Limits...
Dengue-2 structural proteins associate with human proteins to produce a coagulation and innate immune response biased interactome.

Folly BB, Weffort-Santos AM, Fathman CG, Soares LR - BMC Infect. Dis. (2011)

Bottom Line: A 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Federal University of Paraná, Pharmaceutical Sciences Post-graduation Program, Av. Pref. Lothário Meissner 632, CEP 80210-170, Curitiba-PR, Brazil.

ABSTRACT

Background: Dengue 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.

Methods: A 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.

Results: Combining 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.

Conclusions: Our 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.

Show MeSH

Related in: MedlinePlus

(A) Graphical representation of the interaction network from "figure 1A" after enrichment with first neighbors (level 2 interactions) for the 31 primary interactors. In (B), the same network seen in "A" with the nodes colored according to their gene ontology classifications.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3037883&req=5

Figure 2: (A) Graphical representation of the interaction network from "figure 1A" after enrichment with first neighbors (level 2 interactions) for the 31 primary interactors. In (B), the same network seen in "A" with the nodes colored according to their gene ontology classifications.

Mentions: Ontological analysis of the D2-H network, now including the level 2.351 interactions, again making use of DAVID, revealed that the categories "Blood coagulation", "Regulation of body fluid levels", "Cell death", "Response to wounding" and "Acute inflammatory response" were overrepresented (Table 3and Figure 2B) as were the KEGG pathways "Complement and coagulation cascades", "MAPK signaling", "TGF-beta signaling", "Focal adhesion", "Adherens junctions" and "Toll-like receptor signaling" (Table 3). Particularly important to this analysis, it seems that the dengue virus targets distinct pathways, as it has to deal with distinct biological processes in order to achieve stable infection.


Dengue-2 structural proteins associate with human proteins to produce a coagulation and innate immune response biased interactome.

Folly BB, Weffort-Santos AM, Fathman CG, Soares LR - BMC Infect. Dis. (2011)

(A) Graphical representation of the interaction network from "figure 1A" after enrichment with first neighbors (level 2 interactions) for the 31 primary interactors. In (B), the same network seen in "A" with the nodes colored according to their gene ontology classifications.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3037883&req=5

Figure 2: (A) Graphical representation of the interaction network from "figure 1A" after enrichment with first neighbors (level 2 interactions) for the 31 primary interactors. In (B), the same network seen in "A" with the nodes colored according to their gene ontology classifications.
Mentions: Ontological analysis of the D2-H network, now including the level 2.351 interactions, again making use of DAVID, revealed that the categories "Blood coagulation", "Regulation of body fluid levels", "Cell death", "Response to wounding" and "Acute inflammatory response" were overrepresented (Table 3and Figure 2B) as were the KEGG pathways "Complement and coagulation cascades", "MAPK signaling", "TGF-beta signaling", "Focal adhesion", "Adherens junctions" and "Toll-like receptor signaling" (Table 3). Particularly important to this analysis, it seems that the dengue virus targets distinct pathways, as it has to deal with distinct biological processes in order to achieve stable infection.

Bottom Line: A 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Federal University of Paraná, Pharmaceutical Sciences Post-graduation Program, Av. Pref. Lothário Meissner 632, CEP 80210-170, Curitiba-PR, Brazil.

ABSTRACT

Background: Dengue 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.

Methods: A 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.

Results: Combining 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.

Conclusions: Our 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.

Show MeSH
Related in: MedlinePlus