Infiltrating Macrophages Are Key to the Development of Seizures following Virus Infection

Cusick, Matthew F.; Libbey, Jane E.; Patel, Dipan; Doty, Daniel J.; Fujinami, Robert S.

doi:10.1128/jvi.02747-12

Cited by 101 publications

(184 citation statements)

References 53 publications

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“…In murine models of CNS disease, either degenerative or as a result of viral infection, the infiltration of activated monocytes defined as blood-derived MNCs expressing Ly6C hi and CCR2 (iMo) has been associated with sustained inflammation and increased pathology (67,(69)(70)(71)(72)(73)(74). We next analyzed the activation state of iMo infiltrating the CNS of MCMV-infected newborn mice before and after TNF-NAb treatment by measuring the expression of the CCR2 receptor, the major histocompatibility complex class II (MHC-II), and the costimulatory molecule CD80.…”

Section: Resultsmentioning

confidence: 99%

“…Finally, it is important to note that although treatment with TNF-NAb dramatically reduced the frequency of activated microglia in the brains of infected animals to levels measured in mock-infected animals, iMo that infiltrated the brains of TNF-NAb-treated animals continued to express activation markers, providing evidence that resident cells of the infected brain are not the sole determinants of inflammation in the brain in infected animals. Studies in other small-animal models of virus-induced CNS disease associated with inflammation have described the importance of infiltrating monocytes in the induction of disease (38,74,92). Furthermore, limiting the infiltration of peripheral blood monocytes, including the Ly6C hi CCR2 ϩ subset, into the CNS resulted in improved disease outcomes in murine models of amyotrophic lateral sclerosis (ALS), demyelinating diseases associated with virus infection, experimental autoimmune encephalitis (EAE), and CNS ischemia (67,69,93,94).…”

Section: Discussionmentioning

confidence: 99%

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Tumor Necrosis Factor Alpha-Induced Recruitment of Inflammatory Mononuclear Cells Leads to Inflammation and Altered Brain Development in Murine Cytomegalovirus-Infected Newborn Mice

Seleme

Kosmac

Jonjić³

et al. 2017

J Virol

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Congenital human cytomegalovirus (HCMV) infection is a significant cause of abnormal neurodevelopment and long-term neurological sequelae in infants and children. Resident cell populations of the developing brain have been suggested to be more susceptible to virus-induced cytopathology, a pathway thought to contribute to the clinical outcomes following intrauterine HCMV infection. However, recent findings in a newborn mouse model of the infection in the developing brain have indicated that elevated levels of proinflammatory mediators leading to mononuclear cell activation and recruitment could underlie the abnormal neurodevelopment. In this study, we demonstrate that treatment with tumor necrosis factor alpha (TNF-␣)-neutralizing antibodies decreased the frequency of CD45 ϩ Ly6C hi CD11b ϩ CCR2 ϩ activated myeloid mononuclear cells (MMCs) and the levels of proinflammatory cytokines in the blood and the brains of murine CMVinfected mice. This treatment also normalized neurodevelopment in infected mice without significantly impacting the level of virus replication. These results indicate that TNF-␣ is a major component of the inflammatory response associated with altered neurodevelopment that follows murine CMV infection of the developing brain and that a subset of peripheral blood myeloid mononuclear cells represent a key effector cell population in this model of virus-induced inflammatory disease of the developing brain.IMPORTANCE Congenital human cytomegalovirus (HCMV) infection is the most common viral infection of the developing human fetus and can result in neurodevelopmental sequelae. Mechanisms of disease leading to neurodevelopmental deficits in infected infants remain undefined, but postulated pathways include loss of neuronal progenitor cells, damage to the developing vascular system of the brain, and altered cellular positioning. Direct virus-mediated cytopathic effects cannot explain the phenotypes of brain damage in most infected infants. Using a mouse model that recapitulates characteristics of the brain infection described in human infants, we have shown that TNF-␣ plays a key role in brain inflammation, including recruitment of inflammatory mononuclear cells. Neutralization of TNF-␣ normalized neurodevelopmental abnormalities in infected mice, providing evidence that virus-induced inflammation is a major component of disease in the developing brain. These results suggest that interventions limiting inflammation associated with the infection could potentially improve the neurologic outcome of infants infected in utero with HCMV.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Tumor Necrosis Factor Alpha-Induced Recruitment of Inflammatory Mononuclear Cells Leads to Inflammation and Altered Brain Development in Murine Cytomegalovirus-Infected Newborn Mice

Seleme

Kosmac

Jonjić³

et al. 2017

J Virol

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“…19 After the viruses cross the blood-brain barrier, they can cause brain damage via inflammation, and direct infection. [20][21][22] The viruses trigger an anti-viral immune response, which initiates an inflammatory cascade to control viral replication and dissemination. [20][21][22] The extent of the pro-inflammatory response in the CNS and the timing of the release of pro-inflammatory cytokines, such as tumor necrosis factor-α and interleukin-6, can lead to neuronal excitability and injury.…”

Section: Discussionmentioning

confidence: 99%

“…[20][21][22] The viruses trigger an anti-viral immune response, which initiates an inflammatory cascade to control viral replication and dissemination. [20][21][22] The extent of the pro-inflammatory response in the CNS and the timing of the release of pro-inflammatory cytokines, such as tumor necrosis factor-α and interleukin-6, can lead to neuronal excitability and injury. [20][21][22] We performed tests that included PCR to identify the viral pathogens, and we found no significant differences in the viral pathogens of the meningitis and encephalitis patients.…”

Section: Discussionmentioning

confidence: 99%

Comparison of the Demographic and Laboratory Profiles of Patients with Aseptic Meningitis and Encephalitis: Significance of Age and C-reactive Protein

Park

Shin

et al. 2014

Korean J Clin Neurophysiol

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Background: Viruses can cause either meningitis or encephalitis. It is unclear why some people suffer from aseptic meningitis, and others acquire aseptic encephalitis when infected with the same viral pathogens. The aim of this study was to compare demographic and laboratory factors between patients with aseptic meningitis and encephalitis. Methods: The demographic and laboratory differences were analyzed according to age, sex, diabetes, hypertension, C-reactive protein in the blood, white blood cell and protein in the cerebrospinal fluid, and glucose ratio (cerebrospinal fluid/blood). Additionally, we analyzed the nation-wide differencesin age between the patients with aseptic meningitis and those with encephalitis in Korea. Results: The patients with aseptic encephalitis were older, more likely to have hypertension, and had higher levels of C-reactive protein than did the patients with aseptic meningitis. However, the numbers of white blood cells in the cerebrospinal fluid were significantly higher in the patients with meningitis than in the patients with encephalitis. Multivariable analysis revealed that age >49 years, hypertension and a C-reactive protein level >5.81 mg/dL were independent and significant variables in the prediction of aseptic encephalitis. Additionally, the patients with aseptic encephalitis were older than those with aseptic meningitis in the nation-wide Korean database. Conclusions: Older age, hypertension, and higher levels of C-reactive protein are useful factors for the prediction of aseptic encephalitis. (Korean J Clin Neurophysiol 2014;16:55-61)

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“…Decreased cognitive performance correlated with increased monocyte infiltration in HIVassociated neurocognitive disorders (HAND) (1). Additionally, infiltration of monocytes was found to be important for seizure development in a mouse model of Theiler's murine encephalitis (7). Recent studies in a mouse model of experimental autoimmune encephalitis (EAE) demonstrated that CCR2 ϩ infiltrating monocytes, but not CX3CR1 ϩ microglia, were responsible for axonal demyelination (8).…”

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confidence: 99%

Neuropeptide Y Negatively Influences Monocyte Recruitment to the Central Nervous System during Retrovirus Infection

Woods

Carmody

et al. 2016

J Virol

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Monocyte infiltration into the CNS is a hallmark of several viral infections of the central nervous system (CNS), including retrovirus infection.Understanding the factors that mediate monocyte migration in the CNS is essential for the development of therapeutics that can alter the disease process. In the current study, we found that neuropeptide Y (NPY) suppressed monocyte recruitment to the CNS in a mouse model of polytropic retrovirus infection. NPY ؊/؊ mice had increased incidence and kinetics of retrovirus-induced neurological disease, which correlated with a significant increase in monocytes in the CNS compared to wildtype mice. Both Ly6C hi inflammatory and Ly6C lo alternatively activated monocytes were increased in the CNS of NPY ؊/؊ mice following virus infection, suggesting that NPY suppresses the infiltration of both cell types. Ex vivo analysis of myeloid cells from brain tissue demonstrated that infiltrating monocytes expressed high levels of the NPY receptor Y2R. Correlating with the expression of Y2R on monocytes, treatment of NPY ؊/؊ mice with a truncated, Y2R-specific NPY peptide suppressed the incidence of retrovirus-induced neurological disease. These data demonstrate a clear role for NPY as a negative regulator of monocyte recruitment into the CNS and provide a new mechanism for suppression of retrovirus-induced neurological disease. IMPORTANCEMonocyte recruitment to the brain is associated with multiple neurological diseases. However, the factors that influence the recruitment of these cells to the brain are still not well understood. In the current study, we found that neuropeptide Y, a protein produced by neurons, affected monocyte recruitment to the brain during retrovirus infection. We show that mice deficient in NPY have increased influx of monocytes into the brain and that this increase in monocytes correlates with neurological-disease development. These studies provide a mechanism by which the nervous system, through the production of NPY, can suppress monocyte trafficking to the brain and reduce retrovirus-induced neurological disease. The recruitment of monocytes into the central nervous system (CNS) is associated with a number of neurological diseases. Monocyte recruitment to the CNS has been reported for traumatic brain injury (TBI), misfolded-protein diseases, and multiple sclerosis (MS), as well as many different viral infections, including West Nile virus (WNV), herpes simplex virus (HSV), and retroviruses, such as HIV (1-4). Monocyte trafficking is particularly important for retrovirus-induced neurological diseases, as monocytes are susceptible to retrovirus infection (5, 6).Monocytes recruited to the CNS may contribute to pathogenesis in these neurological diseases. Decreased cognitive performance correlated with increased monocyte infiltration in HIVassociated neurocognitive disorders (HAND) (1). Additionally, infiltration of monocytes was found to be important for seizure development in a mouse model of Theiler's murine encephalitis (7). Recent studies in a mouse mo...

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Infiltrating Macrophages Are Key to the Development of Seizures following Virus Infection

Cited by 101 publications

References 53 publications

Tumor Necrosis Factor Alpha-Induced Recruitment of Inflammatory Mononuclear Cells Leads to Inflammation and Altered Brain Development in Murine Cytomegalovirus-Infected Newborn Mice

Tumor Necrosis Factor Alpha-Induced Recruitment of Inflammatory Mononuclear Cells Leads to Inflammation and Altered Brain Development in Murine Cytomegalovirus-Infected Newborn Mice

Comparison of the Demographic and Laboratory Profiles of Patients with Aseptic Meningitis and Encephalitis: Significance of Age and C-reactive Protein

Neuropeptide Y Negatively Influences Monocyte Recruitment to the Central Nervous System during Retrovirus Infection

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