Neuroinvasive Potential Research Articles

O IMPACTO DA COVID-19 NA SAÚDE MENTAL DOS IDOSOS: UMA REVISÃO DE LITERATURA

The SARS-CoV-2 coronavirus, which causes Covid-19 disease, was first detected on December 31, 2019, in Wuhan province, China. On March 11, 2020, the World Health Organization (WHO) declared the start of the pandemic. Although the number of cases has decreased significantly compared to the height of the pandemic, we still face major biopsychosocial, economic and political impasses. These prolonged impasses and complications caused by the coronavirus can be called “Long Covid”. Furthermore, the neuroinvasive potential of the virus in the nervous system is worrying, especially in elderly people and associated with other comorbidities. The main objective of this study is to mention the impacts that Covid-19 can have on the mental health of the elderly, based on a literature review. A bibliographical review was carried out based on articles and publications available in the SciELO, VHL Health and Google Scholar databases, with a time frame from 2020 to 2023. The results indicate that among the main impacts on mental health associated with Covid- 19 in elderly patients there is a worsening of comorbidities, a more frequent feeling of loneliness, socioeconomic vulnerability, worsening of mental disorders, among others.

SARS-CoV-2-Mimicking Pseudoviral Particles Accelerate α-Synuclein Aggregation In Vitro.

Since the SARS-CoV-2 virus started spreading worldwide, evidence pointed toward an impact of the infection on the nervous system. COVID-19 patients present neurological manifestations and have an increased risk of developing brain-related symptoms in the long term. In fact, evidence in support of the neuroinvasive potential of SARS-CoV-2 has emerged. Considering that viral parkisonism was observed as a consequence of encephalopathies caused by viral infections, it has been already suggested that COVID-19 could affect the dopaminergic neurons and contribute to neurodegeneration in Parkinson's disease (PD), by promoting the formation of amyloid fibrils constituted by the PD-related protein α-synuclein. Here, we observe not only that SARS-CoV-2 viral spike protein and nucleocapsid protein can alone promote α-synuclein aggregation but also that the spike protein organization in a corona shape on the viral envelope may be crucial in triggering fast amyloid fibrils formation, thus possibly contributing to PD pathogenesis.

Lower locus coeruleus integrity in older COVID‐19 survivors: initial findings from an international 7T MRI consortium

AbstractBackgroundThe SARS‐CoV‐2 coronavirus has been associated with structural brain changes, consistent with its neurological manifestations. Recent studies showed a specific predilection for brainstem glial activation and hypometabolism, possibly indicating involvement of the locus coeruleus. The locus coeruleus (LC) modulates many cognitive functions and behaviors and its norepinephrine projections regulate both immune responses and vascular reactivity. We aimed to examine differences in LC integrity between COVID‐19 survivors and controls.MethodParticipants are enrolled across 3 US and 1 UK sites using harmonized cognitive and 7T MR‐imaging protocols. Here, we analyzed data from 18 participants enrolled at Houston Methodist (12 COVID‐19 survivors, 6 controls; Figure 1). COVID‐19 survivors were required to have had a positive antigen test and an illness syndrome consistent with COVID‐19. Healthy controls were required to have no significant pre‐existing medical, neurologic, or psychiatric illness and no illness requiring hospitalization in the last 2 years. LC imaging was performed using a dedicated 7T MT‐TFL sequence (0.4×0.4×0.5mm). A site‐specific normalized template was constructed using ANTs/FSL. The entire average LC integrity as well as voxel‐wise integrity values were compared between COVID‐19 survivors and controls using a robust linear regression (age‐controlled and threshold free cluster enhancement corrected). LC integrity was correlated with age, sex, ethnicity and cognition using Spearman’s rank correlation.ResultAverage LC integrity was not correlated with age, sex, or Hispanic ethnicity (p>0.3). COVID‐19 survivors did not differ from Controls when examining the entire LC (p = 0.54). Voxel‐wise analyses revealed a small cluster (19 voxels) in the middle portion of the left LC where COVID‐19 survivors exhibited lower LC integrity than controls (p = 0.005; Figure 2). Integrity of this cluster was not related to age or Hispanic ethnicity (p = 0.9). LC integrity did not correlate with cognitive performance within the COVID‐19 survivors (Trail Making Test B: p = 0.43; Craft Story delayed recall p = 0.47; MoCA p = 0.84).ConclusionConsistent with previous animal and human studies, our initial findings provide evidence for neuroinvasive potential of SARS‐CoV‐2 localized in the middle LC. In the future, we aim to expand our sample and link these observations to the neurocognitive sequelae of COVID‐19.

COVID-19 and Alzheimer's Disease Share Common Neurological and Ophthalmological Manifestations: A Bidirectional Risk in the Post-Pandemic Future.

A growing body of evidence indicates that a neuropathological cross-talk takes place between the coronavirus disease 2019 (COVID-19) -the pandemic severe pneumonia that has had a tremendous impact on the global economy and health since three years after its outbreak in December 2019- and Alzheimer's Disease (AD), the leading cause of dementia among human beings, reaching 139 million by the year 2050. Even though COVID-19 is a primary respiratory disease, its causative agent, the so-called Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), is also endowed with high neuro-invasive potential (Neurocovid). The neurological complications of COVID-19, resulting from the direct viral entry into the Central Nervous System (CNS) and/or indirect systemic inflammation and dysregulated activation of immune response, encompass memory decline and anosmia which are typically associated with AD symptomatology. In addition, patients diagnosed with AD are more vulnerable to SARS-CoV-2 infection and are inclined to more severe clinical outcomes. In the present review, we better elucidate the intimate connection between COVID-19 and AD by summarizing the involved risk factors/targets and the underlying biological mechanisms shared by these two disorders with a particular focus on the Angiotensin-Converting Enzyme 2 (ACE2) receptor, APOlipoprotein E (APOE), aging, neuroinflammation and cellular pathways associated with the Amyloid Precursor Protein (APP)/Amyloid beta (Aβ) and tau neuropathologies. Finally, the involvement of ophthalmological manifestations, including vitreo-retinal abnormalities and visual deficits, in both COVID-19 and AD are also discussed. Understanding the common physiopathological aspects linking COVID-19 and AD will pave the way to novel management and diagnostic/therapeutic approaches to cope with them in the post-pandemic future.

ICU Delirium Is Associated with Cardiovascular Burden and Higher Mortality in Patients with Severe COVID-19 Pneumonia.

COVID-19 can lead to functional disorders and complications, e.g., pulmonary, thromboembolic, and neurological. The neuro-invasive potential of SARS-CoV-2 may result in acute brain malfunction, which manifests as delirium as a symptom. Delirium is a risk factor for death among patients hospitalized due to critical illness. Taking the above into consideration, the authors investigated risk factors for delirium in COVID-19 patients and its influence on outcomes. A total of 335 patients hospitalized due to severe forms of COVID-19 were enrolled in the study. Data were collected from medical charts. Delirium occurred among 21.5% of patients. In the delirium group, mortality was significantly higher compared to non-delirium patients (59.7% vs. 28.5%; p < 0.001). Delirium increased the risk of death, with an OR of 3.71 (95% CI 2.16-6.89; p < 0.001). Age, chronic atrial fibrillation, elevated INR, urea, and procalcitonin, as well as decreased phosphates, appeared to be the independent risk factors for delirium occurrence. Delirium occurrence in patients with severe COVID-19 significantly increases the risk of death and is associated with a cardiovascular burden. Hypophosphatemia is a promising reversible factor to reduce mortality in this group of patients. However, larger studies are essential in this area.

Schizophrenia and the COVID-19 pandemic: A narrative review from the biomedical perspective.

The outbreak of the Coronavirus Disease 2019 (COVID-19) pandemic in 2020 caused a rapid worsening of global mental health. Patients with severe mental disorders, including schizophrenia, are at higher risk of being infected. The neuroinvasive potential of the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) has been confirmed. The aim of this article was to present a narrative and comprehensive review of multidimensional associations between schizophrenia and COVID-19 with special emphasis on common biological pathways. Online searches were performed in the PubMed database and covered the publication period until September 17, 2022. Search terms included "psychosis", "schizophrenia", "inflammation" and "COVID-19". Viewed as a neuroinflammatory state, schizophrenia shares several neurobiological mechanisms with the COVID-19. Environmental stress, common comorbidities of schizophrenia and adverse effects of antipsychotic treatment are associated with the higher severity and mortality of the COVID-19. Additionally, more frequent relapses of psychosis have been observed, and might be related to lower treatment adherence. In the context of clinical manifestation, higher level of negative symptoms has been identified among patients with schizophrenia during the pandemic. Improvements in mental health care policy and treatment adjustment are necessary to protect people with schizophrenia who are the population that is particularly vulnerable to the consequences of the COVID-19 pandemic. Future research will show if prenatal infection with the SARS-CoV-2 increases a risk of psychosis.

Unilateral Diaphragm Paralysis Following COVID-19 Infection: A Case Report

We report a patient case of unilateral diaphragm paralysis following COVID-19 infection. A 55-year-old healthy man was infected with SARS-CoV-2 before the availability of a vaccine. He was intubated and pronated for respiratory failure. He experienced new debilitating dyspnea and orthopnea for 6 months after recovery. Dynamic chest radiography demonstrated a new hemidiaphragm paralysis. After surgical plication of the diaphragm, the patient's symptoms resolved. This patient case demonstrates the importance of thorough evaluation for diaphragm paralysis in patients who have suffered COVID-19 infection when there is persistent dyspnea or orthopnea, as well as the neuroinvasive potential of the virus that has yet to be fully explained.

Main mechanisms of central nervous system damage with combined infection of HIV and SARS-COV-2: review

OBJECTIVE: Assess the degree of elaboration regarding mechanisms of the nervous system damage in HIV infection to further evaluate SARS-CoV-2, as a possible contributing factor in emergence and worsening psycho-neurological pathology in HIV-infected patients. MATERIALS AND METHODS: The analytical review was conducted using the medical database PubMed. More than 20 domestic and 30 foreign publications were studied on the mechanisms of the nervous system damage in HIV infection and SARS-CoV-2 between 2019-2022.Some preliminary study was conducted. Outpatient charts data of 146 HIV-infected patients were analyzed; a confirmed diagnosis of COVID-19 mild or moderate form (between 2020-2022) appeared in 42 (25,8%) cases (1st group). The comparison group (2nd group) included 40 patients without HIV infection, but suffered COVID-19, who were surveyed after signing voluntary informed consent. The survey data provided insight into the frequency and severity of neuropsychiatric manifestations and their possible connection with COVID-19. RESULTS: The high neuroinvasive and neurotropic HIV potential was demonstrated and implemented in a variety of ways and mechanisms that manifests in clinical practice by the appearance of diverse neuropsychiatric symptomatology. The study proved the influence of HIV infection on ACE-2 receptor expression by neurovascular cells (NVC) and also revealed some other features, contributing to the potentiation of SARS-CoV-2 invasion in CNS. The results of the preliminary study showed that in the group with HIV-infected 9 patients (21,4% of recover from COVID-19) experienced long-term neuropsychiatric manifestations after coronavirus infection, while all patients had long-term suppressed HIV viral load against the backdrop of regular ARV therapy and satisfactory immune status (CD4+ T-lymphocytes count). In the group without HIV infection after COVID-19 22 (55%) patients experienced neuropsychiatric complications, estimated by them as “extremely strong”. DISCUSSION: Although the study did not reveal a clear link between the presence of immunodeficiency in HIV infection and manifestation of neuropsychiatric pathology after COVID-19, further research is needed to define mutual influence of HIV and SARS-CoV-2 on the emergence of neuropsychiatric pathology. CONCLUSION: Considering a lack of research, where the results obtained could reliably confirm increased risk of complications from the nervous system, caused by SARS-CoV-2 against the backdrop of the existing HIV infection, there is reason to believe that this problem remains relevant today. This dictates the need to examine closely neurological status in patients of this category and monitor neurological complications.

Morphological features of brain damage in severe COVID-19

Background: The damage to the nervous system in COVID-19 reflects the systemic nature of the infection. The question of the neuroinvasive potential of SARS-CoV-2 remains open, the role of "pseudovirions" in the development of the endothelial dysfunction, as well as of the S1 subunit in the TLR activation, and the importance of the blood-brain barrier are discussed. The immunological, non-immunological, and cytopathic mechanisms of the virus's action are described; there is no clear understanding of the genesis of neuropathological changes caused by SARS-CoV-2. In this tragic pandemic, the lessons of the dead should help save lives and health. Aim: to study and explain the features of brain damage in COVID-19. Methods: Brain fragments from 20 patients who died due to severe COVID-19 were studied, the sections were stained with hematoxylin and eosin, according to van Gieson and Nissl, IHC reactions were performed with antibodies to the S-protein, CD68 and CD8, the changes were compared with those related to the lethal outcomes of pancreatic necrosis and ruptured aortic aneurysm. Results: The following changes in the olfactory analyzer were revealed: sharp edema, dystrophic changes in neurons, gliosis, accumulations of starchy bodies, which explains the neuronal pathway of SARS-CoV-2 invasion; vascular plethora, erythrostasis and thrombosis, perivenular hemorrhages, diffuse edema, macroglia proliferation, perivascular astrocytosis and satellite. A positive reaction with the antibodies to the S1 and S2 subunits of the spike protein was detected, while the result of the reaction with antibodies to the N-protein of the virus, confirming the active replication of the virus, was doubtful. The S-protein expression in individual endotheliocytes makes the transendothelial route of the virus entry unlikely, in contrast to the hematogenous and neuronal pathways. The viral DNA was not detected by PCR. A weak inflammatory reaction was revealed in the form of perivascular accumulations of lymphocytes, scattered T-lymphocytes. Conclusions: 2 groups of changes were identified, the first group included circulatory disorders with a tendency to thrombosis, edema, dystrophic-necrotic changes in neurons, glial proliferation, the second group included inflammatory-degenerative changes, a weak inflammatory reaction and amyloid-like bodies. Further morphometric and statistical studies are needed to obtain the reliable conclusions.

Isolation of Flaviviruses and Alphaviruses with Encephalitogenic Potential Diagnosed by Evandro Chagas Institute (Pará, Brazil) in the Period of 1954-2022: Six Decades of Discoveries.

Viruses with encephalitogenic potential can cause neurological conditions of clinical and epidemiological importance, such as Saint Louis encephalitis virus, Venezuelan equine encephalitis virus, Eastern equine encephalitis virus, Western equine encephalitis virus, Dengue virus, Zika virus, Chikungunya virus, Mayaro virus and West Nile virus. The objective of the present study was to determine the number of arboviruses with neuroinvasive potential isolated in Brazil that corresponds to the collection of viral samples belonging to the Department of Arbovirology and Hemorrhagic Fevers, Evandro Chagas Institute (SAARB/IEC) of the Laboratory Network of National Reference for Arbovirus Diagnosis from 1954 to 2022. In the analyzed period, a total of 1,347 arbovirus samples with encephalitogenic potential were isolated from mice; 5,065 human samples were isolated exclusively by cell culture; and 676 viruses were isolated from mosquitoes. The emergence of new arboviruses may be responsible for diseases still unknown to humans, making the Amazon region a hotspot for infectious diseases due to its fauna and flora species characteristics. The detection of circulating arboviruses with the potential to cause neuroinvasive diseases is constant, which justifies the continuation of active epidemiological surveillance work that offers adequate support to the public health system regarding the virological diagnosis of circulating arboviruses in Brazil.

Detection of SARS-CoV-2 viral proteins and genomic sequences in human brainstem nuclei

Neurological manifestations are common in COVID-19, the disease caused by SARS-CoV-2. Despite reports of SARS-CoV-2 detection in the brain and cerebrospinal fluid of COVID-19 patients, it is still unclear whether the virus can infect the central nervous system, and which neuropathological alterations can be ascribed to viral tropism, rather than immune-mediated mechanisms. Here, we assess neuropathological alterations in 24 COVID-19 patients and 18 matched controls who died due to pneumonia/respiratory failure. Aside from a wide spectrum of neuropathological alterations, SARS-CoV-2-immunoreactive neurons were detected in the dorsal medulla and in the substantia nigra of five COVID-19 subjects. Viral RNA was also detected by real-time RT-PCR. Quantification of reactive microglia revealed an anatomically segregated pattern of inflammation within affected brainstem regions, and was higher when compared to controls. While the results of this study support the neuroinvasive potential of SARS-CoV-2 and characterize the role of brainstem inflammation in COVID-19, its potential implications for neurodegeneration, especially in Parkinson’s disease, require further investigations.

Hallucination in Relation to Coronavirus Disease: A Case Report

Background and Objectives: Coronavirus disease (COVID-19) respiratory manifestations range from mild signs to respiratory failure. Nevertheless, Coronavirus is not limited to the respiratory system and affects other organs, including the central nervous system. In this study, we reported a case of COVID-19 associated with the first episode of psychotic symptoms. Case presentation: The patient was a 39-year man who was brought to the emergency ward with loss of consciousness, following opioid overdose. He was intubated for airway protection. After the naloxone infusion, he became alert. The brain CT scan was normal, but the findings of the chest CT scan were compatible with COVID-19 involvement. In addition, his throat swab sample was positive. On the second day, he stated that he heard strange voices talking to each other, but he could not figure out where those voices were coming from. He did not experience hallucinations in any other sensory modalities. On the third day, three episodes of generalized tonic colonic seizures suddenly emerged. The brain CT scan demonstrated bilateral parieto-occipital hypoattenuation, which extended to the frontal lobes. Cortical hemorrhage was also seen in the right parietal lobe. Implications for Practice: The evidence indicates the neuroinvasive potential of COVID-19. Therefore, psychiatric symptoms are a novel phenomenon related to this disease. Clinicians should consider psychiatric representations in COVID-19 patients in order to decrease the complication of this disease.

West Nile virus in India: An update on its genetic lineages.

West Nile virus (WNV) is a rapidly spreading mosquito-transmitted zoonotic flavivirus. Mosquitoes belonging to the genus Culex are incriminated as the principal vectors of the virus, which causes West Nile fever (WNF) in humans. Manifestations of WNF include a mild, self-limiting, flu-like illness, which in severe cases (rare) may progress to encephalitis, resulting in life-threatening consequences. WNV is geographically distributed worldwide, covering Africa, the Americas, Europe, and Asia (except Antarctica). The virus exists in a bird-mosquito transmission cycle in nature, with humans and horses as incidental/accidental hosts. The virus can infect a large variety of hosts worldwide, i.e., about 300 birds and around 70 different mosquito species belonging to several genera. For a long time, it was believed that WNV was not highly virulent and caused only mild infection globally. However, the recent frequent and increasing incidence of clinically severe WNV infections, such as encephalitis in humans and horses with significant mortality, has been reported in the Americas, Europe, and several East Asian countries. The emergence of lineage 2 strains endemic to Africa, with epidemic potential in humans and horses in Europe, is considered a serious global health concern. Although WNV is known to circulate in India since 1952, its re-emergence with severe neuro-invasive pathogenic potential in humans in Assam, Kerala, West Bengal and Tamil Nadu states signals urgent efforts to understand the dynamics of circulating strains with regard to its vector, hosts, and environment. This could be done by prioritizing "One Health" approach for developing effective preventive and control strategies. In view of the global interest, we present an overview of the circulating genetic lineages of WNV in India in comparison with the global scenario. In addition, we stress on holistic approaches of "One Health" strategy as the current need of the hour for designing effective preventive and control strategies in the country.

Catatonia during COVID-19 pandemic - diagnostic and therapeutic approach.

Catatonia can be defined as an etiologically heterogeneous syndrome, with predominant psychomotor disturbances. Historically, the concept of catatonia has been associated with mental disorders, especially schizophrenia. However, nowadays our understanding of catatonia has evolved to recognize it as neuropsychiatric syndrome that can arise from diverse etiological factors ranging from neurological to systemic diseases. Furthermore, there is now a recognized association between catatonia and a broader spectrum of mental disorders. Catatonia as a secondary neuropsychiatric syndrome may be a clinical manifestation of COVID-19 also due to the known neuroinvasive potential of the SARS-CoV-2 virus or in connection with the overall somatic alteration of the patient. In clinical practice, co-infection with SARS-CoV-2 could impede the process of diagnosing and treating catatonia as the primary psychopathological syndrome. The administration of benzodiazepines and electroconvulsive therapy could endanger the patient's physical health with active COVID-19 infection. Management of catatonic syndrome associated with COVID-19 is a challenge and requires a comprehensive therapeutic approach. The article demonstrates the above-mentioned difficulties of treatment through two case presentations (Tab. 2, Ref. 29). Text in PDF www.elis.sk Keywords: catatonia, COVID-19, SARS-CoV-2, neuropsychiatry, diagnosis, differential.

THE IMPACT OF COVID-19 CONCERNING THE CENTRAL NERVOUS SYSTEM

Since the beginning of the pandemic, emerging information regarding manifestations of the infection with Sars-Cov-2 virus has been laid out, mainly involving the respiratory consequences as it impacts profoundly the global death rates. In February 2020, fi rst publications that sustain the theory the virus could also possess neuroinvasive potential, have been reported. Until present, there is consistent evidence on the consequences over the CNS (central nervous system) and PNS (peripheral nervous system). To shed light over the central nervous system implications, this paper aims to review some of the clinical entities involved.

Bovine neutrophil chemotaxis to Listeria monocytogenes in neurolisteriosis depends on microglia-released rather than bacterial factors

BackgroundListeria monocytogenes (Lm) is a bacterial pathogen of major concern for humans and ruminants due to its neuroinvasive potential and its ability to cause deadly encephalitis (neurolisteriosis). On one hand, polymorphonuclear neutrophils (PMN) are key players in the defense against Lm, but on the other hand intracerebral infiltration with PMN is associated with significant neural tissue damage. Lm-PMN interactions in neurolisteriosis are poorly investigated, and factors inducing PMN chemotaxis to infectious foci containing Lm in the central nervous system (CNS) remain unidentified.MethodsIn this study, we assessed bovine PMN chemotaxis towards Lm and supernatants of infected endogenous brain cell populations in ex vivo chemotaxis assays, to identify chemotactic stimuli for PMN chemotaxis towards Lm in the brain. In addition, microglial secretion of IL-8 was assessed both ex vivo and in situ.ResultsOur data show that neither Lm cell wall components nor intact bacteria elicit chemotaxis of bovine PMN ex vivo. Moreover, astrocytes and neural cells fail to induce bovine PMN chemotaxis upon infection. In contrast, supernatant from Lm infected microglia readily induced chemotaxis of bovine PMN. Microglial expression and secretion of IL-8 was identified during early Lm infection in vitro and in situ, although IL-8 blocking with a specific antibody could not abrogate PMN chemotaxis towards Lm infected microglial supernatant.ConclusionsThese data provide evidence that host-derived rather than bacterial factors trigger PMN chemotaxis to bacterial foci in the CNS, that microglia have a primary role as initiators of bovine PMN chemotaxis into the brain during neurolisteriosis and that blockade of these factors could be a therapeutic target to limit intrathecal PMN chemotaxis and PMN associated damage in neurolisteriosis.

COVID-19-Associated Encephalopathy (COVEP): Basic Aspects of Neuropathology

SARS-CoV-2, a member of the betacoronavirus group and causative agent of COVID-19, is a virus affecting multiple systems, not only the respiratory. One of the systems affected by the virus is the central nervous system, with neuropathological studies reporting a wide set of morphological phenomena—neuroinflammation, vascular and blood-brain barrier alterations, neurodegeneration, and accelerated aging, while contradicting data is present on the direct neuroinvasive potential of the virus and active viral replication within neurons. The depicted changes, other than an acute effect (which may contribute to the death of the patient) also have chronic sequelae in the context of post-COVID syndrome cognitive impediments, sleep, and mood disorders. The following chapter describe the basic neuropathological aspects of SARS-CoV-2 as based on the present evidence in scientific literature and propose the term COVEP—COVID-associated encephalopathy—to unite the undisputed effects of the infection on nervous system morphology and function.

Nerve Growth Factor (NGF) Encourages the Neuroinvasive Potential of Pancreatic Cancer Cells by Activating the Warburg Effect and Promoting Tumor Derived Exosomal miRNA-21 Expression.

Background It has been reported that signaling from the nerve growth factor (NGF) pathway associated with peripheral nerves is able to contribute to perineural invasion (PNI) of pancreatic cancer (PC). Nevertheless, the underlying mechanism by which NGF leads to PNI remained poorly understood. Methods Western blotting was employed to determine NGF level in PC and paracarcinoma tissues and in PC cell lines as well as pancreatic ductal epithelial cells. MiaPaCa-2 and CFPAC-1 cells were treated with 100 ng/ml of NGF or the NGF inhibitor Tanezumab for 24 h, CCK-8 and Transwell assays were employed to test cell proliferation, invasion, and migration, respectively. TrkA expression was knocked down in MiaPaCa-2 and dorsal root ganglion (DRG) cells treated with NGF to determine its effect on the Warburg effect. To reveal that the NGF-TrkA signaling pathway was closely associated with PC PNI, in vitro neuroinvasion model was established by using MiaPaCa-2 cells via coculturing DRG cells in Matrigel. Further, exosomes were extracted from PC cells and identified by examining the levels of specific markers for exosomes. Then RT-qPCR was applied to test miR-21-5p level in tumor derived exosomal (TDE-miR-21-5p). RIP assay was performed to validate NGF and miR-21 binding ability in MiaPaCa-2 cells. Rescue experiments were performed by using coprocessing of Tanezumab and miR-21-5p mimic on MiaPaCa-2 cells, followed by coculture with DRG cells. Subsequently, we used a model of neuroinvasion in nude mice to assess the effect of NGF in vivo on tumor nerve invasion as well as on nociceptive transmission. Results NGF level was preeminently higher in PC tissues and cell lines than in paracarcinoma tissues and normal pancreatic epithelial cell lines. NGF promoted MiaPaCa-2 and CFPAC-1 cell invasion and migration, while Tanezumab treatment showed the opposite results. Besides, NGF binding to TrkA receptors encouraged the intracellular Warburg effect in PC and DRG cells. TrkA blocking-up could restrain NGF induced PC cell migration and neural invasion. Mechanistically, NGF could upregulate TDE-miR-21-5p levels, and DRG cells took up TDE to activate the Warburg effect and stimulate nociceptor gene expression. miR-21-5p inhibitor could abolish the facilitative effect of NGF on PNI in MiaPaCa-2 cells. In vivo tumorigenesis experiments, Tanezumab markedly alleviated nerve invasion of PC cells as well as relieved nociceptive conduction in animal models. Conclusions These findings displayed that NGF/TrkA encouraged the neuroinvasive potential of PC cells by activating the Warburg effect in DRG cells through upregulation of TDE-miR-21-5p expression.

A Journey to the Central Nervous System: Routes of Flaviviral Neuroinvasion in Human Disease.

Many arboviruses, including viruses of the Flavivirus genera, are known to cause severe neurological disease in humans, often with long-lasting, debilitating sequalae in surviving patients. These emerging pathogens impact millions of people worldwide, yet still relatively little is known about the exact mechanisms by which they gain access to the human central nervous system. This review focusses on potential haematogenous and transneural routes of neuroinvasion employed by flaviviruses and identifies numerous gaps in knowledge, especially regarding lesser-studied interfaces of possible invasion such as the blood–cerebrospinal fluid barrier, and novel routes such as the gut–brain axis. The complex balance of pro-inflammatory and antiviral immune responses to viral neuroinvasion and pathology is also discussed, especially in the context of the hypothesised Trojan horse mechanism of neuroinvasion. A greater understanding of the routes and mechanisms of arboviral neuroinvasion, and how they differ between viruses, will aid in predictive assessments of the neuroinvasive potential of new and emerging arboviruses, and may provide opportunity for attenuation, development of novel intervention strategies and rational vaccine design for highly neurovirulent arboviruses.

In vitro and in vivo differences in neurovirulence between D614G, Delta And Omicron BA.1 SARS-CoV-2 variants

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with various neurological complications. Although the mechanism is not fully understood, several studies have shown that neuroinflammation occurs in the acute and post-acute phase. As these studies have predominantly been performed with isolates from 2020, it is unknown if there are differences among SARS-CoV-2 variants in their ability to cause neuroinflammation. Here, we compared the neuroinvasiveness, neurotropism and neurovirulence of the SARS-CoV-2 ancestral strain D614G, the Delta (B.1.617.2) and Omicron BA.1 (B.1.1.529) variants using in vitro and in vivo models. The Omicron BA.1 variant showed reduced neurotropism and neurovirulence compared to Delta and D614G in human induced pluripotent stem cell (hiPSC)-derived cortical neurons co-cultured with astrocytes. Similar differences were obtained in Syrian hamsters inoculated with D614G, Delta and the Omicron BA.1 variant 5 days post infection. Replication in the olfactory mucosa was observed in all hamsters, but most prominently in D614G inoculated hamsters. Furthermore, neuroinvasion into the CNS via the olfactory nerve was observed in D614G, but not Delta or Omicron BA.1 inoculated hamsters. Furthermore, neuroinvasion was associated with neuroinflammation in the olfactory bulb of hamsters inoculated with D614G. Altogether, our findings suggest differences in the neuroinvasive, neurotropic and neurovirulent potential between SARS-CoV-2 variants using in vitro hiPSC-derived neural cultures and in vivo in hamsters during the acute phase of the infection.