CMV Labyrinthitis Induced in Immunodeficient SCID Mice

University Of California San Diego, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant):Experimental cytomegalovirus (CMV) labyrinthitis and encephalitis in SCID (severe combined immunodeficiency) mutant mice provides a useful model for the auditory system pathologies and hearing loss observed in immunodeficient patients, like those with acquired immune deficiency syndrome (AIDS). Auditory and vestibular system neuropathologies are common clinical signs in AIDS patients. Sensory system disorders in these immunocompromised patients arise primarily from opportunistic coinfections, and not from the direct effects of human immunodeficiency virus (HIV) infection. By far the most common opportunistic coinfection in AIDS is CMV. While CMV retinitis remains the most frequently recognized sensory system pathology in AIDS, up to 60 percent of AIDS patients reportedly experience CMV induced auditory and vestibular system neuro-otological disorders. CMV exhibits strict species-specificity, and therefore it is not possible to develop an animal model using human virus. However, while inimunocompetent mice are resistant to munne CMV (MCMV) infection, we have demonstrated that intrathecal (i.e., CSF) inoculation of SCID mice with 68 PFU of MCMV induces labyrinthitis, encephalitis and sensorineural hearing losses which closely resemble human disease. We propose to utilize a new recombinant MCMV expressing an enhanced green fluorescent protein reporter gene (rMCMV) in our SCID) mouse model to investigate the following basic questions: 1) How do cellular tropisms influence rMCMV neuropathogenesis in the peripheral and central auditory nervous system? 2) By what mechanism is rMCMV propagated between cells in neural circuits within the auditory nervous system? 3) What are the roles of cellular calcium-binding protein expression, apoptosis, and DNA repair mechanisms in the evolution of rMCM labyrinthitis and encephalitis? 4) How does cytokine- and chemokine-specific immunity influence rMCMV clearance and neuropathogenesis in the auditory system? 5) How closely do the clinical signs of rMCMV infections in SCID mice resemble AIDS-associated neuropathologies in the auditory system of humans? An interdisciplinary approach will be used to investigate the clinical symptoms, immunologic, virologic, histopathologic, molecular biologic and electrophysiologic aspects of MCMV infections within the peripheral and central auditory system of immunodeficient SCID mice.