Infectious Disorders - Drug Targets (Formerly Current Drug Targets - Infectious Disorders) - Volume 12, Issue 1, 2012

As an Editor-in-Chief of the journal ‘Infectious Disorders - Drug Targets’, I am very pleased to announce that it is now an internationally well-recognized and competitive journal with an always growing audience in various areas of research, such as virology, bacteriology, medicinal chemistry, pharmacology, biochemistry, molecular biology and genomics. By publishing both timely in-depth review articles (see special issues) and original research works, it is actually an invaluable ‘tool’ that helps the scientists to update their education and to survey the main discoveries and developments in the variety of topics, which is often an asset to their own scientific research. Indeed, it appears to be of the utmost importance to cover the latest state of knowledge in each field to help researchers and clinicians opening new routes of investigation in this particularly ‘complex’ world of drug design, infectious diseases and related molecular targets. For 2012 (and upcoming years), we expect and strongly encourage the contribution of distinguished researchers and clinicians to the journal, which is a basis of its success and further development. Also, I would like to thank section editors and members of the editorial board for providing outstanding expertise in their respective fields; I congratulate Drs Matthew Honan and Ambreen Wasim (editorial office of Bentham Science Publishers) for the efficient promotion of our journal and their constant support and efforts to maintain its high standard. Finally, I wish the contributors and readers of the journal ‘Infectious Disorders - Drug Targets’ a happy and fruitful new year, expected to be rich in discoveries.

Conventional therapies for microbial infection including vaccines, antibiotics and antivirals principally target specific properties of the microbe, such as antigen expression, attachment proteins for host cell interaction and entry, and microbial enzymes involved in replication and assembly. The efficacy of such approaches to protect human populations from disease is limited by the ability of known microbial pathogens to mutate in order to evade immune detection or circumvent the activity of antimicrobial drugs, and also by the emergence of novel, previously uncharacterised, lethal microbes/strains, exemplified by zoonotic diseases such as SARS and influenza. As a result, increasing research effort has focussed on the molecular basis of host:pathogen interactions, with a view to identifying novel therapeutic targets. Central to the biology of intracellular pathogens (viruses and certain bacteria, protozoa and fungi) are specific interactions with host cell intracellular transport machinery including the cytoskeleton, the nucleocytoplasmic trafficking system, and membrane trafficking systems. These interactions enable cell entry and efficient intracellular trafficking of pathogens to their sites of replication, exemplified by neurotropic viruses that invade the periphery and traffic in neurons to the central nervous system. Furthermore, specific pathogen products have evolved to exploit subcellular trafficking mechanisms to enable targeting to compartments/organelles such as the nucleus and mitochondria, which may be physically separated from the compartment in which the microbe resides and replicates. This enables microbial subversion of fundamental cellular processes including transcription, apoptosis and innate immunity, and, thereby, reprogramming of host cells to create an environment conducive to infection and spread. Thus, these molecular interactions represent promising, as yet unexploited, targets for novel therapeutic approaches. Importantly, because such approaches would target host cell factors and processes, rather than the idiosyncrasies of specific microbes/strains, they would not be readily circumvented by microbial mutation, and may prove broadly applicable for the treatment of infections by diverse pathogens, including newly emerging microbes. Further, because pathogens, including relatively simple viruses, have evolved specific mechanisms to exploit trafficking pathways, their characterisation has made significant contributions to our understanding of complex subcellular trafficking mechanisms underlying normal cell biology. This issue aims to introduce the diversity and importance of host cell subcellular trafficking processes in the biology of human pathogens, and the significance of this area to the development of novel therapies. In the first review, “Tetraspanins: Gateways to Infection,” Peter Monk and Linda Partridge introduce the tetraspanins, a highly conserved protein superfamily with diverse functions in cell biology. The exploitation of tetraspanin functions in numerous human diseases serves to highlight the paradigm that diverse intracellular pathogens including bacteria, viruses, fungi and protozoa can target and modify many fundamental cellular processes including trafficking to facilitate infection, and that these processes can provide targets for intervention. In “Viral Product Trafficking to Mitochondria, Mechanisms and Roles in Pathogenesis”, Williamson et al. discuss the specific targeting of mitochondria by viral products, which provides viruses with the means to modify mitochondrial processes important to cellular metabolism, apoptosis and innate immunity. This enables viral modification of the cellular environment to conditions favourable for replication, regulation of cell death according to viral requirements, and evasion of cellular antiviral systems. The following article, “Subcellular Trafficking in Rhabdovirus Infection and Immune Evasion: A Novel Target for Therapeutics” by Oksayan et al., examines viral cell invasion and subsequent intracellular trafficking via microtubule-dependent transport to reach cytoplasmic viral “factories”, which may be localized at great anatomical distances from the initial infection site. The role of intricately regulated interactions of viral proteins with nuclear trafficking machinery, enabling cytoplasmic viruses to target nuclear functions including immune signalling is also introduced, and its potential for inhibition as a therapeutic strategy is discussed. In Younessi et al. “Modulation of Host Cell Nucleocytoplasmic Trafficking During Picornavirus Infection”, the theme of cytoplasmic virus-expressed protein interactions with the nucleus is further developed, highlighting mechanisms by which proteins from viruses such as polio and rhinovirus not only undergo regulated nuclear trafficking themselves, but specifically target and modify the nuclear trafficking apparatus to direct host cell biology to support viral propagation and suppress antiviral responses. Finally, in “Artificial Viruses: Exploiting Viral Trafficking for Therapeutics”, Dominic Glover describes how our increasing understanding of pathogen subcellular trafficking can have broad medical applications beyond antimicrobial therapy. In this context, pathogens are infiltrators of cellular transport systems that can reveal the mechanisms by which cargoes can be efficiently delivered to specific subcellular sites by regulated interaction with transport machinery. Armed with this knowledge, researchers are constructing tailored nanomachines able to deliver therapeutics to specific organelles, with great promise for the treatment of diseases such as cancer and genetic disorders. Our intention in this special edition is to introduce the theme of subcellular trafficking of pathogens and pathogen products as an essential component in the biology of intracellular pathogens, the exciting possibilities for new generations of therapeutics targeting these processes, and the paradoxical role of human pathogens in revealing the mechanisms of transport systems that have informed basic cell biology and medicine for the production of new drug delivery approaches for non-microbial diseases. We extend our thanks to both the authors and reviewers who have contributed to this project.

The tetraspanins constitute a conserved superfamily of four-span membrane proteins that are widely distributed in multi-cellular organisms. A characteristic property of tetraspanins is their ability to form lateral associations with one another and with other membrane proteins, giving rise to tetraspanin enriched microdomains (TEM) that are involved in the molecular organisation of many membrane-associated functions such as adhesion, fusion and trafficking. Increasing evidence suggests that intracellular pathogens, especially viruses, have “hijacked” tetraspanins as a means of entering, traversing and exiting cells during the course of infection. This article reviews current evidence for the role of tetraspanins in the uptake, trafficking and spread of viruses as well as intracellular bacteria, fungi and parasites. Finally, the prospects of targeting tetraspanins for therapeutic intervention in infections caused by such pathogens are discussed.

A wide variety of viruses cause significant morbidity and mortality in humans. However, targeted antiviral therapies have been developed for only a subset of these viruses, with the majority of currently licensed antiviral drugs targeting viral entry, replication or exit steps during the viral life cycle. Due to increasing emergence of antiviral drug resistant viruses, the isolation of multiple viral subtypes, and toxicities of existing therapies, there remains an urgent need for the timely development of novel antiviral agents, including those targeting host factors essential for viral replication. This review summarizes viral products that target mitochondria and their effects on common mitochondria regulated pathways. These viral products and the mitochondrial pathways affected by them provide potential novel targets for the rational design of antiviral drugs. Viral products alter oxidative balance, mitochondrial permeability transition pore, mitochondrial membrane potential, electron transport and energy production. Moreover, viruses may cause the Warburg Effect, in which metabolism is reprogrammed to aerobic glycolysis as the main source of energy. Finally, viral products affect proapoptotic and antiapoptotic signaling, as well as mitochondrial innate immune signaling. Because of their importance for the generation of metabolic intermediates and energy as well as cell survival, mitochondrial pathways are targeted by multiple independent viral products. Structural modifications of existing drugs targeted to mitochondrial pathways may lead to the development of novel antiviral drugs with improved efficacy and reduced toxicity.

Vesicular stomatitis virus (VSV) and Rabies Virus (RABV) are the prototypic members of the rhabdovirus family. These viruses have a particularly broad host range, and despite the availability of vaccines, RABV still causes more than 50,000 human deaths a year. Trafficking of the virion or viral particles is important at several stages of the replicative life cycle, including cellular entry, localization into the cytoplasmic inclusion bodies which primarily house the transcription and replication of the viral genome, and migration to the plasma membrane from whence the virus is released by budding. Intriguingly, specific viral proteins, VSV M and RABV P have also been shown to undergo intracellular trafficking independent of the other viral apparatus. These proteins are multifunctional, and play roles in antagonism of host processes, namely the IFN system, and as such enable viral evasion of the innate cellular antiviral response. A body of recent research has been aimed at characterizing the mechanisms by which these proteins are able to shuttle between and localize to various subcellular sites, including the nucleus, which is not required during the cytoplasmic replicative life cycle of the virus. This work has indicated that trafficking of these proteins plays a significant role in determining the ability of the viruses to replicate and cause infection, and as such, represents a viable target for development of a new generation of vaccines and prophylactic therapeutics which are required to battle these pathogens of human and agricultural significance.

Picornavirus infection is characterised by host cell shutoff, wherein host transcription and translation processes are severely impaired. Picornavirus proteins interact with host cell proteins, resulting in alterations in the host cell synthetic, signalling and secretory machinery, and facilitating transcription and translation of viral proteins to achieve increased virus replication and assembly. Among the many cellular pathways affected, recent studies have shown that disruption of nucleocytoplasmic trafficking via inhibition of the functions of the nuclear pore may be a common means of picornavirus- induced pathogenesis. Disruption of nuclear pore functions results in nuclear proteins being relocalised to the cytoplasm and reduced export of RNA, and may be a mechanism by which picornaviruses evade host cell defences such as interferon signalling, by blocking signal transduction across the nuclear membrane. However, the mechanisms used and the viral proteins responsible differ between different genera and even between viruses in the same genus. This review aims to summarise current understanding of the mechanisms used by picornaviruses to disrupt host cell nucleocytoplasmic trafficking.

Improved understanding of the signals that direct the intracellular transport of endogenous mammalian proteins, as well as the means by which viral invaders hijack transport pathways during infection, has revealed a plethora of methods for enhancing drug and gene delivery. Multi-component delivery vectors with virus-like functionality are being developed to assemble with therapeutic DNA into structured nanoparticles that are internalized and actively transported to specific locations within mammalian cells. Furthermore, the mimicking of viral mechanisms can be extended to nuclear maintenance and replication of exogenous DNA, through either site-specific integration into safe genomic regions, or extra- chromosomal maintenance as episomally replicating plasmids. The development of increasingly sophisticated artificial viruses has enormous potential to overcome numerous intracellular barriers that have, thus far, prevented efficient and sustained non-viral gene therapy.

Tat is a viral protein secreted from HIV infected cells and extra cellular Tat is suspected to prevent destruction of HIV infected cells from cells of the cellular immunity. The effect of anti retroviral therapy (ART) on Tat secretion has never been investigated. In this study, we tested for antibody reactivity against Tat variants representative of the main HIV subtypes in HIV positive patients receiving ART with undetectable viral loads (< 40 copies/mL) over the course of one year with a blood sampling every three months. For each of theses five blood sampling, an average of 50 % of patients had Anti-Tat IgG, it turned out that 86% of patients could recognize Tat at least in one blood sampling during the course of the study. Amazingly, anti-Tat IgG appeared and/or disappeared in 66 % of patients. Only 20% had anti-Tat IgG remaining persistently while 14% were consistently without anti Tat IgG in the five blood sampling. No significant correlation was found between anti-Tat IgG and CD4+ T cell, CD8+ T cell and B cell counts revealing the incapacity of these anti Tat IgG to neutralize extra cellular Tat. Interestingly the absence and then the appearance of anti-Tat IgG in patients suggest the presence of HIV infected cells in the blood that may constitute a significant reservoir of HIV infected cells. As a conclusion antiretroviral therapy does not block the secretion of Tat and may explain why HIV infected cells can survive in spite of an effective ART treatment.