Understanding polyomavirus CNS disease – a perspective from mouse models

Abstract

JC polyomavirus (JCPyV), a ubiquitous human pathogen, causes several devastating brain diseases in immune compromised individuals. The most notable of these JCPyV-associated CNS diseases is the frequently fatal demyelinating brain disease progressive multifocal leukoencephalopathy (PML).PML, an AIDS-defining disease in the pre-cART epoch, has emerged as a life-threatening complication in patients receiving immunomodulatory agents for autoimmune and inflammatory disorders and treatment for certain hematological malignancies. Among the rapidly expanding list of PML-associated biologics, natalizumab (Tysabri ® ) has the highest incidence and is an ominous sequela for multiple sclerosis (MS) patients who otherwise benefit from dramatic reductions in relapses using this immunomodulatory agent. Drug withdrawal, the only therapeutic option for PML, is often complicated by a high-mortality cerebral inflammatory reaction. No anti-JCPyV agents are Accepted ArticleThis article is protected by copyright. All rights reserved available. Lack of a tractable animal model of polyomavirus-induced central nervous system (CNS) disease is an acknowledged bottleneck to elucidating PML pathogenesis, immunological mechanisms that control JCPyV, in vivo evaluation of agents that inhibit polyomavirus replication in tissue culture and uncovering early events that presage JCPyV-associated neuropathology. The natural virus-host mouse polyomavirus (MuPyV) model has recently been developed to explore mechanisms of polyomavirus-associated CNS disease. In this review, we will cover the benefits of using the MuPyV model to answer fundamental questions about innate and adaptive immune control of JCPyV, the impact of immunomodulation on JCPyV pathogenesis, and how this MuPyV CNS infection model will help improve criteria for identifying patients at risk for JCPyV-associated CNS diseases before development of irreversible lesions.

Polyomavirus Wakes Up and Chooses Neurovirulence

“…Alternatively, the immune system maintains a subclinical smoldering infection. In an immunocompetent host, B cells and T cells control lytic infection because deficiencies in either B cells or T cells allow MuPyV to cause disease [ 14 , 25 , 114 , 120 , 121 , 122 , 123 , 124 ].…”

“…Mouse polyomavirus (MuPyV), the inaugural polyomavirus, has been established as a model for studying CNS-associated polyomavirus infection [ 14 ]. MuPyV is prevalent in wild mouse populations [ 15 ] and, like JCPyV, causes an asymptomatic and persistent infection in its immunocompetent host [ 16 , 17 ].…”

Viral Proteins with PxxP and PY Motifs May Play a Role in Multiple Sclerosis

“…Finally, human polyomavirus 2 or JC virus (JCV) is another highly ubiquitous, latent virus, with associations to MS. It is linked to several brain diseases, particularly in immune-compromised patients [121], such as progressive multifocal leukoencephalopathy (PML) [122]. The link between JCV, PML and MS is indirect: PML was first reported after the α4 integrin monoclonal antibody natalizumab, approved for treatment of multiple sclerosis, was widely used [123].…”

Comparando a apresentação por imagem da leucoencefalopatia multifocal progressiva em pacientes com infecção pelo HIV e em pacientes em uso de natalizumab

“…Os linfócitos Th1 possuem funções efetoras diversas, merecendo destaque a secreção da citocina interferon-γ (IFN-γ), por meio da qual fazem aumentar a capacidade fagocítica dos macrófagos, os quais eliminam as células infectadas (12). Existem fortes evidências da grande importância das células Th1 para controle e erradicação da infecção (21,41).…”

“…À semelhança dos macrófagos, os linfócitos T efetores citotóxicos também eliminam células infectadas, não por meio de fagocitose, mas por meio da indução de apoptose e lesão da membrana celular. Existem evidências de que a sobrevivência e funcionamento adequado dos CTL depende dos linfócitos Th1 (13,20,22,41).…”