Search

The severity of COVID-19 infection is surging day by day. With the cases increasing daily, it is becoming more and more essential to understand the pathogenic mechanisms underlying the severity of the disease. It is now well known that the infection manifests itself primarily as respiratory, but the involvement of the other organ systems has now been documented in many studies. SARS-CoV-2 can invade the nervous system by a multitude of proposed mechanisms that have been discussed in this review. NF-κB and Nrf2 are transcription factors that regulate genes responsible for inflammatory and anti-oxidant response respectively. Specific focus in this review has been given to NF-κB and Nrf2 pathways that are involved in the cytokine storm and oxidative stress that are the hallmarks of COVID-19. As the immune injury is an important mechanism of neuro-invasion and neuroinflammation, there is the possible involvement of these two pathways in the neurological complications. The crosstalk mechanisms of these signaling pathways have also been discussed. Immuno-modulators both synthetic and natural are promising candidates in catering to the pathologies targeted in the aforementioned pathways.

Zika virus (ZIKV) infection during pregnancy can result in congenital Zika syndrome which is characterized by microcephaly and other neurodevelopmental disorders. In this chapter, we describe methods to model ex vivo ZIKV infection in astrocytes and tissue explants from human fetal brain. These cell- and tissue-based platforms have been useful to elucidate mechanisms of ZIKV persistence and might lead to important clues about virus-induced neuropathogenesis. In addition, these ex vivo model systems allow researchers to conduct drug discovery and development experiments in more representative settings of the developing human brain.

Infection of the central nervous system (CNS) by the human immunodeficiency virus (HIV) causes a broad spectrum of behavioral, motor, and cognitive dysfunctions. In its most severe form, HIV-1-associated dementia or HAD, occurs late in viral infection, often associated with profound immunosuppression. Disease is perpetuated by cellular and viral neurotoxins produced from brain mononuclear phagocytes (MP; macrophages and microglia) without direct infection of neurons. Such MP neurotoxins are, in measure, homeostatic immune products that negatively affect neuronal function when produced in abundance. Induction of disease through metabolic events perpetrated by pro-inflammatory cytokines, chemokines, platelet-activating factor, arachidonic acid and its metabolites, nitric oxide, quinolinc acid, glutamate viral structural, and regulatory proteins makes the neuropathogenesis of HIV infection unique.

Physical and psychosocial stressors have been shown to compromise immune function (Ader et al., 1991; Kielcolt-Glaser and Glaser, 1995). The immune suppressive effects of stress may be more pronounced in individuals that already have limited immune competence, such as infants, individuals with a predisposition to autoimmune disease, and the elderly (Kielcolt-Glaser and Glaser, 1995). An individual’s response to a stressor is manifested in physiological, hormonal, behavioral, and immunological changes. These stress-induced responses are initiated by the hypothalamus and translated into action by the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system. Products from these two systems (e.g., corticoid hormones and catecholamines) can directly modulate the activity of various immune effector cells (Ader et al., 1991).

HIV Associated Dementia (HAD) and peripheral neuropathy result from HIV-1 infection and several parameters impact on their initiation and course. These parameters include properties of the virus such as sequence heterogeneity of the envelope protein and virus and host gene expression in infected and uninfected macrophages in HIV infected individuals. The infection of brain cells such as macrophage/microglia may influence the course and duration of HAD through the elaboration of toxic molecules and viral host by-products of infection. Drugs of abuse complicate our interpretation of the resulting pathologies and affect the molecular and biochemical processes involved in HIV-1 infection and its life cycle. Furthermore, abused drugs may modulate the biology and function of macrophage/microglia as well as other cells in brain. Total HIV-1 virus load in the brain may also impact the clinical consequences of infection. Although specific strains of HIV-1 may inflict HAD by interactions at the molecular level, other mechanisms may operate in the initiation and development of peripheral neuropathy. An important aspect of these studies is the determination of their accuracy, specificity, sensitivity, and reproducibility. We describe important caveats involved in the performance, analysis, and interpretation of the results.

Since human immunodeficiency virus (HIV) is species-specific, how we study the neuropathogenesis of this infection is open to different approaches. Neuroscientists have historically utilized primary dissociated neural cells from rats and immortalized human neural cell lines (neuroblastoma and glioma) to study mechanisms associated with brain dysfunction. This is due in part to the technical difficulties involved in primary human neuronal cultures. While primary neural cells from rat can serve as a model for neural cell metabolism, species differences may limit the interpretation and extrapolation of the findings from neural cells to the human brain. Therefore, immortalized human cell lines have been widely used and have the advantage of being easy to maintain and able to produce abundant amounts for experimentation. However, the use of human neural tumor cell lines may not represent the normal environment.

Viral invasion of the nervous system and the development of neurological symptoms is characteristic of many retroviruses. This neuropathogenesis was initially recognized by investigators studying visna virus, the classic lentivirus of sheep. With the appearance of the human immunodeficiency virus (HIV-1), which can also cause disease in the nervous system, investigation of the pathogenesis of neurological problems induced by retroviruses has become more important. While the etiology of these syndromes is clearly associated with specific viruses, the mechanisms underlying the neurological dysfunction are unclear and many hypotheses have been proposed. Most controversial is the role of direct retroviral infection of glia and neurons versus indirect effects resulting from infection of microglia or lymphoid elements in the generation of neurological dysfunction. This chapter will discuss the pathophysiology of retrovirally mediated neurological disease in lentiviruses and in murine retroviruses, with particular attention to this question. Work with the human retroviruses depends on the availability of appropriate tissue models, many of which are obtained from different species. These inherent difficulties have resulted in a relatively slow rate of progress in comparison with the more focused animal systems, particularly murine.

There has been a tremendous increase in interest in the neuropathogenicity of viruses during the past decade as we have come to recognize that the human immunodeficiency virus, which causes the acquired immunodeficiency syndrome (AIDS), can infect glial cells and cause neurological disease. Yet this increase has not been limited to AIDS but has extended to viruses that infect either or both the central and peripheral nervous systems. The changes examined here include both neurological and psychological diseases or syndromes. Moreover, the chapters in this volume review the interaction of the host immune system with the viruses examined and how such interactions may increase or decrease the neuropatho genicity of the viruses. Questions regarding viral neuropathogenesis include: (I) What is the mode of transmission of virus to the nervous system? (2) What types of cells are infected, and do they contain receptors for the virus? (3) What is the extent of damage that results from viral infection? (4) What are the immunologic mecha nisms by which damage is mediated or limited? Many of these questions remain unanswered, but this volume delves into efforts to provide some answers."