Measles virus infection of the CNS: human disease, animal models, and approaches to therapy

Reuter, Dajana; Schneider-Schaulies, J.

doi:10.1007/s00430-010-0153-2

Cited by 82 publications

(71 citation statements)

References 140 publications

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“…CNS complications of MV infection may occur soon after infection in the case of acute encephalomyelitis, or years after infection, as a result of viral persistence in subacute sclerosing panencephalitis (SSPE) and progressive infectious encephalitis or measles inclusion body encephalitis (MIBE). There are no specific therapies for acute complications of MV or for persistent MV infections (85)(86)(87)(88). Since we expect our proposed antiviral strategy to be host factor independent, it will fill a specific need for immunocompromised people at risk for MV infection, who cannot be vaccinated or do not respond adequately to vaccine.…”

Section: Discussionmentioning

confidence: 99%

Prevention of Measles Virus Infection by Intranasal Delivery of Fusion Inhibitor Peptides

Mathieu

Huey

Jurgens

et al. 2015

J Virol

100

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Measles virus (MV) infection is undergoing resurgence and remains one of the leading causes of death among young children worldwide despite the availability of an effective measles vaccine. MV infects its target cells by coordinated action of the MV H and the fusion (F) envelope glycoprotein; upon receptor engagement by H, the prefusion F undergoes a structural transition, extending and inserting into the target cell membrane and then refolding into a postfusion structure that fuses the viral and cell membranes. By interfering with this structural transition of F, peptides derived from the heptad-repeat (HR) regions of F can potently inhibit MV infection at the entry stage. We show here that specific features of H's interaction with its receptors modulate the susceptibility of MV F to peptide fusion inhibitors. A higher concentration of inhibitory peptides is required to inhibit F-mediated fusion when H is engaged to its nectin-4 receptor than when H is engaged to its CD150 receptor. Peptide inhibition of F may be subverted by continued engagement of receptor by H, a finding that highlights the ongoing role of H-receptor interaction after F has been activated and that helps guide the design of more potent inhibitory peptides. Intranasal administration of these peptides results in peptide accumulation in the airway epithelium with minimal systemic levels of peptide and efficiently prevents MV infection in vivo in animal models. The results suggest an antiviral strategy for prophylaxis in vulnerable and/or immunocompromised hosts. IMPORTANCE Measles virus (MV) infection causes an acute illness that may be associated with infection of the central nervous system (CNS)and severe neurological disease. No specific treatment is available. We have shown that parenterally delivered fusion-inhibitory peptides protect mice from lethal CNS MV disease. Here we show, using established small-animal models of MV infection, that fusion-inhibitory peptides delivered intranasally provide effective prophylaxis against MV infection. Since the fusion inhibitors are stable at room temperature, this intranasal strategy is feasible even outside health care settings, could be used to protect individuals and communities in case of MV outbreaks, and could complement global efforts to control measles.

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Section: Discussionmentioning

confidence: 99%

Prevention of Measles Virus Infection by Intranasal Delivery of Fusion Inhibitor Peptides

Mathieu

Huey

Jurgens

et al. 2015

J Virol

100

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“…From the genetic study of SSPE strains, it has been thought that defects of the M protein play a crucial role in MV neuropathogenicity (55,56). While cumulative mutations in the M protein may lead to the lack of virus particle formation and escape from host immune responses, the deletion of the M protein can also enhance membrane fusion (37).…”

Section: Discussionmentioning

confidence: 99%

Mutant Fusion Proteins with Enhanced Fusion Activity Promote Measles Virus Spread in Human Neuronal Cells and Brains of Suckling Hamsters

Watanabe

Shirogane

Suzuki

et al. 2013

J Virol

110

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“…Long-term maintenance of antiviral ASCs is essential for continued local Ab production and is likely to be important for the prevention of viral recrudescence. Retention of antiviral ASCs has been observed following other neurotropic virus infections, such as those caused by measles virus (38), West Nile virus (48), rabies virus (17), and mouse hepatitis virus (52,53). Clinical evidence of the importance of sustained suppression of virus replication in the CNS comes from experience with rituximab (anti-CD20) for the elimination of B cells and with natalizumab (anti-VLA-4) for prevention of the entry of inflammatory cells into the CNS, where a major complication has been reactivation of CNS virus infection (8,20).…”

Section: Igdmentioning

confidence: 99%

Alphavirus-Induced Encephalomyelitis: Antibody-Secreting Cells and Viral Clearance from the Nervous System

Metcalf

Griffin

2011

J Virol

104

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Sindbis virus (SINV) infection of the central nervous system (CNS) provides a model for understanding the role of the immune response in recovery from alphavirus infection of neurons. Virus clearance occurred in three phases: clearance of infectious virus (days 3 to 7), clearance of viral RNA (days 8 to 60), and maintenance of low levels of viral RNA (>day 60). The antiviral immune response was initiated in the cervical lymph nodes with rapid extrafollicular production of plasmablasts secreting IgM, followed by germinal center production of IgG-secreting and memory B cells. Alphaviruses of the family Togaviridae are an important cause of acute mosquito-borne viral encephalomyelitis in the Americas (7, 59). Neurons of the brain and spinal cord are the primary target cells, and recovery requires immune-mediated control of infection in these nonrenewable cells. Virus clearance from neurons poses unique challenges for the immune system. The restriction of the blood-brain barrier to immune effector entry into the central nervous system (CNS), reduced expression of major histocompatibility complex (MHC) classes I and II, and terminal differentiation of neurons make virus clearance more difficult (15). A noncytolytic process is needed to avoid irreversible neurologic damage, and the process must be effective to avoid chronic or progressive neurologic disease. Previous studies of immunodeficient mice infected with Sindbis virus (SINV), the prototype alphavirus, have shown that clearance of infectious virus from neurons within 7 to 8 days is mediated by gamma interferon (IFN-␥) produced by T cells and anti-E2 glycoprotein antibodies (Abs) produced by B cells (4, 23).Although infectious virus is cleared from the CNS to undetectable levels after infection, viral RNA encoding both structural and nonstructural viral proteins can be detected in the brains and spinal cords of SINV-infected BALB/c mice for at least a year after recovery (55,22). In severe combined immunodeficiency (SCID) mice, production of infectious SINV resumes as levels of passively transferred Ab decrease, indicating that persistent RNA is capable of renewed replication (22).Persistence of viral RNA in the CNS suggests the need for long-term immune-mediated suppression of SINV reactivation after the acute phase of infection. Previous studies of BALB/c mice have shown that the acute inflammatory response to SINV infection includes the infiltration of T cells and B cells into the CNS (18,40). Additional studies have shown that B-cell-deficient (MT) C57BL/6 mice are unable to clear infectious virus from cortical and hippocampal neurons and that initial successful SINV clearance from brain stem and spinal cord motor neurons is followed by virus reactivation after 18 to 22 days, demonstrating a critical role for Ab in recovery (4, 6). The presence of SINV-specific Ab-secreting cells (ASCs) in the brains of immunologically normal mice for at least a year after recovery from infection further suggests a role for intrathecal Ab production in the long-term suppres...

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Measles virus infection of the CNS: human disease, animal models, and approaches to therapy

Cited by 82 publications

References 140 publications

Prevention of Measles Virus Infection by Intranasal Delivery of Fusion Inhibitor Peptides

Prevention of Measles Virus Infection by Intranasal Delivery of Fusion Inhibitor Peptides

Mutant Fusion Proteins with Enhanced Fusion Activity Promote Measles Virus Spread in Human Neuronal Cells and Brains of Suckling Hamsters

Alphavirus-Induced Encephalomyelitis: Antibody-Secreting Cells and Viral Clearance from the Nervous System

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