A number of neurological disease complications have been seen following infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While most person with COVID-19 respiratory disease demonstrate headache, nausea and vomiting, up to 40% present also experience dizziness, confusion, cerebrovascular disease, muscle pain, ataxia and seizures. Loss of taste and smell, defects in visual acuity and pain occur in parallel. Such central nervous system (CNS) signs and symptoms linked to laboratory-confirmed SARS-CoV-2 infection is often life threatening. Health care providers currently evaluating patients with neurologic symptoms need consider COVID-19 in any differential diagnosis. These considerations will facilitate prompt testing, isolation and prevention of viral transmission speeding best clinical outcomes.
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This guest commentary introduces “The Neuroimmune Pharmacology of SARS-CoV-2,” a special theme issue for The Journal of Neuroimmune Pharmacology led by the Society on NeuroImmune Pharmacology. The issue builds on the Society’s Virtual Workshop on COVID-19 held April 9, 2021.
Graphical abstractTop row from left: Drs. Santosh Kumar, Sowmya Yelamanchili, Pankaj Seth, Jean M. Bidlack; Bottom row from left: Drs. Gurudutt Pendyala, Sanjay Maggirwar, and Sulie L. Chang.
Hydroxychloroquine (HCQ) is an old medication for malaria. In addition to handling this parasitic disease, HCQ is also used to treat a number of autoimmune disorders including rheumatoid arthritis and systemic lupus erythematosus when other medications are not effective. Recently a new viral infection (COVID-19) is rocking the entire world so much that it has already taken more than 200,000 lives throughout the world within the last two months and the World Health Organization was forced to declare it as a pandemic on March 11, 2020. Interestingly, some reports indicate that this wonder drug may be also beneficial for COVID-19 and accordingly, many clinical trials have begun. Here, we discuss different modes of action (anti-inflammatory, antioxidant, inhibition of endosomal acidification, suppression of angiotensin-converting enzyme 2 or ACE2 glycosylation, etc.) of HCQ that might be responsible for its possible anti-COVID-19 effect. On the other hand, this review also makes an honest attempt to delineate mechanisms (increase in vasoconstriction, inhibition of autophagy, depletion of T cells, etc.) indicating how it may aggravate certain conditions and why caution should be taken before granting widespread repurposing of HCQ for COVID-19.
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Multiple sclerosis (MS) is the most common chronic autoimmune disease of the central nervous system. Efficacy of treatments for MS is associated with risk of adverse effects, and effective and well-tolerated drugs remain a major unmet need. Cannabis (Cannabis sativa L., fam. Cannabaceae) and cannabinoids are popular among MS patients to treat spasticity and pain. Cannabinoids are endowed with remarkable immunomodulating properties, and in particular the non-psychotropic cannabinoid cannabidiol (CBD) is increasingly recognized as anti-inflammatory and immunosuppressive, nevertheless with excellent tolerability even at high doses. In this systematic review, we retrieved and critically evaluated available evidence regarding the immune and disease-modifying effects of CBD in experimental autoimmune encephalomyelitis (EAE) and in MS. Evidence in rodent models of EAE strongly supports CBD as effective, while clinical evidence is still limited and usually negative, due to paucity of studies and possibly to the use of suboptimal dosing regimens. Better characterization of targets acted upon by CBD in MS should be obtained in ex vivo/in vitro studies in human immune cells, and higher doses should be tested in well-designed clinical trials with clinically relevant efficacy endpoints.
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Globally, cannabis is the most commonly used illicit drug, with disproportionately high use among persons with HIV. Despite advances in HIV care, nearly half of persons living with HIV continue to experience neurocognitive deficits or impairments that may have negative impacts on their daily function. Chronic cannabis use may play a role in the development or exacerbation of these impairments. Here we present a review summarizing existing research detailing the effect of cannabis use associated with the neuropathogenesis of HIV. We examine evidence for possible additive or synergistic effects of HIV infection and cannabis use on neuroHIV in both the preclinical and adult human literatures, including in vitro studies, animal models, clinical neuroimaging research, and studies examining the cognitive effects of cannabis. We discuss the limitations of existing research, including methodological challenges involved with clinical research with human subjects. We identify gaps in the field and propose critical research questions to advance our understanding of how cannabis use affects neuroHIV.
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SARS-CoV-2 infection begins with the attachment of its spike (S) protein to angiotensin-converting enzyme-2 (ACE2) followed by complex host immune responses with cardiovascular and neurological implications. Our meta-analyses used QIAGEN Ingenuity Pathway Analysis (IPA) and Knowledge Base (QKB) to investigate how the expression of amyloid precursor protein (APP) was modulated by attachment of SARS-CoV-2 S protein in the brain microvascular endothelial cells (BMVECs) and during COVID-19 in progress. Published 80 host response genes reported to be modulated in BMVECs following SARS-CoV-2 S protein binding were used to identify key canonical pathways and intermediate molecules mediating the regulation of APP production following the attachment of S protein to endothelial cells. This revealed that the attachment of SARS-CoV-2 S protein may inhibit APP expression in the BMVECs. Our results shed light on the molecular mechanisms by which SARS-CoV-2 infection may potentiate the incidence of stroke by inhibiting the production of APP in the BMVECs. We also analyzed molecules associated with COVID-19, which revealed six upstream regulators, TNF, IFNG, STAT1, IL1β, IL6, and STAT3. The upstream regulators mediate the increased production of APP via intermediators, with eleven regulated by all six upstream regulators. These COVID-19 upstream regulators increased APP expression with a statistically significant Z-score of 3.705 (p value = 0.000211). These findings have revealed molecular mechanisms by which COVID-19 disease may lead to long-term neurological manifestations resulting from the elevated APP expression in line with immune response in the host. Altogether, our study revealed two distinct scenarios which may have differential impact on APP expression.
Graphic AbstractThe SARS-CoV-2 spike protein has been shown to disrupt blood–brain barrier (BBB) function, but its pathogenic mechanism of action is unknown. Whether angiotensin converting enzyme 2 (ACE2), the viral binding site for SARS-CoV-2, contributes to the spike protein-induced barrier disruption also remains unclear. Here, a 3D-BBB microfluidic model was used to interrogate mechanisms by which the spike protein may facilitate barrier dysfunction. The spike protein upregulated the expression of ACE2 in response to laminar shear stress. Moreover, interrogating the role of ACE2 showed that knock-down affected endothelial barrier properties. These results identify a possible role of ACE2 in barrier homeostasis. Analysis of RhoA, a key molecule in regulating endothelial cytoskeleton and tight junction complex dynamics, reveals that the spike protein triggers RhoA activation. Inhibition of RhoA with C3 transferase rescues its effect on tight junction disassembly. Overall, these results indicate a possible means by which the engagement of SARS-CoV-2 with ACE2 facilitates disruption of the BBB via RhoA activation. Understanding how SARS-CoV-2 dysregulates the BBB may lead to strategies to prevent the neurological deficits seen in COVID-19 patients.
Graphic AbstractHIV infection affects an estimated 38 million people. Approximately 50% of HIV patients exhibit neurocognitive dysfunction termed HIV-Associated Neurocognitive Disorder (HAND). HAND is a consequence of chronic low-level neuroinflammation due to HIV entry into the brain. Initially, monocytes become activated in circulation and traffic to the brain. Monocytes, when activated, become susceptible to infection by HIV and can then carry the virus across the blood brain barrier. Once in the brain, activated monocytes secrete chemokines, which recruit virus-specific CD8+ T cells into the brain to further promote neuroinflammation. HAND is closely linked to systemic inflammation driven, in part, by HIV but is also due to persistent translocation of microorganisms across the GI tract. Persistent anti-viral responses in the GI tract compromise microbial barrier integrity. Indeed, HIV patients can exhibit remarkably high levels of activated (CD16+) monocytes in circulation. Recent studies, including our own, show that HIV patients using medical marijuana exhibit lower levels of circulating CD16+ monocytes than non-cannabis using HIV patients. Cannabis is a known immune modulator, including anti-inflammatory properties, mediated, in part, by ∆9-tetrahydrocannabinol (THC), as well as less characterized minor cannabinoids, such as cannabidiol (CBD), terpenes and presumably other cannabis constituents. The immune modulating activity of THC is largely mediated through cannabinoid receptors (CB) 1 and 2, with CB1 also responsible for the psychotropic properties of cannabis. Here we discuss the anti-inflammatory properties of cannabinoids in the context of HIV and propose CB2 as a putative therapeutic target for the treatment of neuroinflammation.
HIV-associated neurocognitive disorder is a systemic inflammatory disease leading to activation of plasmacytoid dendritic cells, monocytes and T cells. Monocyte and CD8 T cell migration across the BBB and interaction with astrocytes promotes neurotoxic inflammatory mediators release. CB2 ligands are proposed as therapeutics capable of suppressing systemic and localized inflammation.
The CRISPR/Cas9 system is a revolutionary gene editing technology that combines simplicity of use and efficiency of mutagenesis. As this technology progresses toward human therapies, valid concerns including off-target mutations and immunogenicity must be addressed. One approach to address these issues is to minimize the presence of the CRISPR/Cas9 components by maintaining a tighter temporal control of Cas9 endonuclease and reducing the time period of activity. This has been achieved to some degree by delivering the CRISPR/Cas9 system via pre-formed Cas9 + gRNA ribonucleoprotein (RNP) complexes. In this review, we first discuss the molecular modifications that can be made using CRISPR/Cas9 and provide an overview of current methods for delivering Cas9 RNP complexes both in vitro and in vivo. We conclude with examples of how Cas9 RNP delivery may be used to target neuroinflammatory processes, namely in regard to viral infections of the central nervous system and neurodegenerative diseases. We propose that Cas9 RNP delivery is a viable approach when considering the CRISPR/Cas9 system for both experimentation and the treatment of disease.
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HIV-1 infection causes chronic neuroinflammation resulting in cognitive decline associated with diminution of survival of neural stem cells (NSC). In part, this is attributable to production of toxic viral proteins (gp120 and tat) by infected cells in the brain that can activate microglia. Here, we evaluated a novel model for HIV-1 neuropathogenesis by direct administration of viral proteins into the hippocampus. Chronic administration of either HIV-1 gp120 or tat over 14 days significantly decreased NSC proliferation, survival and neuroblast formation (by 32–37%) within the hippocampal subgranular zone as detected by doublecortin/BrdU or Ki67-positive cells. Intrahippocampal administration of gp120 or tat induced microglial activation within the hippocampus as determined by increases in microglial number and increases in the volume of the microglia (2.5–3-fold, evaluated by double IBA-1/CD68 staining). We further assessed inflammatory responses within the hippocampus by RNAseq and Ingenuity Pathway Analysis. There was a significant mRNA upregulation of numerous inflammatory mediators including Il1b, Icam1, Il12a, Ccl2, and Ccl4. These data suggest that chronic administration induces a prolonged inflammatory state within the hippocampus that negatively affects NSC survival potentially leading to cognitive dysfunction.
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HIV affects 37 million people worldwide, 25–69% of which develop HIV-associated neurocognitive disorders (HAND) regardless of antiviral treatment. HIV infection of the brain decreases cognitive function, disrupts/impairs learning and memory, and reduces quality of life for those affected. HIV-induced neuroinflammation has been associated with viral proteins such as gp120 and Tat, which remain elevated in the CNS even in patients with low peripheral viremia counts. In this study, we examined the effects of gp120 on neuroinflammation in immunodeficient vs. immunocompetent states by examining neuroinflammatory markers in gp120tg mice with or without systemic immunodeficiency caused by murine retroviral administration (LP-BM5 murine AIDS). Changes in inflammatory cytokine/chemokine mRNA expression was complex and dependent upon expression of gp120 protein, immunodeficiency status, brain region (hippocampus, frontal lobe, or striatum), and age. Gp120 expression reduced hippocampal synaptophysin expression but did not affect animals’ learning/memory on the spontaneous T-maze test in our experimental conditions. Our results emphasize the critical role of the neuroinflammatory micro-environment and the peripheral immune system context in which gp120 acts. Multiple factors, particularly system-level differences in the immune response of different brain regions, need to be considered when developing treatment for HAND.
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Oxidant toxicity has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), an insidiously progressive neurodegenerative disorder involving upper and lower motor neurons. Here, we investigated the cellular and molecular mechanisms underlying the neuroprotective effects of an anti-oxidant genistein in SOD1-G93A transgenic mouse model of ALS. Rotarod test, hanging wire test and hindlimb clasping test were used to determined disease onset and assess motor performance. Immunostaining together with neuronal size measurement were used to count viable motor neurons. In addition, immunostaining procedure and ELISA kit were used to assess the inflammatory response in the spinal cord. Our results showed that Genistein administration suppressed the production of pro-inflammatory cytokines and alleviated gliosis in the spinal cord of SOD1-G93A mice. In addition, genistein administration induced autophagic processes and enhanced the viability of spinal motor neurons. As a result, genistein alleviated ALS-related symptoms and slightly prolonged the lifespan of SOD1-G93A mice. Taken together, our results indicate that genistein is neuroprotective in SOD1-G93A mice, suggesting genistein could be a promising treatment for human ALS.
Genistein protects impariments in SOD1-G93A transgenic mouse model.
Extracellular vesicles (EVs) are the common designation for ectosomes, microparticles and microvesicles serving dominant roles in intercellular communication. Both viable and dying cells release EVs to the extracellular environment for transfer of cell, immune and infectious materials. Defined morphologically as lipid bi-layered structures EVs show molecular, biochemical, distribution, and entry mechanisms similar to viruses within cells and tissues. In recent years their functional capacities have been harnessed to deliver biomolecules and drugs and immunological agents to specific cells and organs of interest or disease. Interest in EVs as putative vaccines or drug delivery vehicles are substantial. The vesicles have properties of receptors nanoassembly on their surface. EVs can interact with specific immunocytes that include antigen presenting cells (dendritic cells and other mononuclear phagocytes) to elicit immune responses or affect tissue and cellular homeostasis or disease. Due to potential advantages like biocompatibility, biodegradation and efficient immune activation, EVs have gained attraction for the development of treatment or a vaccine system against the severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) infection. In this review efforts to use EVs to contain SARS CoV-2 and affect the current viral pandemic are discussed. An emphasis is made on mesenchymal stem cell derived EVs’ as a vaccine candidate delivery system.
Graphical AbstractChronic and debilitating neurodegenerative diseases, such as Parkinson’s disease (PD), impose an immense medical, emotional, and economic burden on patients and society. Due to a complex interaction between genetic and environmental risk factors, the etiology of PD remains elusive. However, the cumulative evidence emerging from clinical and experimental research over the last several decades has identified mitochondrial dysfunction, oxidative stress, neuroinflammation, and dysregulated protein degradation as the main drivers of PD neurodegeneration. The genome-editing system CRISPR (clustered regularly interspaced short palindromic repeats) has recently transformed the field of biotechnology and biomedical discovery and is poised to accelerate neurodegenerative disease research. It has been leveraged to generate PD animal models, such as Parkin, DJ-1, and PINK1 triple knockout miniature pigs. CRISPR has also allowed the deeper understanding of various PD gene interactions, as well as the identification of novel apoptotic pathways associated with neurodegenerative processes in PD. Furthermore, its application has been used to dissect neuroinflammatory pathways involved in PD pathogenesis, such as the PKCδ signaling pathway, as well as the roles of novel compensatory or protective pathways, such as Prokineticin-2 signaling. This review aims to highlight the historical milestones in the evolution of this technology and attempts to illustrate its transformative potential in unraveling disease mechanisms as well as in the development of innovative treatment strategies for PD.
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Extensive work has characterized endoplasmic reticulum (ER) and mitochondrial stress responses. In contrast, very little has been published about stress responses in lysosomes; subcellular acidic organelles that are physiologically important and are of pathological relevance. The greater lysosomal system is dynamic and is comprised of endosomes, lysosomes, multivesicular bodies, autophagosomes, and autophagolysosomes. They are important regulators of cellular physiology, they represent about 5% of the total cellular volume, they are heterogeneous in their sizes and distribution patterns, they are electron dense, and their subcellular positioning within cells varies in response to stimuli, insults and pH. These organelles are also integral to the pathogenesis of lysosomal storage diseases and it is increasingly recognized that lysosomes play important roles in the pathogenesis of such diverse conditions as neurodegenerative disorders and cancer. The purpose of this review is to focus attention on lysosomal stress responses (LSR), compare LSR with better characterized stress responses in ER and mitochondria, and form a framework for future characterizations of LSR. We synthesized data into the concept of LSR and present it here such that the definition of LSR can be modified as new knowledge is added and specific therapeutics are developed.
Graphical AbstractVirus-induced diseases or neurological complications are huge socio-economic burden to human health globally. The complexity of viral-mediated CNS pathology is exacerbated by reemergence of new pathogenic neurotropic viruses of high public relevance. Although the central nervous system is considered as an immune privileged organ and is mainly protected by barrier system, there are a vast majority of neurotropic viruses capable of gaining access and cause diseases. Despite continued growth of the patient population and a number of treatment strategies, there is no successful viral specific therapy available for viral induced CNS diseases. Therefore, there is an urgent need for a clear alternative treatment strategy that can effectively target neurotropic viruses of DNA or RNA genome. To address this need, rapidly growing gene editing technology based on CRISPR/Cas9, provides unprecedented control over viral genome editing and will be an effective, highly specific and versatile tool for targeting CNS viral infection. In this review, we discuss the application of this system to control CNS viral infection and associated neurological disorders and future prospects.
CRISPR/Cas9 technology as agent control over CNS viral infection.
Neuropathy, typically diagnosed by the presence of either symptoms or signs of peripheral nerve dysfunction, remains a frequently reported complication in the antiretroviral (ART)-treated HIV population. This study was conducted in 109 healthy controls and 57 HIV-infected individuals to investigate CNS regions associated with neuropathy. An index of objective neuropathy was computed based on 4 measures: deep tendon ankle reflex, vibration sense (great toes), position sense (great toes), and 2-point discrimination (feet). Subjective neuropathy (self-report of pain, aching, or burning; pins and needles; or numbness in legs or feet) was also evaluated. Structural MRI data were available for 126/166 cases. The HIV relative to the healthy control group was impaired on all 4 signs of neuropathy. Within the HIV group, an objective neuropathy index of 1 (bilateral impairment on 1 measure) or 2 (bilateral impairment on at least 2/4 measures) was associated with older age and a smaller volume of the cerebellar vermis. Moderate to severe symptoms of neuropathy were associated with more depressive symptoms, reduced quality of life, and a smaller volume of the parietal precuneus. This study is consistent with the recent contention that ART-treated HIV-related neuropathy has a CNS component. Distinguishing subjective symptoms from objective signs of neuropathy allowed for a dissociation between the precuneus, a brain region involved in conscious information processing and the vermis, involved in fine tuning of limb movements.
In HIV patients, objective signs of neuropathy correlated with smaller cerebellar vermis (red) volumes whereas subjective symptoms of neuropathy were associated with smaller precuneus (blue) volumes.
Mixed lineage kinases (MLKs) are a group of serine-threonine kinases that evolved in part to respond to endogenous and exogenous insults that result in oxidative stress and pro-inflammatory responses from innate immune cells. Human immunodeficiency virus type 1 (HIV-1) thrives in these conditions and is associated with the development of associated neurocognitive disorders (HAND). As part of a drug discovery program to identify new therapeutic strategies for HAND, we created a library of broad spectrum MLK inhibitors with drug-like properties. Serendipitously, the lead compound, URMC-099 has proved useful not only in reversing damage to synaptic architecture in models of HAND, but also serves to restore autophagy as a protective response when given in concert with nanoformulated antiretroviral therapy (nanoART) in persistently infected macrophages. These findings are reviewed in the context of MLK3 biology and cellular signaling pathways relevant to new HIV-1 therapies.
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