The pathogenesis of measles
ABSTRACT Measles is an important cause of childhood morbidity and mortality in developing countries. Measles virus (MV) is transmitted via the respiratory route and causes systemic disease. Over the last decade, identification of new cellular receptors and studies in animal models have challenged the historic concepts of measles pathogenesis. It is thought that MV enters the host by infection of alveolar macrophages and/or dendritic cells in the airways, and is amplified in local lymphoid tissues. Viremia mediated by infected CD150+ lymphocytes results in systemic dissemination. Infection of lymphocytes and dendritic cells in the respiratory submucosa facilitates basolateral infection of epithelial cells via the newly identified receptor Nectin-4. Concomitant and extensive epithelial damage may contribute to efficient transmission to the next host.
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Article: Measles immunometrics.Proceedings of the National Academy of Sciences 08/2012; 109(37):14724-5. DOI:10.1073/pnas.1212243109 · 9.81 Impact Factor
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ABSTRACT: Introduction: Replication-competent oncolytic measles virus (MV) strains preferentially infect and destroy a wide variety of cancer tissues. Clinical translation of engineered attenuated MV vaccine derivatives is demonstrating the therapeutic potential and negligible pathogenicity of these strains in humans. Areas covered: The present review summarizes the mechanisms of MV tumor selectivity and cytopathic activity as well as the current data on the oncolytic efficacy and preclinical testing of MV strains. Investigational strategies to reprogram MV selectivity, escape antiviral immunity and modulate the immune system to enhance viral delivery and tumor oncolysis are also discussed. Expert opinion: Clinical viral kinetic data derived from noninvasive monitoring of reporter transgene expression will guide future protocols to enhance oncolytic MV efficacy. Anti-measles immunity is a major challenge of measles-based therapeutics and various strategies are being investigated to modulate immunity. These include the combination of MV therapy with immunosuppressive drugs, such as cyclophosphamide, the use of cell carriers and the introduction of immunomodulatory transgenes and wild-type virulence genes. Available MV retargeting technologies can address safety considerations that may arise as more potent oncolytic MV vectors are being developed.Expert opinion on biological therapy 01/2013; 13(4). DOI:10.1517/14712598.2013.749851 · 3.65 Impact Factor
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ABSTRACT: Introduction: The measles virus is a major human pathogen responsible for approximately 150,000 deaths annually. The disease is vaccine preventable and eradication of the virus is considered feasible, in principle. However, a herd immunity exceeding 95% is required to prevent sporadic viral outbreaks in a population. Declining disease prevalence, combined with public anxiety over the vaccination's safety, has led to increased vaccine refusal, especially in Europe. This has led to the resurgence of measles in some areas. Areas covered: This article discusses whether synergizing effective measles therapeutics with the measles vaccination could contribute to finally eradicating measles. The authors identify key elements in a desirable drug profile and review current disease management strategies and the state of experimental inhibitor candidates. The authors also evaluate the risk associated with viral escape from inhibition, and consider the potential of measles therapeutics in the management of persistent central nervous system (CNS) viral infection. Finally, the authors contemplate the possible impact of therapeutics in controlling the threat imposed by closely related zoonotic pathogens of the same genus as measles. Expert opinion: Efficacious therapeutics used for post-exposure prophylaxis of high-risk social contacts of confirmed index cases may aid measles eradication by closing herd immunity gaps; this is due to vaccine refusal or failure in populations with overall good vaccination coverage. The envisioned primarily prophylactic application of measles therapeutics to a predominantly pediatric and/or adolescent population, dictates the drug profile. It also has to be safe and efficacious, orally available, shelf-stable at ambient temperature and amenable to cost-effective manufacturing.Expert Opinion on Drug Discovery 12/2013; 9(2). DOI:10.1517/17460441.2014.867324 · 3.47 Impact Factor