infections of the nervous system what is the idntity of this microbe course hero

How does a virus infect the central nervous system (CNS)?

Virus infections usually begin in peripheral tissues and can invade the mammalian nervous system (NS), spreading into the peripheral (PNS) and more rarely the central (CNS) nervous systems. The CNS is protected from most virus infections by effective immune responses and multilayer barriers.

How is the central nervous system protected from viral infections?

The CNS is protected from most virus infections by effective immune responses and multilayer barriers. However, some viruses enter the NS with high efficiency via the bloodstream or by directly infecting nerves that innervate peripheral tissues, resulting in debilitating direct and immune-mediated pathology.

What are acute CNS infections?

Acute infections of the central nervous system (CNS) are medical emergencies that if not addressed promptly result in significant mortality or long-term sequelae that have catastrophic implications for the quality of life of affected individuals.

How are central nervous system infections diagnosed?

Central Nervous System Infections are necessarily confirmed by MRI detection of inflammatory changes in the brain or membranes, signs of intracranial hypertension in the fundus, as well as specific immunological blood parameters. Identification of the causative agent of infectious brain disease is essential.

Which is more accessible to peripheral infections, the PNS or the CNS?

How do viruses enter the nervous system?

How do viruses spread?

How are neurotropic viruses polarized?

How do viruses enter the PNS?

Where do viral infections occur?

Who are the members of the Enquist lab?

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Which is more accessible to peripheral infections, the PNS or the CNS?

While the PNS is relatively more accessible to peripheral infections because nerves are in direct contact with tissues of all types, the CNS proper has several layers of protection. Spread of infection from the blood to the cerebral spinal fluid and CNS cells is limited by the blood brain barrier (BBB). The BBB is mainly composed of endothelial cells, pericytes, astrocytes, and the basement membrane ( Figure 2 D). Pericytes project finger-like processes to ensheath the capillary wall and coordinate the neurovascular functions of the BBB. The star shaped astrocytes (i.e., astroglia) are the major glial cell type in the CNS. The astrocyte endfeet projections ensheath the capillary, regulating BBB homeostasis and blood flow. Brain microvascular endothelial cells (BMVECs) that line the CNS vasculature are connected by tight junctions not found in capillaries in other tissues. These junctions restrict the egress of bacteria, virus particles, and large protein molecules from the lumen of the blood vessel, while allowing the transport of metabolites, small hydrophobic proteins, and dissolved gasses in and out of the CNS. The basement membrane, a thick extracellular matrix, also surrounds these capillaries, further limiting movement of pathogens. Perivascular macrophages (i.e., microglia) residing between the endothelial and glial cells further provide immune surveillance in the CNS tissue. Virus infections that leave the periphery and find their way into the PNS or CNS do so either by direct infection of nerve endings in the tissues or by infecting cells of the circulatory system that ultimately carry the infection through the BBB into the CNS ( Table 1 and Figure 2 ).

How do viruses enter the nervous system?

The CNS is protected from most virus infections by effective immune responses and multilayer barriers . However, some viruses enter the NS with high efficiency via the bloodstream or by directly infecting nerves that innervate peripheral tissues, resulting in debilitating direct and immune-mediated pathology. Most viruses in the NS are opportunistic or accidental pathogens, but a few, most notably the alpha herpesviruses and rabies virus, have evolved to enter the NS efficiently and exploit neuronal cell biology. Remarkably, the alpha herpesviruses can establish quiescent infections in the PNS, with rare but often fatal CNS pathology. Here we review how viruses gain access to and spread in the well-protected CNS, with particular emphasis on alpha herpesviruses, which establish and maintain persistent NS infections.

How do viruses spread?

Virions do not typically spread by free diffusion, but rather between tightly connected neurons via neurochemical synapses or other close cell-cell contacts. Infected PNS neurons often are in direct synaptic contact with CNS neurons, providing a direct route of spread from the periphery. Consequently, CNS infection is determined in part by the directionality of virus spread along neuronal circuits, which is influenced by directional intracellular virus transport and egress. Motor neurons receive input from CNS neurons via synapses on the somatodendritic plasma membrane (i.e., postsynaptic contacts) and relay these signals to neuromuscular junctions at axon termini. RABV, which typically infects motor neurons, spreads exclusively in the retrograde direction along neuronal circuits, exiting from the somatodendritic plasma membrane to spread toward the CNS ( Figure 2 B). Most neurotropic viruses are capable of spreading retrograde in neural circuits, suggesting that there may be common or default somatodendritic transport pathways. In contrast to motor neurons, sensory neurons are typically pseudounipolar, with two axon-like projections: one innervating peripheral tissues, and the other making presynaptic contact with CNS neurons ( Figure 2 A). To be able to spread within this pseudounipolar architecture, the alpha herpesviruses have evolved the capacity to spread in the anterograde direction, exiting from axon termini. The alpha herpesviruses are among the very few viruses that are capable of bidirectional spread (both anterograde and retrograde direction) ( Figure 3 B).

How are neurotropic viruses polarized?

The maintenance and the communication of distal axons with their cell bodies requires highly specialized signal transduction, intracellular sorting, trafficking, and membrane systems. As obligate intracellular parasites, viruses are dependent on these cellular functions that are often cell-type specific. Accordingly, neurotropic viruses can be divided into two categories: those that accidentally or opportunistically spread to the specialized NS (e.g., WNV, HCV, and EBV) and those that have adapted to the NS (e.g., alpha herpesviruses and RABV). From a human health perspective, these fundamental differences in virus-host interaction result in the broad range of viral pathogenesis. In this section, we will summarize how viral infections engage neuronal cell biology to enter, traffic, and spread between neurons.

How do viruses enter the PNS?

Invasion of Sensory Nerve Endings. Some viruses can enter the PNS by binding to receptors on axon termini of sensory and autonomic neurons, which respectively convey sensory and visceral information. Most alpha herpesviruses use this route to enter the PNS and establish a life-long persistent infection (

Where do viral infections occur?

Most acute and persistent viral infections begin in the periphery, often at epithelial or endothelial cell surfaces . Infection of cells at these sites usually induces a tissue-specific antiviral response that includes both a cell-autonomous response (intrinsic immunity) and paracrine signaling from the infected cell to surrounding uninfected cells by secreted cytokines (innate immunity). This local inflammatory response usually contains the infection. After several days, the adaptive immune response may be activated and the infection cleared by the action of infection-specific antibodies and T cells (acquired immunity). Viral infections that escape local control at the site of primary infection can spread to other tissues, where they can cause more serious problems due to robust virus replication or overreacting innate immune response. This latter reaction is sometimes called a “cytokine storm” because both proinflammatory and anti-inflammatory cytokines are elevated in the serum leading to vigorous systemic immune activity ( Figure 1 ). Such a response in the brain is usually devastating and can lead to meningitis, encephalitis, meningoencephalitis, or death.

Who are the members of the Enquist lab?

We thank the members of the Enquist lab, especially M.P. Taylor, R. Song, E. Engel, K. Lancaster, and A. Ambrosini, for critical reading of the manuscript. L.W.E. acknowledges support from US National Institutes of Health grants NS033506 and NS060699. I.B.H. is supported by fellowship PF-13-050-01-MPC from the American Cancer Society.

How do viruses enter the nervous system?

The CNS is protected from most virus infections by effective immune responses and multilayer barriers . However, some viruses enter the NS with high efficiency via the bloodstream or by directly infecting nerves that innervate peripheral tissues, resulting in debilitating direct and immune-mediated pathology. Most viruses in the NS are opportunistic or accidental pathogens, but a few, most notably the alpha herpesviruses and rabies virus, have evolved to enter the NS efficiently and exploit neuronal cell biology. Remarkably, the alpha herpesviruses can establish quiescent infections in the PNS, with rare but often fatal CNS pathology. Here we review how viruses gain access to and spread in the well-protected CNS, with particular emphasis on alpha herpesviruses, which establish and maintain persistent NS infections.

How is the CNS protected from viruses?

The CNS is protected from most virus infections by effective immune responses and multilayer barriers. However, some viruses enter the NS with high efficiency via the bloodstream or by directly infecting nerves that innervate peripheral tissues, resulting in debilitating direct and immune-mediated pathology.

What are the most common viruses in the NS?

Most viruses in the NS are opportunistic or accidental pathogens, but a few, most notably the alpha herpesviruses and rabies virus, have evolved to enter the NS efficiently and exploit neuronal cell biology.

What is an acute CNS infection?

Acute infections of the central nervous system (CNS) are medical emergencies that if not addressed promptly result in significant mortality or long-term sequelae that have catastrophic implications for the quality of life of affected individuals. To fully understand the pathogenesis, clinical implications, and management of CNS infections, some knowledge of applied neuroanatomy is essential.

What are the serogroups of N. meningitidisare?

meningitidisare characterized according to the serologic recognition of polysaccharide epitopes on their capsule and outer membrane and are classified into serogroups A, B, C, W135, and Y. In the United States, strains from serogroups B, C, and Y cause the majority (45 %) of infections, whereas in less-developed countries serogroups A and C predominate; serogroup A has also been implicated in epidemics in sub-Saharan Africa.

What pathogens invade the subarachnoid space?

N. meningitis, S. pneumoniae, H. influenzaetype b and other pathogens are capable of invading the CNS and infecting the meninges due to the incorporation of virulence factors [28]. The chain of events that ultimately lead to invasion of the subarachnoid space by these pathogens includes a cascade of events involving nasopharyngeal or middle ear colonization, bloodstream dissemination of the respective pathogen, crossing of the blood–brain and blood-CSF barriers, and finally entrance and survival of the implicated pathogen into the subarachnoid space and subsequent infection [28]. Bacteria migrate through the brain microvascular endothelial cells in enclosed vacuoles via a mechanism that is dependent on F-actin. Thus, transport through the cell appears to be dependent on cytoskeletal rearrangement involving both microfilaments and microtubules. Because of the blood–brain barrier, immunoglobulin and complement protein levels and leukocytes are significantly lower in CSF than in serum and interstitial fluid. Thus, in the early phase of infection involving the subarachnoid space, bacterial replication proceeds virtually unchecked by host defense mechanisms. Although the major host response to the invasion of the subarachnoid space by pathogenic microorganisms is a rapid influx of polymorphonuclear leukocytes, opsonization of bacteria and subsequent phagocytosis by neutrophils are hindered by the relative paucity of complement and immunoglobulins and the intrinsic fluid nature of CSF which is less facilitating to phagocytosis as compared to solid tissues. In addition, leukocyte proteases derived from the initial influx of leukocytes degrade whatever complement components are present in the CSF [29–31].

What are the structures of the CNS?

The CNS is defined by the brain (cerebrum and cerebellum), spinal cord, optic nerves, and their covering membranes. These structures are protected within the rigid confines of the skull and spinal canal of the vertebral column. The cerebral cortex (the outermost, gray tissue layer of the cerebrum) and the spinal cord are covered by three layers of continuous protective tissue called the meninges. The innermost meningeal layer that directly overlies the cerebral cortex is called the pia mater. The middle and outermost layers are known as the arachnoid and dura mater, respectively. The dura mater forms several intracranial compartments, including sinuses for venous drainage. Parts of the arachnoid—the arachnoid villi—project into these sinuses. The subpial space is continuous with the Virchow-Robin spaces. These two spaces transmit penetrating vessels to and from the brain parenchyma and do not connect with the subarachnoid space. The subarachnoid space lies between the pia mater and the arachnoid and is continuous in nature; the subdural space lies between the arachnoid and the dura mater. The epidural space lies between the dura and the skull. Certain infections can access the subpial and Virchow-Robin spaces, while most do not. Infections within the epidural spaces are usually caused by direct extension from adjacent infections and the infection remains in close proximity to the inciting source. Subdural infections are often associated with an extracerebral source, but these infections can spread widely within the subdural compartment well away from the inciting source. It is not uncommon to develop serous subdural effusions in bacterial meningitis. Subarachnoid infections are most often caused by hematogenous dissemination of organisms or viruses.

How does cerebral edema affect the ICP?

The ICP is raised via several mechanisms. First, vasogenic cerebral edema is caused by the increased permeability of the blood–brain barrier, which is a direct result of inflammatory bacterial products or the inflammatory cytokines released in response to these products. Second, the alterations in brain cellular membranes lead to cytotoxic cerebral edema resulting from increased intracellular water content, potassium leakage, and a shift in brain metabolism to anaerobic glycolysis with increased lactate production. And third, as a result of the inflammation in the subarachnoid space, there is decreased ability to reabsorb CSF, which leads to interstitial edema in brain parenchyma. All three mechanisms contribute to increased ICP pressure, which in turn may precipitate transtentorial brain herniation.

What is the blood supply to the brain?

A working knowledge of the blood supply is also essential for understanding the pathogenesis of CNS infections. The capillary supply to the brain and spinal cord is unique—the outermost layers of endothelial cells are fused together. These specialized brain microvascular endothelial cells constitute the blood–brain barrier, which separates the brain and the meninges from the circulating blood and impedes the influx of microorganisms, toxic agents, and most other compounds, while regulating the flow of essential nutrients and molecules for normal neural function. Thus, pathogens that breach the blood–brain barrier can cause CNS infections. Causes of such breaches include damage (e.g., microhemorrhage or necrosis of surrounding tissue) to the barrier; mechanical obstruction of microvessels by parasitized red blood cells, leukocytes, or platelets; overproduction of cytokines that degrade tight junction proteins; or microbe-specific interactions with the blood–brain barrier that facilitate transcellular passage of the microorganism (e.g., Escherichia coli, mycobacteria, and spirochaetes). The therapeutic implications are obvious—to be effective, antimicrobials prescribed for CNS infections must be able to cross the blood–brain barrier.

What is the main mode of transmission of meningitis?

The main mode of transmission is via direct contact with large droplet respiratory secretions from patients or asymptomatic carriers; humans are the only host. Invasive disease caused by this organism occurs in three clinical forms: meningitis (50 % of cases), blood infection (30 %), and pneumonia (10 %); other forms account for the remainder (10 %) of the cases. N. meningitidishas now become the leading cause of bacterial meningitis in the United States with an estimated annual incidence of approximately 0.5–1.5 cases per 100,000 population and at least tenfold higher in less-developed countries [1]. Persons at risk include household contacts of infected patients, military recruits, college freshmen who live in dormitories, microbiologists who work with isolates of N. meningitidis, persons traveling to a country where meningococcal disease is epidemic or highly endemic, and patients without spleens or with terminal complement component deficiencies. Infants less than 1 year of age and adolescents ages 16–21 years have higher rates of disease than other age groups, although infection can occur in all age groups including the elderly.

Which is more accessible to peripheral infections, the PNS or the CNS?

While the PNS is relatively more accessible to peripheral infections because nerves are in direct contact with tissues of all types, the CNS proper has several layers of protection. Spread of infection from the blood to the cerebral spinal fluid and CNS cells is limited by the blood brain barrier (BBB). The BBB is mainly composed of endothelial cells, pericytes, astrocytes, and the basement membrane ( Figure 2 D). Pericytes project finger-like processes to ensheath the capillary wall and coordinate the neurovascular functions of the BBB. The star shaped astrocytes (i.e., astroglia) are the major glial cell type in the CNS. The astrocyte endfeet projections ensheath the capillary, regulating BBB homeostasis and blood flow. Brain microvascular endothelial cells (BMVECs) that line the CNS vasculature are connected by tight junctions not found in capillaries in other tissues. These junctions restrict the egress of bacteria, virus particles, and large protein molecules from the lumen of the blood vessel, while allowing the transport of metabolites, small hydrophobic proteins, and dissolved gasses in and out of the CNS. The basement membrane, a thick extracellular matrix, also surrounds these capillaries, further limiting movement of pathogens. Perivascular macrophages (i.e., microglia) residing between the endothelial and glial cells further provide immune surveillance in the CNS tissue. Virus infections that leave the periphery and find their way into the PNS or CNS do so either by direct infection of nerve endings in the tissues or by infecting cells of the circulatory system that ultimately carry the infection through the BBB into the CNS ( Table 1 and Figure 2 ).

How do viruses enter the nervous system?

The CNS is protected from most virus infections by effective immune responses and multilayer barriers . However, some viruses enter the NS with high efficiency via the bloodstream or by directly infecting nerves that innervate peripheral tissues, resulting in debilitating direct and immune-mediated pathology. Most viruses in the NS are opportunistic or accidental pathogens, but a few, most notably the alpha herpesviruses and rabies virus, have evolved to enter the NS efficiently and exploit neuronal cell biology. Remarkably, the alpha herpesviruses can establish quiescent infections in the PNS, with rare but often fatal CNS pathology. Here we review how viruses gain access to and spread in the well-protected CNS, with particular emphasis on alpha herpesviruses, which establish and maintain persistent NS infections.

How do viruses spread?

Virions do not typically spread by free diffusion, but rather between tightly connected neurons via neurochemical synapses or other close cell-cell contacts. Infected PNS neurons often are in direct synaptic contact with CNS neurons, providing a direct route of spread from the periphery. Consequently, CNS infection is determined in part by the directionality of virus spread along neuronal circuits, which is influenced by directional intracellular virus transport and egress. Motor neurons receive input from CNS neurons via synapses on the somatodendritic plasma membrane (i.e., postsynaptic contacts) and relay these signals to neuromuscular junctions at axon termini. RABV, which typically infects motor neurons, spreads exclusively in the retrograde direction along neuronal circuits, exiting from the somatodendritic plasma membrane to spread toward the CNS ( Figure 2 B). Most neurotropic viruses are capable of spreading retrograde in neural circuits, suggesting that there may be common or default somatodendritic transport pathways. In contrast to motor neurons, sensory neurons are typically pseudounipolar, with two axon-like projections: one innervating peripheral tissues, and the other making presynaptic contact with CNS neurons ( Figure 2 A). To be able to spread within this pseudounipolar architecture, the alpha herpesviruses have evolved the capacity to spread in the anterograde direction, exiting from axon termini. The alpha herpesviruses are among the very few viruses that are capable of bidirectional spread (both anterograde and retrograde direction) ( Figure 3 B).

How are neurotropic viruses polarized?

The maintenance and the communication of distal axons with their cell bodies requires highly specialized signal transduction, intracellular sorting, trafficking, and membrane systems. As obligate intracellular parasites, viruses are dependent on these cellular functions that are often cell-type specific. Accordingly, neurotropic viruses can be divided into two categories: those that accidentally or opportunistically spread to the specialized NS (e.g., WNV, HCV, and EBV) and those that have adapted to the NS (e.g., alpha herpesviruses and RABV). From a human health perspective, these fundamental differences in virus-host interaction result in the broad range of viral pathogenesis. In this section, we will summarize how viral infections engage neuronal cell biology to enter, traffic, and spread between neurons.

How do viruses enter the PNS?

Invasion of Sensory Nerve Endings. Some viruses can enter the PNS by binding to receptors on axon termini of sensory and autonomic neurons, which respectively convey sensory and visceral information. Most alpha herpesviruses use this route to enter the PNS and establish a life-long persistent infection (

Where do viral infections occur?

Most acute and persistent viral infections begin in the periphery, often at epithelial or endothelial cell surfaces . Infection of cells at these sites usually induces a tissue-specific antiviral response that includes both a cell-autonomous response (intrinsic immunity) and paracrine signaling from the infected cell to surrounding uninfected cells by secreted cytokines (innate immunity). This local inflammatory response usually contains the infection. After several days, the adaptive immune response may be activated and the infection cleared by the action of infection-specific antibodies and T cells (acquired immunity). Viral infections that escape local control at the site of primary infection can spread to other tissues, where they can cause more serious problems due to robust virus replication or overreacting innate immune response. This latter reaction is sometimes called a “cytokine storm” because both proinflammatory and anti-inflammatory cytokines are elevated in the serum leading to vigorous systemic immune activity ( Figure 1 ). Such a response in the brain is usually devastating and can lead to meningitis, encephalitis, meningoencephalitis, or death.

Who are the members of the Enquist lab?

We thank the members of the Enquist lab, especially M.P. Taylor, R. Song, E. Engel, K. Lancaster, and A. Ambrosini, for critical reading of the manuscript. L.W.E. acknowledges support from US National Institutes of Health grants NS033506 and NS060699. I.B.H. is supported by fellowship PF-13-050-01-MPC from the American Cancer Society.