Abstract

Background

   Influenza A virus (IAV) infection is a serious public health problem
   not only in South East Asia but also in European and African countries.
   Scientists are using network biology to dig deep into the essential
   host factors responsible for regulation of virus infections.
   Researchers can explore the virus invasion into the host cells by
   studying the virus-host relationship based on their protein-protein
   interaction network.

Methods

   In this study, we present a comprehensive IAV-host protein-protein
   interaction network that is obtained based on the literature-curated
   protein interaction datasets and some important interaction databases.
   The network is constructed in Cytoscape and analyzed with its plugins
   including CytoHubba, CytoCluster, MCODE, ClusterViz and ClusterOne. In
   addition, Gene Ontology and KEGG enrichment analyses are performed on
   the highly IAV-associated human proteins. We also compare the current
   results with those from our previous study on Hepatitis C Virus
   (HCV)-host protein-protein interaction network in order to find out
   valuable information.

Results

   We found out 1027 interactions among 829 proteins of which 14 are viral
   proteins and 815 belong to human proteins. The viral protein NS1 has
   the highest number of associations with human proteins followed by NP,
   PB2 and so on. Among human proteins, LNX2, MEOX2, TFCP2, PRKRA and DVL2
   have the most interactions with viral proteins. Based on KEGG pathway
   enrichment analysis of the highly IAV-associated human proteins, we
   found out that they are enriched in the KEGG pathway of basal cell
   carcinoma. Similarly, the result of KEGG analysis of the common host
   factors involved in IAV and HCV infections shows that these factors are
   enriched in the infection pathways of Hepatitis B Virus (HBV), Viral
   Carcinoma, measles and certain other viruses.

Conclusion

   It is concluded that the list of proteins we identified might be used
   as potential drug targets for the drug design against the infectious
   diseases caused by Influenza A Virus and other viruses.

   Keywords: Influenza a virus, Hepatitis C virus, Protein-protein
   interaction networks, Cytoscape, KEGG

Introduction

   The first case of human infection with Influenza A Virus (IAV) was
   reported in Hong Kong in 1997. Since then, the virus has spread from
   South East Asia to Europe and Africa, and now it has become a serious
   threat to human life causing 250,000–500,000 deaths annually worldwide
   [[33]1–[34]3]. Although the risk of IAV virus to humans is sporadic, it
   has the potential to produce a severe pandemic because of its plethora
   of strains and strong capability to transmit easily from person to
   person [[35]4–[36]6]. Influenza A virus is a negative-sense RNA virus
   which belongs to the family Orthomyxoviridae [[37]7]. Its genome
   comprises eight segments, each of which encodes one or more proteins.
   The ten conventional proteins are M1, M2, PB1, PB2, NS1, NS2, NA, HA,
   PA and NP. In addition to these, IAV virus encodes several other
   proteins with complementary and frameshift sequences [[38]4, [39]7,
   [40]8].

   Protein interaction networks can help researchers gain innumerable
   insights into functional organizations of proteomes, life cycles of
   pathogens and molecular pathogen-host relationship. As a virus relies
   heavily on the host cellular machinery for its replication, the
   established intermolecular interactions between virus and host are
   probably necessary for its propagation [[41]9]. Thus based on the study
   of virus-host protein-protein interactions, scientists can find out the
   essential host factors that are enriched in the infectious pathway and
   might be used as potential drug targets [[42]10, [43]11]. In our
   previous study on the protein interaction network of Hepatitis C virus
   (HCV) with host Homo sapiens, we did find out some important proteins
   that might serve as potential drug targets for the treatment of HCV
   infections.

   The goal of our study is to construct a comprehensive protein
   interaction network of IAV with human host by integrating both
   small-scale and large-scale researches carried out experimentally or
   computationally. Based on the network, the IAV-host relationship can be
   explored at a molecular level in terms of the biochemical pathways, and
   the important human proteins can be dug out which are highly involved
   in the IAV infectious pathway.

Materials and methods

Data collection

   The first step of this study is to get a state-of-the-art picture of
   the studies on IAV specifically in the context of protein-protein
   interactions. In order to obtain the related literature, an advanced
   search for articles is performed in PubMed using multiple keywords
   restricted to protein-protein interactions between IAV and Homo
   sapiens. As a result, we got 2005 research papers involving IAV-human
   protein-protein interactions, and among them 19 papers contain the
   protein-protein interaction data, as shown in Table [44]1. Besides the
   data, we also collected the protein-protein interaction data from
   databases including VirusMINT, IntAct and VirusMentha where the data
   were obtained using a variety of high-throughput protein-protein
   interaction detection methods including yeast two-hybrid,
   co-immunoprecipitation and mass spectrometry, and some computational
   methods.

Table 1.

   List of the papers and the numbers of IAV-human protein-protein
   interactions reported in them
   No.      Paper       No. of Interactions References