The Neurobiology of Modern Viral Scourges: ZIKV and COVID-19

The interactions of viruses with the nervous system were thought to be well understood until the recent outbreaks of Zika and SARS-CoV-2. In this review, we consider these emerging pathogens, the range and mechanisms of the neurological disease in humans, and how the biomedical research enterprise has pivoted to answer questions about viral pathogenesis, immune response, and the special vulnerability of the nervous system. ZIKV stands out as the only new virus in a generation, associating with congenital brain defects, neurological manifestations of microcephaly in newborns, and radiculopathy in adults. COVID-19, the disease caused by SARS-CoV-2, has swept the planet in an unprecedented manner and is feared worldwide for its effect on the respiratory system, but recent evidence points to important neurological sequelae. These can include anosmia, vasculopathy, paresthesias, and stroke. Evidence of ZIKV and SARS-CoV-2 genetic material from neural tissue, and evidence of infection of neural cells, raises questions about how these emerging viruses produce disease, and where new therapies might emerge.

Download Full-text

COVID-19 and Neurological Manifestations

Annals of the National Academy of Medical Sciences (India) ◽

10.1055/s-0040-1714153 ◽

2020 ◽

Vol 56 (03) ◽

pp. 177-182

Author(s):

Neeraj Balaini ◽

Manish Modi

Keyword(s):

Central Nervous System ◽

Cerebrospinal Fluid ◽

Nervous System ◽

Neurological Diseases ◽

Neural Tissue ◽

Retrograde Transport ◽

Shortness Of Breath ◽

Neurological Manifestations ◽

Virus Rna ◽

Viral Illness

AbstractCoronavirus disease 2019 (COVID-19) is a viral illness caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) which has taken the form of a pandemic. It mainly presents as fever, cough, shortness of breath involving respiratory system but neurological manifestations are increasingly being recognized worldwide and even virus RNA was demonstrated to be present in cerebrospinal fluid of a patient. SARS-CoV-2 involves both central nervous system and peripheral nervous system. Virus can enter the neural tissue from hematological route or through retrograde transport from nerve endings. Physicians especially neurologists should be aware regarding neurological manifestations as patient can present with these conditions in emergency. We therefore reviewed the neurological diseases or complications associated with COIVID-19 in available literature.

Download Full-text

Physiology of Astroglia

Physiological Reviews ◽

10.1152/physrev.00042.2016 ◽

2018 ◽

Vol 98 (1) ◽

pp. 239-389 ◽

Cited By ~ 312

Author(s):

Alexei Verkhratsky ◽

Maiken Nedergaard

Keyword(s):

Neural Networks ◽

Central Nervous System ◽

Nervous System ◽

Neural Tissue ◽

Membrane Transporters ◽

Adaptive Plasticity ◽

Neural Cells ◽

Levels Of Organization ◽

The Central Nervous System ◽

Development And Aging

Astrocytes are neural cells of ectodermal, neuroepithelial origin that provide for homeostasis and defense of the central nervous system (CNS). Astrocytes are highly heterogeneous in morphological appearance; they express a multitude of receptors, channels, and membrane transporters. This complement underlies their remarkable adaptive plasticity that defines the functional maintenance of the CNS in development and aging. Astrocytes are tightly integrated into neural networks and act within the context of neural tissue; astrocytes control homeostasis of the CNS at all levels of organization from molecular to the whole organ.

Download Full-text

The neurological sequelae of pandemics and epidemics

Journal of Neurology ◽

10.1007/s00415-020-10261-3 ◽

2020 ◽

Author(s):

Fernanda Valerio ◽

Daniel P. Whitehouse ◽

David K. Menon ◽

Virginia F. J. Newcombe

Keyword(s):

Nervous System ◽

Neurological Manifestations ◽

Human History ◽

Neurological Damage ◽

Secondary Complications ◽

Neurological Sequelae ◽

Physiological Processes ◽

Short And Long Term ◽

Long Term Consequences

Abstract Neurological manifestations in pandemics frequently cause short and long-term consequences which are frequently overlooked. Despite advances in the treatment of infectious diseases, nervous system involvement remains a challenge, with limited treatments often available. The under-recognition of neurological manifestations may lead to an increase in the burden of acute disease as well as secondary complications with long-term consequences. Nervous system infection or dysfunction during pandemics is common and its enduring consequences, especially among vulnerable populations, are frequently forgotten. An improved understanding the possible mechanisms of neurological damage during epidemics, and increased recognition of the possible manifestations is fundamental to bring insights when dealing with future outbreaks. To reverse this gap in knowledge, we reviewed all the pandemics, large and important epidemics of human history in which neurological manifestations are evident, and described the possible physiological processes that leads to the adverse sequelae caused or triggered by those pathogens.

Download Full-text

Non-permissive SARS-CoV-2 infection in human neurospheres

10.1101/2020.09.11.293951 ◽

2020 ◽

Author(s):

Carolina da S. G. Pedrosa ◽

Livia Goto-Silva ◽

Jairo R. Temerozo ◽

Ismael C. Gomes ◽

Leticia R. Q. Souza ◽

...

Keyword(s):

Viral Infection ◽

Inflammatory Responses ◽

Cell Damage ◽

Neural Tissue ◽

Neural Cells ◽

Neurological Manifestations ◽

Viral Particles ◽

Number Of Patients ◽

The Central Nervous System ◽

The Impact

AbstractCoronavirus disease 2019 (COVID-19) was initially described as a viral infection of the respiratory tract. It is now known, however, that several biological systems are also affected, including the central nervous system (CNS). Neurological manifestations such as stroke, encephalitis, and psychiatric conditions have been reported in COVID-19 patients, but the neurotropic potential of the virus is still debated. Herein, we sought to investigate SARS-CoV-2 infection in human neural cells. We demonstrated that SARS-CoV-2 infection of neural tissue is non-permissive, however it can elicit inflammatory response and cell damage. These findings are consistent with the hypothesis that most of the neural damage caused by SARS-CoV-2 infection is due to a systemic inflammation leading to indirect harmful effects on the CNS despite the absence of local viral replication.Author SummarySevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of Coronavirus disease 2019 (COVID-19). COVID-19 was initially described as a pulmonary disease, however, with an increased number of patients showing neurological manifestations, the SARS-CoV-2 neurotropism became an important issue. It is still unclear whether the new coronavirus causes direct damage to the neural tissue or if the neurological symptoms are the result of systemic vascular and inflammatory responses. Here, we investigated the consequences of the infection of human neurospheres by SARS-CoV-2. Despite SARS-CoV-2 RNA occurrence in the supernatant of neurospheres, we did not detect viral particles with infective capacity. Nevertheless, we observed some neuroinflammatory markers and cell cytotoxicity as a consequence of viral infection. Our study suggests that the impact of virus infection in the CNS is limited and massive damage may be caused by general inflammation.

Download Full-text

Dendrimers As Vectors for Genetic Material Delivery to the Nervous System

Current Medicinal Chemistry ◽

10.2174/0929867311209025101 ◽

2012 ◽

Vol 19 (29) ◽

pp. 5101-5108 ◽

Cited By ~ 14

Author(s):

F.C. Perez-Martinez ◽

A.V. Ocana ◽

M.D. Perez-Carrion ◽

V. Cena

Keyword(s):

Nervous System ◽

Genetic Material

Download Full-text

SARS-CoV-2 and the Nervous System: From Clinical Features to Molecular Mechanisms

International Journal of Molecular Sciences ◽

10.3390/ijms21155475 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5475 ◽

Cited By ~ 11

Author(s):

Manuela Pennisi ◽

Giuseppe Lanza ◽

Luca Falzone ◽

Francesco Fisicaro ◽

Raffaele Ferri ◽

...

Keyword(s):

Nervous System ◽

Molecular Mechanisms ◽

Neuronal Damage ◽

Neurological Complications ◽

Neurological Manifestations ◽

Wide Range ◽

Inflammatory State ◽

Acute Polyneuropathy ◽

The Central Nervous System ◽

The Impact

Increasing evidence suggests that Severe Acute Respiratory Syndrome-coronavirus-2 (SARS-CoV-2) can also invade the central nervous system (CNS). However, findings available on its neurological manifestations and their pathogenic mechanisms have not yet been systematically addressed. A literature search on neurological complications reported in patients with COVID-19 until June 2020 produced a total of 23 studies. Overall, these papers report that patients may exhibit a wide range of neurological manifestations, including encephalopathy, encephalitis, seizures, cerebrovascular events, acute polyneuropathy, headache, hypogeusia, and hyposmia, as well as some non-specific symptoms. Whether these features can be an indirect and unspecific consequence of the pulmonary disease or a generalized inflammatory state on the CNS remains to be determined; also, they may rather reflect direct SARS-CoV-2-related neuronal damage. Hematogenous versus transsynaptic propagation, the role of the angiotensin II converting enzyme receptor-2, the spread across the blood-brain barrier, the impact of the hyperimmune response (the so-called “cytokine storm”), and the possibility of virus persistence within some CNS resident cells are still debated. The different levels and severity of neurotropism and neurovirulence in patients with COVID-19 might be explained by a combination of viral and host factors and by their interaction.

Download Full-text

Zika Virus Infection Leads to Demyelination and Axonal Injury in Mature CNS Cultures

Viruses ◽

10.3390/v13010091 ◽

2021 ◽

Vol 13 (1) ◽

pp. 91

Author(s):

Verena Schultz ◽

Stephanie L. Cumberworth ◽

Quan Gu ◽

Natasha Johnson ◽

Claire L. Donald ◽

...

Keyword(s):

Nervous System ◽

Neural Development ◽

Zika Virus ◽

Developmental Stages ◽

Cell Types ◽

Neural Cells ◽

Zikv Infection ◽

Axonal Pathology ◽

Time Frames

Understanding how Zika virus (Flaviviridae; ZIKV) affects neural cells is paramount in comprehending pathologies associated with infection. Whilst the effects of ZIKV in neural development are well documented, impact on the adult nervous system remains obscure. Here, we investigated the effects of ZIKV infection in established mature myelinated central nervous system (CNS) cultures. Infection incurred damage to myelinated fibers, with ZIKV-positive cells appearing when myelin damage was first detected as well as axonal pathology, suggesting the latter was a consequence of oligodendroglia infection. Transcriptome analysis revealed host factors that were upregulated during ZIKV infection. One such factor, CCL5, was validated in vitro as inhibiting myelination. Transferred UV-inactivated media from infected cultures did not damage myelin and axons, suggesting that viral replication is necessary to induce the observed effects. These data show that ZIKV infection affects CNS cells even after myelination—which is critical for saltatory conduction and neuronal function—has taken place. Understanding the targets of this virus across developmental stages including the mature CNS, and the subsequent effects of infection of cell types, is necessary to understand effective time frames for therapeutic intervention.

Download Full-text

Polyneuropathy following COVID-19 infection: the rehabilitation approach

BMJ Case Reports ◽

10.1136/bcr-2021-242330 ◽

2021 ◽

Vol 14 (5) ◽

pp. e242330

Author(s):

Ahmad Saif ◽

Anton Pick

Keyword(s):

Nervous System ◽

Critical Illness ◽

Peripheral Nervous System ◽

Upper Limb ◽

Inflammatory Disease ◽

Pathological Process ◽

Neurological Manifestations ◽

Sensorimotor Polyneuropathy ◽

System Disease ◽

Symmetrical Pattern

A range of neurological manifestations associated with COVID-19 have been reported in the literature, but the pathogenesis of these have yet to be fully explained. The majority of cases of peripheral nervous system disease published thus far have shown a symmetrical pattern. In contrast, we describe the case of a patient with asymmetrical predominantly upper-limb sensorimotor polyneuropathy following COVID-19 infection, likely due to a multifactorial pathological process involving critical illness neuropathy, mechanical injury and inflammatory disease. His presentation, management and recovery contribute to the understanding of this complex condition and informs rehabilitation approaches.

Download Full-text

Host-Pathogen Adhesion as the Basis of Innovative Diagnostics for Emerging Pathogens

Diagnostics ◽

10.3390/diagnostics11071259 ◽

2021 ◽

Vol 11 (7) ◽

pp. 1259

Author(s):

Alex van Belkum ◽

Carina Almeida ◽

Benjamin Bardiaux ◽

Sarah V. Barrass ◽

Sarah J. Butcher ◽

...

Keyword(s):

Infectious Diseases ◽

Receptor Binding ◽

Pathogen Detection ◽

Host Cells ◽

Emerging Pathogens ◽

Emerging Viruses ◽

Ligand Interaction ◽

Novel Structure ◽

Specificity And Sensitivity

Infectious diseases are an existential health threat, potentiated by emerging and re-emerging viruses and increasing bacterial antibiotic resistance. Targeted treatment of infectious diseases requires precision diagnostics, especially in cases where broad-range therapeutics such as antibiotics fail. There is thus an increasing need for new approaches to develop sensitive and specific in vitro diagnostic (IVD) tests. Basic science and translational research are needed to identify key microbial molecules as diagnostic targets, to identify relevant host counterparts, and to use this knowledge in developing or improving IVD. In this regard, an overlooked feature is the capacity of pathogens to adhere specifically to host cells and tissues. The molecular entities relevant for pathogen–surface interaction are the so-called adhesins. Adhesins vary from protein compounds to (poly-)saccharides or lipid structures that interact with eukaryotic host cell matrix molecules and receptors. Such interactions co-define the specificity and sensitivity of a diagnostic test. Currently, adhesin-receptor binding is typically used in the pre-analytical phase of IVD tests, focusing on pathogen enrichment. Further exploration of adhesin–ligand interaction, supported by present high-throughput “omics” technologies, might stimulate a new generation of broadly applicable pathogen detection and characterization tools. This review describes recent results of novel structure-defining technologies allowing for detailed molecular analysis of adhesins, their receptors and complexes. Since the host ligands evolve slowly, the corresponding adhesin interaction is under selective pressure to maintain a constant receptor binding domain. IVD should exploit such conserved binding sites and, in particular, use the human ligand to enrich the pathogen. We provide an inventory of methods based on adhesion factors and pathogen attachment mechanisms, which can also be of relevance to currently emerging pathogens, including SARS-CoV-2, the causative agent of COVID-19.

Download Full-text