Abrogation of macrophage migration inhibitory factor decreases West Nile virus lethality
by limiting viral neuroinvasion
Alvaro Arjona, Harald G. Foellmer, Terrence Town, Lin Leng, Courtney McDonald, Tian
Wang, Susan J. Wong, Ruth R. Montgomery, Erol Fikrig, and Richard Bucala
The flavivirus West Nile virus (WNV) is an emerging pathogen that causes life-threatening
encephalitis in susceptible individuals. We investigated the role of the proinflammatory
cytokine macrophage migration inhibitory factor (MIF), which is an upstream mediator
of innate immunity, in WNV immunopathogenesis. We found that patients suffering
from acute WNV infection presented with increased MIF levels in plasma and in cerebrospinal
fluid. MIF expression also was induced in WNV-infected mice. Remarkably, abrogation
of MIF action by 3 distinct approaches (antibody blockade, small molecule pharmacologic
inhibition, and genetic deletion) rendered mice more resistant to WNV lethality.
Mif–/– mice showed a reduced viral load and inflammatory response in the
brain when compared with wild-type mice. Our results also indicate that MIF favors
viral neuroinvasion by compromising the integrity of the blood-brain barrier. In
conclusion, the data obtained from this study provide direct evidence for the involvement
of MIF in viral pathogenesis and suggest that pharmacotherapeutic approaches targeting
MIF may hold promise for the treatment of WNV encephalitis.
Read full research article
The Journal of Clinical Investigation Volume 117 Number 10 October
2007
The neurotropic herpes viruses: herpes simplex and varicella-zoster
Israel Steiner, Peter GE Kennedy, Andrew R Pachner
Summary
Herpes simplex viruses types 1 and 2 (HSV1 and HSV2) and varicella-zoster virus
(VZV) establish latent infection in dorsal root ganglia for the entire life of the
host. From this reservoir they can reactivate to cause human morbidity and mortality.
Although the viruses vary in the clinical disorders they cause and in their molecular
structure, they share several features that affect the course of infection of the
human nervous system. HSV1 is the causative agent of encephalitis, corneal blindness,
and several disorders of the peripheral nervous system; HSV2 is responsible for
meningoencephalitis in neonates and meningitis in adults. Reactivation of VZV, the
pathogen of varicella (chickenpox), is associated with herpes zoster (shingles)
and central nervous system complications such as myelitis and focal vasculopathies.
We review the biological, medical, and neurological aspects of acute, latent, and
reactivated infections with the neurotropic herpes viruses.
The Lancet Neurology - Vol. 6, Issue 11, November 2007, Pages 1015-1028
DOI:10.1016/S1474-4422(07)70267-3
Relapsing herpes simplex encephalitis: pathological confirmation of viral reactivation
Yamada, S, Kameyama, T, Nagaya, S, Hashizume, Y, Yoshida, M
Abstract
This case is reported to raise awareness of herpes simplex encephalitis as a
persisting brain disorder. A 66 year old immunocompetent man developed status epilepticus
and died of pneumonia in the course of progressive hemiparesis, cognitive decline,
and atrophy of the brain over a five year period after herpes simplex encephalitis.
In addition to a completely destroyed left temporal lobe, necropsy revealed active
encephalitis consisting of nectosis and lymphocyte infiltration with a large number
of intranuclear inclusions in the neurons and glial cells in the markedly oedematous
parenchyma of the right frontal and parietal lobes. Herpes simplex virus type 1
(HSV-1) antigen was detected by immunohistochemistry, HSV-1 DNA by in situ hybridisation,
and herpes simplex virus nucleocapsids by electronmicroscopy. These clinical and
pathological findings suggest that direct viral reactivation might result in a relapse
of herpes simplex encephalitis, causing progressive clinical deterioration associated
with the persistence of HSV-1 in the brain. This is the first case report demonstrating
HSV-1 antigen, HSV-1 DNA, and herpes simplex virus necleocapsids in a case of relapsing
herpes simplex encepalitis.
Yamada: J Neurol Neurosurg Psychiatry, Volume 74(2), February 2003. 262-264