Abstract
BackgroundDengue virus infection is a public health threat to hundreds of millions of individuals in the tropical regions of the globe. Although Dengue infection usually manifests itself in its mildest, though often debilitating clinical form, dengue fever, life-threatening complications commonly arise in the form of hemorrhagic shock and encephalitis. The etiological basis for the virus-induced pathology in general, and the different clinical manifestations in particular, are not well understood. We reasoned that a detailed knowledge of the global biological processes affected by virus entry into a cell might help shed new light on this long-standing problem.MethodsA bacterial two-hybrid screen using DENV2 structural proteins as bait was performed, and the results were used to feed a manually curated, global dengue-human protein interaction network. Gene ontology and pathway enrichment, along with network topology and microarray meta-analysis, were used to generate hypothesis regarding dengue disease biology.ResultsCombining bioinformatic tools with two-hybrid technology, we screened human cDNA libraries to catalogue proteins physically interacting with the DENV2 virus structural proteins, Env, cap and PrM. We identified 31 interacting human proteins representing distinct biological processes that are closely related to the major clinical diagnostic feature of dengue infection: haemostatic imbalance. In addition, we found dengue-binding human proteins involved with additional key aspects, previously described as fundamental for virus entry into cells and the innate immune response to infection. Construction of a DENV2-human global protein interaction network revealed interesting biological properties suggested by simple network topology analysis.ConclusionsOur experimental strategy revealed that dengue structural proteins interact with human protein targets involved in the maintenance of blood coagulation and innate anti-viral response processes, and predicts that the interaction of dengue proteins with a proposed human protein interaction network produces a modified biological outcome that may be behind the hallmark pathologies of dengue infection.
Highlights
Dengue virus infection is a public health threat to hundreds of millions of individuals in the tropical regions of the globe
Oligonucleotide primers used for the amplification of the cDNA for dengue structural proteins were obtained from the Stanford University PAN facility
Interactions were identified in the bacterial two-hybrid screen by assaying the individual baits against a whole brain, and a liver cDNA library, both cloned into pTRG vectors
Summary
Dengue virus infection is a public health threat to hundreds of millions of individuals in the tropical regions of the globe. Dengue infection usually manifests itself in its mildest, though often debilitating clinical form, dengue fever, life-threatening complications commonly arise in the form of hemorrhagic shock and encephalitis. The disease usually manifests itself in its mildest form, dengue fever, severe forms of the disease: dengue hemorrhagic fever and dengue shock syndrome frequently arise, and are responsible for the full unprocessed prM protein and may represent up to 40% of all extracellular particles in that setting. From two-hybrid technology and systems biology tools, provide evidence that dengue virus structural proteins establish direct interactions with human proteins participating in crucial coagulation and inflammatory responses. These observations may help to explain the faulty behavior of the coagulation pathway in subjects infected by dengue virus
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