Modeling the Acute and Chronic Phases of Theiler Murine Encephalomyelitis Virus Infection

Lipton, Howard L.; Perelson, Alan S.; Dahari, Harel

doi:10.1128/jvi.03395-12

Cited by 16 publications

(12 citation statements)

References 58 publications

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“…Not only are these responses fast with regard to biosynthesis, but it is unlikely that a significant number of cells have even been infected in the brain by 3 hpi. Mathematical modeling constrains the infection rate to only 0.01 to 0.1 cells per minute [ 26 ], suggesting that fewer than 20 cells would be productively infected by 3 hpi. Even if this rate is off by a factor of 100, fewer than 2000 cells are infected by 3 hpi.…”

Section: Discussionmentioning

confidence: 99%

Neuronal CCL2 expression drives inflammatory monocyte infiltration into the brain during acute virus infection

Howe

LaFrance‐Corey

Goddery

et al. 2017

J Neuroinflammation

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BackgroundViral encephalitis is a dangerous compromise between the need to robustly clear pathogen from the brain and the need to protect neurons from bystander injury. Theiler’s murine encephalomyelitis virus (TMEV) infection of C57Bl/6 mice is a model of viral encephalitis in which the compromise results in hippocampal damage and permanent neurological sequelae. We previously identified brain-infiltrating inflammatory monocytes as the primary driver of this hippocampal pathology, but the mechanisms involved in recruiting these cells to the brain were unclear.MethodsChemokine expression levels in the hippocampus were assessed by microarray, ELISA, RT-PCR, and immunofluorescence. Monocyte infiltration during acute TMEV infection was measured by flow cytometry. CCL2 levels were manipulated by immunodepletion and by specific removal from neurons in mice generated by crossing a line expressing the Cre recombinase behind the synapsin promoter to animals with floxed CCL2.ResultsInoculation of the brain with TMEV induced hippocampal production of the proinflammatory chemokine CCL2 that peaked at 6 h postinfection, whereas inoculation with UV-inactivated TMEV did not elicit this response. Immunofluorescence revealed that hippocampal neurons expressed high levels of CCL2 at this timepoint. Genetic deletion of CCR2 and systemic immunodepletion of CCL2 abrogated or blunted the infiltration of inflammatory monocytes into the brain during acute infection. Specific genetic deletion of CCL2 from neurons reduced serum and hippocampal CCL2 levels and inhibited inflammatory monocyte infiltration into the brain.ConclusionsWe conclude that intracranial inoculation with infectious TMEV rapidly induces the expression of CCL2 in neurons, and this cellular source is necessary for CCR2-dependent infiltration of inflammatory monocytes into the brain during the most acute stage of encephalitis. These findings highlight a unique role for neuronal production of chemokines in the initiation of leukocytic infiltration into the infected central nervous system.

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Section: Discussionmentioning

confidence: 99%

Neuronal CCL2 expression drives inflammatory monocyte infiltration into the brain during acute virus infection

Howe

LaFrance‐Corey

Goddery

et al. 2017

J Neuroinflammation

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“…Originally developed for HIV-1 infection [1–5], viral kinetic models has been adapted to numerous infections such as those caused by hepatitis C [6], hepatitis B [7–14], cytomegalovirus [15–17], herpes simplex virus 2 [18–20], influenza [21–34], human T-cell lymphotrophic virus- 1 [35], measles [36] and Theiler murine encephalomyelitis virus [37]. …”

Section: Introductionmentioning

confidence: 99%

Viral kinetic modeling: state of the art

Canini

Perelson

2014

J Pharmacokinet Pharmacodyn

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Viral kinetic modeling has led to increased understanding of the within host dynamics of viral infections and the effects of therapy. Here we review recent developments in the modeling of viral infection kinetics with emphasis on two infectious diseases: hepatitis C and influenza. We review how viral kinetic modeling has evolved from simple models of viral infections treated with a drug or drug cocktail with an assumed constant effectiveness to models that incorporate drug pharmacokinetics and pharmacodynamics, as well as phenomenological models that simply assume drugs have time varying-effectiveness. We also discuss multiscale models that include intracellular events in viral replication, models of drug-resistance, models that include innate and adaptive immune responses and models that incorporate cell-to-cell spread of infection. Overall, viral kinetic modeling has provided new insights into the understanding of the disease progression and the modes of action of several drugs. We expect that viral kinetic modeling will be increasingly used in the coming years to optimize drug regimens in order to improve therapeutic outcomes and treatment tolerability for infectious diseases.

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“…Following the success of models of HIV population dynamics, similar models have been developed to understand the pathogenesis and disease progression following infection with several other viruses, namely hepatitis B virus (HBV) Perelson and Ribeiro 2004), hepatitis C virus (HCV) (Chatterjee et al 2013;Neumann et al 1998), influenza A virus (IAV) (Murillo et al 2013;Smith et al 2011), simian immunodeficiency virus (SIV) (Mohri et al 1998;Vaidya et al 2010), cytomegalovirus (CMV) (Emery et al 1999(Emery et al , 2002, and Theiler's murine encephalomyelitis virus (TMEV) (Zhang et al 2013). Below, we briefly discuss models of hepatitis C and influenza A virus dynamics.…”

Section: Viral Dynamics and Immune Responsementioning

confidence: 99%

Models of Viral Population Dynamics

Padmanabhan

Dixit

2015

Current Topics in Microbiology and Immunology

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Models of viral population dynamics have contributed enormously to our understanding of the pathogenesis and transmission of several infectious diseases, the coevolutionary dynamics of viruses and their hosts, the mechanisms of action of drugs, and the effectiveness of interventions. In this chapter, we review major advances in the modeling of the population dynamics of the human immunodeficiency virus (HIV) and briefly discuss adaptations to other viruses.

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Modeling the Acute and Chronic Phases of Theiler Murine Encephalomyelitis Virus Infection

Cited by 16 publications

References 58 publications

Neuronal CCL2 expression drives inflammatory monocyte infiltration into the brain during acute virus infection

Neuronal CCL2 expression drives inflammatory monocyte infiltration into the brain during acute virus infection

Viral kinetic modeling: state of the art

Models of Viral Population Dynamics

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