, N.W.S.; Pollak, T.A.; Tenorio, E.L.; Sultan, M.; Easton, A.; Breen, G.; Zandi, M.; et al. Neurological and Neuropsychiatric Complications of COVID-19 in 153 Patients: A UK-Wide Surveillance Study. Lancet Psychiatry 2020, 7, 875–882. [Google Scholar] [CrossRef]
  10. Nauen, D.W.; Hooper, J.E.; Stewart, C.M.; Solomon, I.H. Assessing Brain Capillaries in Coronavirus Disease 2019. JAMA Neurol. 2021, 78, 760–762. [Google Scholar] [CrossRef]
  11. Alberti, P.; Beretta, S.; Piatti, M.; Karantzoulis, A.; Piatti, M.L.; Santoro, P.; Viganò, M.; Giovannelli, G.; Pirro, F.; Montisano, D.A.; et al. Guillain-Barré syndrome related to COVID-19 infection. Neurol.—Neuroimmunol. Neuroinflamm. 2020, 7, e741. [Google Scholar] [CrossRef]
  12. Moriguchi, T.; Harii, N.; Goto, J.; Harada, D.; Sugawara, H.; Takamino, J.; Ueno, M.; Sakata, H.; Kondo, K.; Myose, N.; et al. A first case of meningitis/encephalitis associated with SARS-Coronavirus-2. Int. J. Infect. Dis. 2020, 94, 55–58. [Google Scholar] [CrossRef] [PubMed]
  13. Kananeh, M.F.; Thomas, T.; Sharma, K.; Herpich, F.; Urtecho, J.; Athar, M.K.; Jabbour, P.; Shah, S.O. Arterial and venous strokes in the setting of COVID-19. J. Clin. Neurosci. 2020, 79, 60–66. [Google Scholar] [CrossRef] [PubMed]
  14. Mohammad, T.; Shamsi, A.; Anwar, S.; Umair, M.; Hussain, A.; Rehman, M.T.; AlAjmi, M.F.; Islam, A.; Hassan, M.I. Identification of high-affinity inhibitors of SARS-CoV-2 main protease: Towards the development of effective COVID-19 therapy. Virus Res. 2020, 288, 198102. [Google Scholar] [CrossRef] [PubMed]
  15. Shamsi, A.; Mohammad, T.; Anwar, S.; AlAjmi, M.F.; Hussain, A.; Rehman, M.; Islam, A.; Hassan, M. Glecaprevir and Maraviroc are high-affinity inhibitors of SARS-CoV-2 main protease: Possible implication in COVID-19 therapy. Biosci. Rep. 2020, 40, BSR20201256. [Google Scholar] [CrossRef]
  16. Shamsi, A.; Mohammad, T.; Anwar, S.; Amani, S.; Khan, M.S.; Husain, F.M.; Rehman, M.T.; Islam, A.; Hassan, M.I. Potential drug targets of SARS-CoV-2: From genomics to therapeutics. Int. J. Biol. Macromol. 2021, 177, 1–9. [Google Scholar] [CrossRef]
  17. Gheblawi, M.; Wang, K.; Viveiros, A.; Nguyen, Q.; Zhong, J.C.; Turner, A.J.; Raizada, M.K.; Grant, M.B.; Oudit, G.Y. Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2. Circ. Res. 2020, 126, 1456–1474. [Google Scholar] [CrossRef]
  18. Xu, X.; Chen, P.; Wang, J.; Feng, J.; Zhou, H.; Li, X.; Zhong, W.; Hao, P. Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission. Sci. China Life Sci. 2020, 63, 457–460. [Google Scholar] [CrossRef] [Green Version]
  19. Hogberg, H.T.; Lam, A.; Ohayon, E.; Shahbaz, M.A.; Clerbaux, L.-A.; Bal-Price, A.; Coecke, S.; Concha, R.; De Bernardi, F.; Edrosa, E.; et al. The Adverse Outcome Pathway Framework Applied to Neurological Symptoms of COVID-19. Cells 2022, 11, 3411. [Google Scholar] [CrossRef]
  20. Wang, D.; Hu, B.; Hu, C.; Zhu, F.; Liu, X.; Zhang, J.; Wang, B.; Xiang, H.; Cheng, Z.; Xiong, Y.; et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus—Infected pneumonia in Wuhan, China. JAMA 2020, 323, 1061–1069. [Google Scholar] [CrossRef]
  21. Chaudhury, S.S.; Sinha, K.; Majumder, R.; Biswas, A.; Mukhopadhyay, C.D. COVID-19 and central nervous system interplay: A big picturebeyond clinical manifestation. J. Biosci. 2021, 46, 47. [Google Scholar] [CrossRef]
  22. Jaywant, A.; Vanderlind, W.M.; Alexopoulos, G.S.; Fridman, C.B.; Perlis, R.H.; Gunning, F.M. Frequency and profile of objective cognitive deficits in hospitalized patients recovering from COVID-19. Neuropsychopharmacology 2021, 46, 2235–2240. [Google Scholar] [CrossRef]
  23. Méndez, R.; Balanzá-Martínez, V.; Luperdi, S.C.; Estrada, I.; Latorre, A.; González-Jiménez, P.; Feced, L.; Bouzas, L.; Yépez, K.; Ferrando, A.; et al. Short-term neuropsychiatric outcomes and quality of life in COVID-19 survivors. J. Intern. Med. 2021, 290, 621–631. [Google Scholar] [CrossRef]
  24. Helms, J.; Kremer, S.; Merdji, H.; Clere-Jehl, R.; Schenck, M.; Kummerlen, C.; Collange, O.; Boulay, C.; Fafi-Kremer, S.; Ohana, M.; et al. Neurologic Features in Severe SARS-CoV-2 Infection. N. Engl. J. Med. 2020, 382, 2268–2270. [Google Scholar] [CrossRef]
  25. Méndez, R.; Balanzá-Martínez, V.; Luperdi, S.C.; Estrada, I.; Latorre, A.; González-Jiménez, P.; Bouzas, L.; Yépez, K.; Ferrando, A.; Reyes, S.; et al. Long-term neuropsychiatric outcomes in COVID-19 survivors: A 1-year longitudinal study. J. Intern. Med. 2022, 291, 247–251. [Google Scholar] [CrossRef] [PubMed]
  26. Thakur, K.T.; Miller, E.H.; Glendinning, M.D.; Al-Dalahmah, O.; Banu, M.A.; Boehme, A.K.; Boubour, A.L.; Bruce, S.S.; Chong, A.M.; Claassen, J.; et al. COVID-19 neuropathology at Columbia University Irving Medical Center/New York Presbyterian Hospital. Brain 2021, 144, 2696–2708. [Google Scholar] [CrossRef] [PubMed]
  27. Cosentino, G.; Todisco, M.; Hota, N.; Della Porta, G.; Morbini, P.; Tassorelli, C.; Pisani, A. Neuropathological findings from COVID-19 patients with neurological symptoms argue against a direct brain invasion of SARS-CoV-2: A critical systematic review. Eur. J. Neurol. 2021, 28, 3856–3865. [Google Scholar] [CrossRef] [PubMed]
  28. Lu, Y.; Li, X.; Geng, D.; Mei, N.; Wu, P.-Y.; Huang, C.-C.; Jia, T.; Zhao, Y.; Wang, D.; Xiao, A.; et al. Cerebral Micro-Structural Changes in COVID-19 Patients—An MRI-based 3-month Follow-up Study. EClinicalMedicine 2020, 25, 100484. [Google Scholar] [CrossRef]
  29. Jaunmuktane, Z.; Mahadeva, U.; Green, A.; Sekhawat, V.; Barrett, N.A.; Childs, L.; Shankar-Hari, M.; Thom, M.; Jäger, H.R.; Brandner, S. Microvascular injury and hypoxic damage: Emerging neuropathological signatures in COVID-19. Acta Neuropathol. 2020, 140, 397–400. [Google Scholar] [CrossRef] [PubMed]
  30. Krasemann, S.; Haferkamp, U.; Pfefferle, S.; Woo, M.S.; Heinrich, F.; Schweizer, M.; Appelt-Menzel, A.; Cubukova, A.; Barenberg, J.; Leu, J.; et al. The blood-brain barrier is dysregulated in COVID-19 and serves as a CNS entry route for SARS-CoV-2. Stem Cell Rep. 2022, 17, 307–320. [Google Scholar] [CrossRef]
  31. Bohmwald, K.; Gálvez, N.M.; Ríos, M.; Kalergis, A.M. Neurologic Alterations Due to Respiratory Virus Infections. Front. Cell. Neurosci. 2018, 12, 386. [Google Scholar] [CrossRef] [PubMed]
  32. Wierzba-Bobrowicz, T.; Krajewski, P.; Tarka, S.; Acewicz, A.; Felczak, P.; Stępień, T.; Golan, M.P.; Grzegorczyk, M. Neuropathological analysis of the brains of fifty-two patients with COVID-19. Folia Neuropathol. 2021, 59, 219–231. [Google Scholar] [CrossRef] [PubMed]
  33. Wang, L.; Davis, P.B.; Volkow, N.D.; Berger, N.A.; Kaelber, D.C.; Xu, R. Association of COVID-19 with New-Onset Alzheimer’s Disease. J. Alzheimer’s Dis. 2022, 89, 411–414. [Google Scholar] [CrossRef] [PubMed]
  34. Eriksson, P.S.; Perfilieva, E.; Bjork-Eriksson, T.; Alborn, A.-M.; Nordborg, C.; Peterson, D.A.; Gage, F.H. Neurogenesis in the adult human hippocampus. Nat. Med. 1998, 4, 1313–1317. [Google Scholar] [CrossRef]
  35. Brown, J.P.; Couillard-Després, S.; Cooper-Kuhn, C.M.; Winkler, J.; Aigner, L.; Kuhn, H.G. Transient expression of doublecortin during adult neurogenesis. J. Comp. Neurol. 2003, 467, 1–10. [Google Scholar] [CrossRef] [PubMed]
  36. Attardo, A.; Fabel, K.; Krebs, J.; Haubensak, W.; Huttner, W.B.; Kempermann, G. Tis21 expression marks not only populations of neurogenic precursor cells but also new postmitotic neurons in adult hippocampal neurogenesis. Cereb. Cortex 2009, 20, 304–314. [Google Scholar] [CrossRef] [Green Version]
  37. Okano, H.; Sawamoto, K. Neural stem cells: Involvement in adult neurogenesis and CNS repair. Philos. Trans. R. Soc. B Biol. Sci. 2008, 363, 2111–2122. [Google Scholar] [CrossRef] [Green Version]
  38. Gleeson, J.G.; Lin, P.T.; Flanagan, L.A.; Walsh, C.A. Doublecortin is a microtubule-associated protein and is expressed widely by migrating neurons. Neuron 1999, 23, 257–271. [Google Scholar] [CrossRef] [Green Version]
  39. Tanaka, R.; Yamashiro, K.; Mochizuki, H.; Cho, N.; Onodera, M.; Mizuno, Y.; Urabe, T. Neurogenesis after transient global ischemia in the adult hippocampus visualized by improved retroviral vector. Stroke 2004, 35, 1454–1459. [Google Scholar] [CrossRef] [Green Version]
  40. Rodríguez, J.J.; Jones, V.; Tabuchi, M.; Allan, S.; Knight, E.; LaFerla, F.M.; Oddo, S.; Verkhratsky, A. Impaired adult neurogenesis in the dentate gyrus of a triple transgenic mouse model of alzheimer’s disease. PLoS ONE 2008, 3, e2935. [Google Scholar] [CrossRef] [Green Version]
  41. Cano, E.; Hazzalin, C.A.; Kardalinou, E.; Buckle, R.S.; Mahadevan, L.C. Neither ERK nor JNK/SAPK MAP kinase subtypes are essential for histone H3/HMG-14 phosphorylation or c-fos and c-jun induction. J. Cell Sci. 1995, 108 Pt 11, 3599–3609. [Google Scholar] [CrossRef]
  42. Chadee, D.N.; Hendzel, M.; Tylipski, C.P.; Allis, C.D.; Bazett-Jones, D.P.; Wright, J.A.; Davie, J. Increased ser-10 phosphorylation of histone h3 in mitogen-stimulated and oncogene-transformed mouse fibroblasts. J. Biol. Chem. 1999, 274, 24914–24920. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Santarelli, L.; Saxe, M.; Gross, C.; Surget, A.; Battaglia, F.; Dulawa, S.; Weisstaub, N.; Lee, J.; Duman, R.; Arancio, O.; et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 2003, 301, 805–809. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Erta, M.; Quintana, A.; Hidalgo, J. Interleukin-6, a major cytokine in the central nervous system. Int. J. Biol. Sci. 2012, 8, 1254–1266. [Google Scholar] [CrossRef] [PubMed]
  45. Lucassen, P.J.; Meerlo, P.; Naylor, A.S.; Van Dam, A.M.; Dayer, A.G.; Fuchs, E.; Oomen, C.A.; Czéh, B. Regulation of adult neurogenesis by stress, sleep disruption, exercise and inflammation: Implications for depression and antidepressant action. Eur. Neuropsychopharmacol. 2010, 20, 1–17. [Google Scholar] [CrossRef]
  46. Matschke, J.; Lütgehetmann, M.; Hagel, C.; Sperhake, J.P.; Schröder, A.S.; Edler, C.; Mushumba, H.; Fitzek, A.; Allweiss, L.; Dandri, M.; et al. Neuropathology of patients with COVID-19 in Germany: A post-mortem case series. Lancet Neurol. 2020, 19, 919–929. [Google Scholar] [CrossRef] [PubMed]
  47. Tunc-Ozcan, E.; Peng, C.-Y.; Zhu, Y.; Dunlop, S.R.; Contractor, A.; Kessler, J.A. Activating newborn neurons suppresses depression and anxiety-like behaviors. Nat. Commun. 2019, 10, 3768. [Google Scholar] [CrossRef] [Green Version]
  48. Marxreiter, F.; Regensburger, M.; Winkler, J. Adult neurogenesis in Parkinson’s disease. Cell. Mol. Life Sci. 2013, 70, 459–473. [Google Scholar] [CrossRef] [PubMed]
  49. Ransome, M.I.; Renoir, T.; Hannan, A.J. Hippocampal neurogenesis, cognitive deficits and affective disorder in Huntington’s disease. Neural Plast. 2012, 2012, 874387. [Google Scholar] [CrossRef]
  50. Choi, S.H.; Tanzi, R.E. Is Alzheimer’s disease a neurogenesis disorder? Cell Stem Cell 2019, 25, 7–8. [Google Scholar] [CrossRef]
  51. Yi, S.A.; Nam, K.H.; Yun, J.; Gim, D.; Joe, D.; Kim, Y.H.; Kim, H.J.; Han, J.W.; Lee, J. Infection of Brain Organoids and 2D Cortical Neurons with SARS-CoV-2 Pseudovirus. Viruses 2020, 12, 1004. [Google Scholar] [CrossRef]
  52. Jacob, F.; Pather, S.R.; Huang, W.K.; Zhang, F.; Wong, S.Z.; Zhou, H.; Cubitt, B.; Fan, W.; Chen, C.Z.; Xu, M.; et al. Human pluripotent stem cell-derived neural cells and brain Organoids reveal SARSCoV-2 Neurotropism Predominates in Choroid Plexus Epithelium. Cell Stem Cell 2020, 27, 937–950.e9. [Google Scholar] [CrossRef]
  53. McMahon, C.L.; Staples, H.; Gazi, M.; Carrion, R.; Hsieh, J. SARS-CoV-2 targets glial cells in human cortical organoids. Stem Cell Rep. 2021, 16, 1156–1164. [Google Scholar] [CrossRef] [PubMed]
  54. Kandasamy, M.; Anusuyadevi, M.; Aigner, K.M.; Unger, M.S.; Kniewallner, K.M.; de Sousa, D.M.; Altendorfer, B.; Mrowetz, H.; Bogdahn, U.; Aigner, L. TGF-β Signaling: A therapeutic target to reinstate regenerative plasticity in vascular dementia? Aging Dis. 2020, 11, 828–850. [Google Scholar] [CrossRef] [PubMed]
  55. Yarlagadda, A.; Alfson, E.; Clayton, A.H. The Blood Brain Barrier and the Role of Cytokines in Neuropsychiatry. Psychiatry 2009, 6, 18–22. [Google Scholar] [PubMed]
  56. Klein, R.; Soung, A.; Sissoko, C.; Nordvig, A.; Canoll, P.; Mariani, M.; Jiang, X.; Bricker, T.; Goldman, J.; Rosoklija, G.; et al. COVID-19 induces neuroinflammation and loss of hippocampal neurogenesis. Res. Sq. 2021. [Google Scholar] [CrossRef]
  57. Tang, H.; Hammack, C.; Ogden, S.C.; Wen, Z.; Qian, X.; Li, Y.; Yao, B.; Shin, J.; Zhang, F.; Lee, E.M.; et al. Zika Virus Infects Human Cortical Neural Progenitors and Attenuates Their Growth. Cell Stem Cell 2016, 18, 587–590. [Google Scholar] [CrossRef] [Green Version]
  58. Garber, C.; Vasek, M.; Vollmer, L.; Sun, T.; Jiang, X.; Klein, R.S. Astrocytes decrease adult neurogenesis during virus-induced memory dysfunction via IL-1. Nat. Immunol. 2018, 19, 151–161. [Google Scholar] [CrossRef]
  59. Soung, A.L.; Davé, V.A.; Garber, C.; Tycksen, E.D.; Vollmer, L.L.; Klein, R.S. IL-1 reprogramming of adult neural stem cells limits neurocognitive recovery after viral encephalitis by maintaining a proinflammatory state. Brain Behav. Immun. 2022, 99, 383–396. [Google Scholar] [CrossRef]
Cells 12 00244 g001 550
Figure 1. Group patients with diagnosed COVID-19. Temporal lobe. Microbleeds/petechial hemorrhages around the vessels. (A). Hematoxylin and eosin stain (H&E). Magnification ×100. (B). Mallory trichrome stain. Magnification ×200. (C). Frontal lobe. Hemosiderophages (arrow). Hematoxylin and eosin stain (H&E). Magnification ×400.
Figure 1. Group patients with diagnosed COVID-19. Temporal lobe. Microbleeds/petechial hemorrhages around the vessels. (A). Hematoxylin and eosin stain (H&E). Magnification ×100. (B). Mallory trichrome stain. Magnification ×200. (C). Frontal lobe. Hemosiderophages (arrow). Hematoxylin and eosin stain (H&E). Magnification ×400.
Cells 12 00244 g001
Cells 12 00244 g002 550
Figure 2. Dentate gyrus, neural progenitor cells (NPCs, arrows). (A). Control group. (B). Group patients with diagnosed COVID-19. Immunolabeling p-Histone H3Ser10 antibody.
Figure 2. Dentate gyrus, neural progenitor cells (NPCs, arrows). (A). Control group. (B). Group patients with diagnosed COVID-19. Immunolabeling p-Histone H3Ser10 antibody.
Cells 12 00244 g002
Cells 12 00244 g003 550
Figure 3. Subventricular zone, neural progenitor cells (NPCs, arrows). (A). Control group. (B). Group patients with diagnosed COVID-19. Immunolabeling p-Histone H3Ser10 antibody.
Figure 3. Subventricular zone, neural progenitor cells (NPCs, arrows). (A). Control group. (B). Group patients with diagnosed COVID-19. Immunolabeling p-Histone H3Ser10 antibody.
Cells 12 00244 g003
Cells 12 00244 g004 550
Figure 4. Density of neural progenitor cells (NPCs) in the hippocampal dentate gyrus and subventricular zone in the control group and group of patients with diagnosed COVID-19.
Figure 4. Density of neural progenitor cells (NPCs) in the hippocampal dentate gyrus and subventricular zone in the control group and group of patients with diagnosed COVID-19.
Cells 12 00244 g004
Cells 12 00244 g005 550
Figure 5. Dentate gyrus, newborn neurons (arrows). (A). Control group. (B). Group patients with diagnosed COVID-19. Immunolabeling NeuN antibody.
Figure 5. Dentate gyrus, newborn neurons (arrows). (A). Control group. (B). Group patients with diagnosed COVID-19. Immunolabeling NeuN antibody.
Cells 12 00244 g005
Cells 12 00244 g006 550
Figure 6. Subventricular zone, newborn neurons (arrows). (A). Control group. (B). Group patients with diagnosed COVID-19. Immunolabeling NeuN antibody.
Figure 6. Subventricular zone, newborn neurons (arrows). (A). Control group. (B). Group patients with diagnosed COVID-19. Immunolabeling NeuN antibody.
Cells 12 00244 g006
Cells 12 00244 g007 550
Figure 7. Dentate gyrus. (A). Control group. (B). Active ramified microglia (arrows). Group patients with diagnosed COVID-19. Immunolabeling LCA antibody.
Figure 7. Dentate gyrus. (A). Control group. (B). Active ramified microglia (arrows). Group patients with diagnosed COVID-19. Immunolabeling LCA antibody.
Cells 12 00244 g007
Cells 12 00244 g008 550
Figure 8. Subventricular zone. (A). Control group. (B). Active ramified microglia (arrows). Group patients with diagnosed COVID-19. Immunolabeling LCA antibody.
Figure 8. Subventricular zone. (A). Control group. (B). Active ramified microglia (arrows). Group patients with diagnosed COVID-19. Immunolabeling LCA antibody.
Cells 12 00244 g008
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Stępień, T.; Tarka, S.; Chmura, N.; Grzegorczyk, M.; Acewicz, A.; Felczak, P.; Wierzba-Bobrowicz, T. Influence of SARS-CoV-2 on Adult Human Neurogenesis. Cells 2023, 12, 244. https://doi.org/10.3390/cells12020244

AMA Style

Stępień T, Tarka S, Chmura N, Grzegorczyk M, Acewicz A, Felczak P, Wierzba-Bobrowicz T. Influence of SARS-CoV-2 on Adult Human Neurogenesis. Cells. 2023; 12(2):244. https://doi.org/10.3390/cells12020244

Chicago/Turabian Style

Stępień, Tomasz, Sylwia Tarka, Natalia Chmura, Michał Grzegorczyk, Albert Acewicz, Paulina Felczak, and Teresa Wierzba-Bobrowicz. 2023. "Influence of SARS-CoV-2 on Adult Human Neurogenesis" Cells 12, no. 2: 244. https://doi.org/10.3390/cells12020244

APA Style

Stępień, T., Tarka, S., Chmura, N., Grzegorczyk, M., Acewicz, A., Felczak, P., & Wierzba-Bobrowicz, T. (2023). Influence of SARS-CoV-2 on Adult Human Neurogenesis. Cells, 12(2), 244. https://doi.org/10.3390/cells12020244

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop