Lymphocytic choriomeningitis virus infection of the developing brain: critical role of host age

Bonthius, Daniel J.; Nichols, Brent; Harb, Harb; Mahoney, Jo; Karaçay, Bahri

doi:10.1002/ana.21193

Cited by 51 publications

(94 citation statements)

References 43 publications

(67 reference statements)

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“…The authors hypothesize that the wide variability in their cohort's clinical phenotype reflected LCMV infection occurring at different stages of gestation. In a companion paper, they supported this supposition by inoculating rat pups with LCMV at varying gestational ages and observing the same wide variety in clinical pathology as well as differences in cellular targets and immune response (Bonthius et al, 2007a). T-cell response directed to the LCMV antigens in the cell membranes of transplanted, infected tumor cells.…”

Section: Lcmv Infection In Pregnancymentioning

confidence: 90%

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Diseases of the central nervous system caused by lymphocytic choriomeningitis virus and other arenaviruses

Wilson¹,

Peters²

2014

Neurovirology

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Section: Lcmv Infection In Pregnancymentioning

confidence: 90%

“…In fact, cerebellar hypoplasia and retinal damage have been observed in rats infected soon after birth via the intracerebral route (Monjan et al, 1974;Bonthius et al, 2007a). These abnormalities have been observed in neonatal humans as well.…”

Section: Small-animal Model Systemsmentioning

confidence: 98%

Diseases of the central nervous system caused by lymphocytic choriomeningitis virus and other arenaviruses

Wilson¹,

Peters²

2014

Neurovirology

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“…Additionally, reports of transplant-associated LCMV disease and fatality highlight the clinical relevance of arenaviral infection in immunocompromised individuals (15). In addition, congenital transmission of LCMV has been implicated in a variety of clinical conditions that affect mainly the retina and brain (3,4).…”

mentioning

confidence: 99%

Conserved Residues in Lassa Fever Virus Z Protein Modulate Viral Infectivity at the Level of the Ribonucleoprotein

Capul

Torre

Buchmeier

2011

J Virol

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Arenaviruses are negative-strand RNA viruses that cause human diseases such as lymphocytic choriomeningitis, Bolivian hemorrhagic fever, and Lassa hemorrhagic fever. No licensed vaccines exist, and current treatment is limited to ribavirin. The prototypic arenavirus, lymphocytic choriomeningitis virus (LCMV), is a model for dissecting virus-host interactions in persistent and acute disease. The RING finger protein Z has been identified as the driving force of arenaviral budding and acts as the viral matrix protein. While residues in Z required for viral budding have been described, residues that govern the Z matrix function(s) have yet to be fully elucidated. Because this matrix function is integral to viral assembly, we reasoned that this would be reflected in sequence conservation. Using sequence alignment, we identified several conserved residues in Z outside the RING and late domains. Nine residues were each mutated to alanine in Lassa fever virus Z. All of the mutations affected the expression of an LCMV minigenome and the infectivity of virus-like particles, but to greatly varying degrees. Interestingly, no mutations appeared to affect Z-mediated budding or association with viral GP. Our findings provide direct experimental evidence supporting a role for Z in the modulation of the activity of the viral ribonucleoprotein (RNP) complex and its packaging into mature infectious viral particles.Arenaviruses are the causative agents of a number of human diseases, including lymphocytic choriomeningitis, Lassa fever, and Bolivian hemorrhagic fever. These viruses are carried asymptomatically in wild rodents and are transmitted through contact with contaminated excretions. Endemic infection in these rodents maintains a reservoir of virus that can reemerge in human populations as outbreaks (1,18,30) or as novel pathogenic species (6). No FDA-licensed vaccines exist for these viruses, and current antiarenaviral therapy is limited to the off-label use of the nucleoside analogue ribavirin, which has had mixed success in treating cases of arenaviral hemorrhagic fever (HF) disease, while being associated with significant side effects (5).The prototypic arenavirus, lymphocytic choriomeningitis virus (LCMV), is ubiquitous in wild rodents and can infect domesticated mice and hamsters. These infected hamsters have most recently been responsible for reported disease in humans (2, 34). Additionally, reports of transplant-associated LCMV disease and fatality highlight the clinical relevance of arenaviral infection in immunocompromised individuals (15). In addition, congenital transmission of LCMV has been implicated in a variety of clinical conditions that affect mainly the retina and brain (3, 4).Arenaviruses are enveloped viruses bearing a bi-segmented, negative-sense RNA genome. Each segment contains two open reading frames (ORFs) in the ambisense orientation that are separated by a noncoding intergenic region (IGR) and bounded at their 5Ј and 3Ј ends by untranslated regions (UTRs) that are critical for the control of viral R...

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“…Therefore, we directly Symptoms of LCMV infection in mice vary based on the timing of infection. 48 Although LCMV altered the expression of a greater number of host genes as compared with GFP-CVB3, both viruses profoundly affected host chemokine and immune response genes at the early time points analyzed. The substantial induction of MHC class I gene expression by LCMV may account for the high numbers of cytotoxic T lymphocytes typically observed following LCMV infection.…”

Section: Discussionmentioning

confidence: 92%

Distinct neural stem cell tropism, early immune activation, and choroid plexus pathology following coxsackievirus infection in the neonatal central nervous system

Puccini

Ruller

Robinson

et al. 2014

Laboratory Investigation

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Coxsackievirus B3 (CVB3) and lymphocytic choriomeningitis virus (LCMV) are both neurotropic RNA viruses, which can establish a persistent infection and cause meningitis and encephalitis in the neonatal host. Utilizing our neonatal mouse model of infection, we evaluated the consequences of early viral infection upon the host central nervous system (CNS) by comparing CVB3 and LCMV infection. Both viruses expressed high levels of viral protein in the choroid plexus and subventricular zone (SVZ), a region of neurogenesis. LCMV infected a greater number of cells in the SVZ and targeted both nestin þ (neural progenitor cell marker) and olig2 þ (glial progenitor marker) cells at a relatively equal proportion. In contrast, CVB3 preferentially infected nestin þ cells within the SVZ. Microarray analysis revealed differential kinetics and unique host gene expression changes for each infection. MHC class I gene expression, several developmental-related Hox genes, and transthyretin (TTR), a protein secreted in the cerebrospinal fluid by the choroid plexus, were specifically downregulated following CVB3 infection. Also, we identified severe pathology in the choroid plexus of CVB3-infected animals at 48 h post infection accompanied by a decrease in the level of TTR and carbonic anhydrase II. These results demonstrate broader neural progenitor and stem cell (NPSC) tropism for LCMV in the neonatal CNS, whereas CVB3 targeted a more specific subset of NPSCs, stimulated a distinct early immune response, and induced significant acute damage in the choroid plexus.

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Lymphocytic choriomeningitis virus infection of the developing brain: critical role of host age

Abstract: The effect of LCMV infection on the developing brain strongly depends on host age at the time of infection. Much of the variability in neuropathology and outcome among children with congenital LCMV infection probably depends on the gestational age at which the infection occurs.

Cited by 51 publications

References 43 publications

Diseases of the central nervous system caused by lymphocytic choriomeningitis virus and other arenaviruses

Diseases of the central nervous system caused by lymphocytic choriomeningitis virus and other arenaviruses

Conserved Residues in Lassa Fever Virus Z Protein Modulate Viral Infectivity at the Level of the Ribonucleoprotein

Distinct neural stem cell tropism, early immune activation, and choroid plexus pathology following coxsackievirus infection in the neonatal central nervous system

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