Comparative analysis of protein interaction networks reveals that conserved pathways are susceptible to HIV-1 interception

BACKGROUND: Human immunodeficiency virus type one (HIV-1) is the major pathogen that causes the acquired immune deficiency syndrome (AIDS). With the availability of large-scale protein-protein interaction (PPI) measurements, comparative network analysis can provide a promising way to study the host-virus interactions and their functional significance in the pathogenesis of AIDS. Until now, there have been a large number of HIV studies based on various animal models. In this paper, we present a novel framework for studying the host-HIV interactions through comparative network analysis across different species. RESULTS: Based on the proposed framework, we test our hypothesis that HIV-1 attacks essential biological pathways that are conserved across species. We selected the Homo sapiens and Mus musculus PPI networks with the largest coverage among the PPI networks that are available from public databases. By using a local network alignment algorithm based on hidden Markov models (HMMs), we first identified the pathways that are conserved in both networks. Next, we analyzed the HIV-1 susceptibility of these pathways, in comparison with random pathways in the human PPI network. Our analysis shows that the conserved pathways have a significantly higher probability of being intercepted by HIV-1. Furthermore, Gene Ontology (GO) enrichment analysis shows that most of the enriched GO terms are related to signal transduction, which has been conjectured to be one of the major mechanisms targeted by HIV-1 for the takeover of the host cell. CONCLUSIONS: This proof-of-concept study clearly shows that the comparative analysis of PPI networks across different species can provide important insights into the host-HIV interactions and the detailed mechanisms of HIV-1. We expect that comparative multiple network analysis of various species that have different levels of susceptibility to similar lentiviruses may provide a very effective framework for generating novel, and experimentally verifiable hypotheses on the mechanisms of HIV-1. We believe that the proposed framework has the potential to expedite the elucidation of the important mechanisms of HIV-1, and ultimately, the discovery of novel anti-HIV drugs

A zebrafish model to study the schistosome egg granuloma

Schistosomiasis is a disease caused by parasitic flatworms which reside within the venules of their human host. The disease pathology is caused by the eggs which they produce, and is primarily characterized by the granulomas which form around them. While the granulomas have pathological consequences to the host, they are thought to be essential to facilitate egg expulsion and completion of the parasite life cycle. Here, I have developed a larval zebrafish model to study the formation of the schistosome egg granuloma in detail within an optically transparent animal. I have developed the tools and techniques for implantation of individual Schistosoma mansoni eggs into zebrafish, followed by intravital microscopy to observe the formation of the schistosome egg granuloma. Within the zebrafish, eggs induce the formation of epithelioid granulomas, as in mammalian models. I find that while mature schistosome eggs induced granuloma formation, immature eggs do not, and this is due to their eggshell functioning as an immunologically inert barrier between the parasite and host. Complemented by the finding that only mature eggs are shed in both mice and humans, these findings indicate that immature parasite eggs avoid foreign body granuloma formation to prevent premature expulsion during their host-dependent development. Then, after completing development, the mature egg secretes antigens through its eggshell to promote granuloma formation and expulsion to complete its life cycle. I investigate the host and parasite factors involved in granuloma formation, and demonstrate that TNF receptor 1 signaling is not required for either initial macrophage recruitment or granuloma formation, but does contribute to granuloma enlargement. In contrast, the major egg antigen, omega-1, utilizes its RNase activity to induce initial macrophage recruitment