Protection from fatal viral encephalomyelitis: AMPA receptor antagonists have a direct effect on the inflammatory response to infection

Greene, Ivorlyne P.; Lee, Eun Young; Prow, Natalie A.; Ngwang, Brownhilda; Griffin, Diane E.

doi:10.1073/pnas.0712390105

Cited by 42 publications

(46 citation statements)

References 63 publications

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“…�ack of CNS in�ammation was due to failure of treated mice to induce activation and proliferation of lymphocytes in secondary lymphoid tissue aer infection. Antibody responses were also suppressed by talampanel treatment, and virus clearance was delayed [25]. Also, it has been shown that CD4(+) T cells can promote progressive neuronal death and tissue injury, despite clearance of infectious virus [26].…”

Section: Immunity To Infection Sinv Encephalitis In Mice Hasmentioning

confidence: 83%

The Pathogenesis of Alphaviruses

Atkins

2013

ISRN Virology

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Alphaviruses are enveloped single-stranded positive sense RNA viruses of the family Togaviridae. e genus alphavirus contains nine viruses, which are of medical, theoretical, or economic importance, and which will be considered. Sindbis virus (SINV) and Semliki Forest (SFV), although of some medical importance, have largely been studied as models of viral pathogenicity. In mice, SINV and SFV infect neurons in the central nervous system and virulent strains induce lethal encephalitis, whereas avirulent strains of SFV induce demyelination. SFV infects the developing foetus and can be teratogenic. Venezuelan Equine Encephalitis virus, Eastern Equine Encephalitis virus, and Western Equine Encephalitis virus can induce encephalitis in horses and humans. ey are prevalent in the Americas and are mosquito transmitted. Ross River virus, Chikungunya virus (CHIKV), and O'nyong-nyong virus (ONNV) are prevalent in Australasia, Africa and Asia, and Africa, respectively. ONNV virus is transmitted by Anopheles mosquitoes, while the other alphaviruses are transmitted by culicine mosquitoes. CHIKV has undergone adaptation to a new mosquito host which has increased its host range beyond Africa. Salmonid alphavirus is of economic importance in the farmed salmon and trout industry. It is postulated that future advances in research on alphavirus pathogenicity will come in the �eld of innate immunity.

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Section: Immunity To Infection Sinv Encephalitis In Mice Hasmentioning

confidence: 83%

The Pathogenesis of Alphaviruses

Atkins

2013

ISRN Virology

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“…Entry of inflammatory cells into the CNS from the periphery is essential for the clearance of infectious virus (14,34), and previous studies have shown that noncytolytic effectors of virus clearance include IFN-␥ and antiviral IgG (4,23). CD8…”

Section: Discussionmentioning

confidence: 99%

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

Metcalf

Griffin

2011

J Virol

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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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“…96 Protection from fatal disease was observed upon treatment with the AMPA receptor antagonist talampanel, a drug currently undergoing clinical evaluation for the treatment of gliomas. 97 Attenuation of CNS inflammation but no decrease in viral replication was observed upon treatment with talampanel, suggesting that compounds capable of decreasing CNS inflammation may provide a therapeutic benefit in alphavirus infections.…”

Section: Candidate Neuroprotective Interventionsmentioning

confidence: 96%

Alphavirus Antiviral Drug Development: Scientific Gap Analysis and Prospective Research Areas

Reichert

Clase

Bacetty

et al. 2009

Biosecurity and Bioterrorism: Biodefense Strategy, Practice, an

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The New World alphaviruses Venezuelan equine encephalitis virus (VEEV), eastern equine encephalitis virus (EEEV), and western equine encephalitis virus (WEEV) pose a significant threat to human health as the etiological agents of serious viral encephalitis through natural infection as well as through their potential use as a biological weapon. At present, there is no FDA-approved medical treatment for infection with these viruses. The Defense Threat Reduction Agency, Joint Science and Technology Office for Chemical and Biological Defense (DTRA/JSTO), is currently funding research aimed at developing antiviral drugs and vaccines against VEEV, EEEV, and WEEV. A review of antiviral drug discovery efforts for these viruses revealed significant gaps in the data, assays, and models required for successful drug development. This review provides a description of these gaps and highlights specific critical research areas for the development of a target-based drug discovery program for the VEEV, EEEV, and WEEV nonstructural proteins. These efforts will increase the probability of the successful development of a pharmaceutical intervention against these viral threat agents.

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Protection from fatal viral encephalomyelitis: AMPA receptor antagonists have a direct effect on the inflammatory response to infection

Cited by 42 publications

References 63 publications

The Pathogenesis of Alphaviruses

The Pathogenesis of Alphaviruses

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

Alphavirus Antiviral Drug Development: Scientific Gap Analysis and Prospective Research Areas

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