Journal of Clinical Infectious Diseases & Practice
Open Access

Neuroinvasion; Inflammatory response; Microglia

Introduction

Viral infections of the central nervous system (CNS) pose significant challenges to public health, as they can lead to severe neurological complications and even death. The ability of certain viruses to invade the CNS and trigger an inflammatory response is a complex phenomenon known as neuroinvasion and inflammation. Understanding the mechanisms underlying this process is crucial for the development of effective treatment strategies and preventive measures against these devastating infections [1].

Viral central nervous system (CNS) infections can be classified depending on the anatomical site of the inflammation and the entry site of viral pathogens. An infection of the meninges is referred to as meningitis, of the brain as encephalitis, and of the spinal cord as myelitis. When a combination of regions is affected, the terms meningoencephalitis or encephalomyelitis are applied. Despite an often mild acute phase, fatal outcomes are possible, while the long term impact of viral CNS infections has not been elucidated in detail yet [2].

Neuroinvasion mechanisms

Neuroinvasion is the process by which viruses cross the blood-brain barrier (BBB) or peripheral nerves to gain access to the CNS. Various viruses have evolved distinct strategies to exploit different routes of entry into the brain and spinal cord. The most common mechanisms of neuroinvasion include:

Hematogenous route: Many neurotropic viruses enter the CNS through the bloodstream. They breach the BBB by infecting endothelial cells, which line the blood vessels [3], and subsequently cross into the brain or spinal cord. Examples of viruses that employ this route include herpes simplex virus (HSV), West Nile virus (WNV), and human immunodeficiency virus (HIV).

Neuroaxonal transport: Some viruses, such as rabies virus, utilize peripheral nerves as a highway to travel from the periphery to the CNS. After initial infection at the site of entry, these viruses travel along nerve fibers until they reach the CNS, where they initiate infection.

Direct invasion: Certain viruses can directly invade the CNS by infecting nearby cells or tissues. Poliovirus, for instance, initially replicates in the gastrointestinal tract but can spread to the CNS, leading to polio and neurological complications [4].

Inflammatory response in the CNS

Once viruses gain entry into the CNS, they trigger an immune response by activating microglia, the resident immune cells of the brain, as well as infiltrating peripheral immune cells. This immune response is characterized by the release of pro-inflammatory cytokines, chemokines, and other immune signaling molecules.

While the immune response is essential to control viral replication and clear the infection, it can also cause collateral damage to the nervous tissue [5]. Excessive inflammation can lead to neuronal injury, BBB disruption, and the release of neurotoxic molecules, resulting in a cascade of events that exacerbate neurological symptoms.

Models to Study Viral CNS Infection Several in vitro models, both static and under flow conditions, as well as in vivo models, mainly murine, exist to study the pathogenesis of viral CNS infection. Application of in vitro models can facilitate easier handling and may increase the spectrum of potential investigations in comparison to a complex experimental in vivo setup [6]. However, in in vitro setup, it is barely possible to mimic the extremely complex and interrelated structures of the CNS. In vitro models of the BBB can be grouped into two major set ups: (1) single culture models with brain microvascular endothelial cells and (2) coculture models with, for example, BMEC, astrocytes, and pericytes and/or glia cells. A commonly used single culture BBB model to study CNS infection is based on human brain microvascular endothelial cells. This indicates an organ specific mode of entrance into the CNS. A coculture model with HBMEC in combination with human fetal astrocytes was used to investigate HIVassociated encephalitis [7].

The role of microglia

Microglia plays a central role in the inflammatory response within the CNS. These cells act as the first line of defense against viral infections and are responsible for detecting and phagocytosing virus-infected cells. Activated microglia release pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α), to recruit other immune cells and amplify the immune response [8]. However, uncontrolled activation of microglia can contribute to neuroinflammation and neurodegeneration. Overactive microglia can release excessive amounts of reactive oxygen species (ROS) and nitric oxide, leading to oxidative stress and neuronal damage.

BBB disruption and immune cell infiltration

Viral infections and the release of pro-inflammatory molecules can weaken the BBB's integrity. BBB disruption allows immune cells from the bloodstream to infiltrate the CNS [9], exacerbating the inflammatory response. Peripheral immune cells, such as T cells and macrophages, can contribute to both viral clearance and tissue damage in the CNS.

Neurological complications

The neuroinvasion and inflammatory response in viral CNS infections can lead to a wide range of neurological complications, depending on the virus involved and the severity of the infection. Common neurological manifestations include encephalitis (inflammation of the brain), meningitis (inflammation of the meninges surrounding the brain and spinal cord), seizures, cognitive impairments, and motor deficits [10].

Conclusion

Viral infections of the central nervous system involving neuroinvasion and inflammation are serious health concerns with potentially devastating consequences. The intricate interplay between viruses, the immune system, microglia, and the blood-brain barrier determines the severity and outcome of CNS infections. Understanding the underlying mechanisms of neuroinvasion and inflammation is essential for developing targeted therapies and effective vaccines to combat these viral infections and protect the brain from irreversible damage. Continued research in this field will help us better comprehend these complex processes and improve clinical outcomes for patients with viral CNS infections.

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