New Insights into Measles Virus Brain Infections

Watanabe, Shumpei; Shirogane, Yuta; Sato, Yuma; Hanabusa, Takao; Yanagi, Yusuke

doi:10.1016/j.tim.2018.08.010

Cited by 53 publications

(62 citation statements)

References 69 publications

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“…Defects in the M protein results in the failure to form virus particle facilitating persistence of measles virus in neuronal cells. Failure to form virus particle also helps virus evading neutralizing antibodies …”

Section: Genetic Differences Between Sspe Viruses and Wild Measles Virusmentioning

confidence: 99%

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Subacute sclerosing panencephalitis

Garg

Mahadevan

Malhotra

et al. 2019

Reviews in Medical Virology

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Summary Subacute sclerosing panencephalitis (SSPE) is a slowly progressive brain disorder caused by mutant measles virus. SSPE affects younger age groups. SSPE incidence is proportional to that of measles. High‐income countries have seen substantial decline in SSPE incidence following universal vaccination against measles. SSPE virus differs from wild measles virus. Measles virus genome recovered from the autopsied brain tissues demonstrates clustered mutations in virus genome particularly in the M gene. These mutations destroy the structure and functioning of the encoded proteins. Complete infectious virus particle has rarely been recovered from the brain. Human neurons lack required receptor for entry of measles virus inside the neurons. Recent in vitro studies suggest that mutations in F protein confer hyperfusogenic properties to measles virus facilitating transneuronal viral spread. The inflammatory response in the brain leads to extensive tissue damage. Clinically, SSPE is characterized by florid panencephalitis. Clinically, SSPE is characterized by cognitive decline, periodic myoclonus, gait abnormalities, vision loss, and ultimately to a vegetative state. Chorioretinitis is a common ocular abnormality. Electroencephalography (EEG) shows characteristic periodic discharges. Neuroimaging demonstrates periventricular white matter signal abnormalities. In advanced stages, there is marked cerebral atrophy. Definitive diagnosis requires demonstration of elevated measles antibody titers in cerebrospinal fluid (CSF). Many drugs have been used to stabilize the course of the disease but without evidence from randomized clinical trials. Six percent of patients may experience prolonged spontaneous remission. Fusion inhibitor peptide may, in the future, be exploited to treat SSPE. A universal vaccination against measles is the only proven way to tackle this menace currently.

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Section: Genetic Differences Between Sspe Viruses and Wild Measles Virusmentioning

confidence: 99%

“…Fusion inhibitor peptide suppresses membrane fusion mediated by hyperfusogenic measles virus. Fusion inhibitor peptide might in future be exploited to treat SSPE …”

Section: Fusion Inhibitor Peptidementioning

confidence: 99%

Subacute sclerosing panencephalitis

Garg

Mahadevan

Malhotra

et al. 2019

Reviews in Medical Virology

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“…Moreover, 5-10 years after resolution of the primary infection, persistent MeV infections cause lethal subacute sclerosing panencephalitis in about 1 in 10,000 cases, or possibly at a higher incidence when very young children are infected (78,79). A neural receptor accounting for these pathologies has been sought but not yet identified (80). Alternative mechanisms that may account for neuro-invasion include MeV delivery to the brain by SLAM-expressing infected immune cells and a newly discovered form of cytoplasm transfer occurring between nectin-4 -expressing epithelial cells and nectin-1expressing neurons (81).…”

Section: Mev Binds Two Proteins Causing Both Respiratory Disease Andmentioning

confidence: 99%

Receptor-mediated cell entry of paramyxoviruses: Mechanisms, and consequences for tropism and pathogenesis

Navaratnarajah

Generous

Yousaf

et al. 2020

Journal of Biological Chemistry

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Research in the last decade has uncovered many new paramyxoviruses, airborne agents that cause epidemic diseases in animals including humans. Most paramyxoviruses enter epithelial cells of the airway using sialic acid as a receptor and cause only mild disease. However, others cross the epithelial barrier and cause more severe disease. For some of these viruses, the host receptors have been identified, and the mechanisms of cell entry have been elucidated. The tetrameric attachment proteins of paramyxoviruses have vastly different binding affinities for their cognate receptors, which they contact through different binding surfaces. Nevertheless, all input signals are converted to the same output: conformational changes that trigger refolding of trimeric fusion proteins and membrane fusion. Experiments with selectively receptor-blinded viruses inoculated into their natural hosts have provided insights into tropism, identifying the cells and tissues that support growth and revealing the mechanisms of pathogenesis. These analyses also shed light on diabolically elegant mechanisms used by morbilliviruses, including the measles virus, to promote massive amplification within the host, followed by efficient aerosolization and rapid spread through host populations. In another paradigm of receptor-facilitated severe disease, henipaviruses, including Nipah and Hendra viruses, use different members of one protein family to cause zoonoses. Specific properties of different paramyxoviruses, like neurotoxicity and immunosuppression, are now understood in the light of receptor specificity. We propose that research on the specific receptors for several newly identified members of the Paramyxoviridae family that may not bind sialic acid is needed to anticipate their zoonotic potential and to generate effective vaccines and antiviral compounds.

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“…Morbilliviruses, including MeV and canine distemper, can cause neurological diseases. However, a neuronal receptor has not yet emerged (Alves et al, 2015;Ehrengruber et al, 2002;Lawrence et al, 2000;Makhortova et al, 2007;Watanabe et al, 2015Watanabe et al, , 2019. We find that NECT can spread MeV infections from epithelial cells to primary neurons, which is possibly the first step of neuropathology.…”

Section: Discussionmentioning

confidence: 83%

“…Receptors determine tropism and pathogenesis of MeV and the related animal morbilliviruses (Mateo et al, 2014a), which initially use the signaling lymphocytic activation molecule (SLAM, also known as SLAMF1 or CD150) to enter immune cells and cause immunosuppression (Tatsuo et al, 2000), and then N4 to infect the upper respiratory epithelia and to exit the host (Birch et al, 2013;Mateo et al, 2014b;Mühlebach et al, 2011;Noyce et al, 2011Noyce et al, , 2013Pratakpiriya et al, 2012). Since morbilliviruses also cause neurological diseases (Bellini et al, 2005;Cattaneo et al, 1988;da Fontoura Budaszewski and von Messling, 2016;Ludlow et al, 2015;Rudd et al, 2006), a neuronal receptor has been postulated but a consensus candidate has not emerged (Alves et al, 2015;Ehrengruber et al, 2002;Lawrence et al, 2000;Makhortova et al, 2007;Watanabe et al, 2015Watanabe et al, , 2019. With this in mind, we assessed whether the process we discovered can transfer MeV infections from N4-expressing epithelial cells to N1-expressing neurons.…”

Section: Introductionmentioning

confidence: 99%

Trans-endocytosis elicited by nectins transfers cytoplasmic cargo, including infectious material, between cells

Generous

Harrison

Troyanovsky

et al. 2019

Journal of Cell Science

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Here, we show that cells expressing the adherens junction protein nectin-1 capture nectin-4-containing membranes from the surface of adjacent cells in a trans-endocytosis process. We find that internalized nectin-1-nectin-4 complexes follow the endocytic pathway. The nectin-1 cytoplasmic tail controls transfer: its deletion prevents trans-endocytosis, while its exchange with the nectin-4 tail reverses transfer direction. Nectin-1-expressing cells acquire dyelabeled cytoplasmic proteins synchronously with nectin-4, a process most active during cell adhesion. Some cytoplasmic cargo remains functional after transfer, as demonstrated with encapsidated genomes of measles virus (MeV). This virus uses nectin-4, but not nectin-1, as a receptor. Epithelial cells expressing nectin-4, but not those expressing another MeV receptor in its place, can transfer infection to nectin-1expressing primary neurons. Thus, this newly discovered process can move cytoplasmic cargo, including infectious material, from epithelial cells to neurons. We name the process nectin-elicited cytoplasm transfer (NECT). NECT-related trans-endocytosis processes may be exploited by pathogens to extend tropism. This article has an associated First Person interview with the first author of the paper.

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New Insights into Measles Virus Brain Infections

Cited by 53 publications

References 69 publications

Subacute sclerosing panencephalitis

Subacute sclerosing panencephalitis

Receptor-mediated cell entry of paramyxoviruses: Mechanisms, and consequences for tropism and pathogenesis

Trans-endocytosis elicited by nectins transfers cytoplasmic cargo, including infectious material, between cells

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