Current Chemical Biology - Volume 4, Issue 3, 2010

Recently, several methods for infectious disorders have been developed. These include diagnostic methods on the basis of enhanced detection of pathogens, and therapy on the basis of effectively preventing infection or the proliferation of pathogens. Vaccination strategies for pathogens also contribute to reducing the incidence of infection. Accumulated knowledge on pathogens and disease-specific proteins such as receptors would provide useful information for exploring strategies for the treatment of infectious diseases. To discuss this special topic, scientists using various approaches to study the pathogenesis, diagnosis, and prevention of infectious diseases were invited. I am glad to have the honor to organize a Hot Topic issue for Current Chemical Biology and to experience working with eminent scientists to review research on infectious diseases. This issue includes articles on the following topics: candidate for anti-HIV-1 drugs written by Prof. Yoko Aida and Dr. Guangai Xue, recent studies on serological diagnosis of visceral leishmaniasis written by Drs. Yasuyuki Goto and Steven G. Reed, prospects of vaccines for Helicobacter-associated gastritis written by Yasuhisa Ano and colleagues, recent development on PMCA written by Dr. Natalia Fernandez-Borges and Prof. Joaquin Castilla, and influenza virus pathogenesis and their therapy written by Dr. Tomo Daidoji and colleagues. Hopefully, readers will enjoy this issue, obtain useful information for their own research, and be inspired with new ideas for future research on infectious diseases.

Current therapeutic strategies to inhibit the replication of human immunodeficiency virus type 1 (HIV-1) use a combination of drugs targeted at the viral reverse transcriptase, protease and integrase enzymes. The clinical advantages of this combination therapy are considerable, although the emergence of drug-resistant viral strains still presents a challenge. Import of the HIV-1 viral pre-integration complex (PIC) into the nucleus is a vital step in the process of viral replication in non-dividing cells (such as terminally differentiated macrophages). The interaction between the HIV-1 accessory protein, Vpr, and the cellular protein, importin-α, is critical for nuclear import of the PIC. Targeting the protein-protein interactions involved in the regulation of HIV-1 replication might be one way to combat the continued emergence of drug-resistant HIV-1 mutants. In this review, the current status of AIDS therapy, the mechanisms involved in the nuclear import of the PIC and the discovery of a new small molecular inhibitor of HIV-1 replication are discussed.

Protein Misfolding Cyclic Amplification (PMCA) is a 10 years old in vitro technique based on a cyclic process leading to accelerate prion replication in vitro. The technique has been modified and adapted several times since its inception: new ideas, more sophisticated equipments and new applications have been essential elements for its upgrading. PMCA has proved to be an efficient method mimicking in vitro some of the fundamental steps involved in prion replication in vivo. Thus, it can be used to efficiently replicate a variety of infectious prion strains/species maintaining their strain specificity. It is an eminent technique for TSE diagnosis and is being used for detecting prions in blood in presymptomatic samples. On the other hand, the in vitro prion replication has been decisive to prove the protein only hypothesis, thanks to the generation of infectious prions by using substrates based exclusively on recombinant PrPC without any mammalian or synthetic co-factors. These achievements, in addition to the ability of PMCA for generating de novo prions in vitro as well as its use for evaluating the potential risks of different prion strains to humans and animals, make this technique as one of the most important tools from the last decade in the prion field.

Because pandemic influenza virus infection can result in large-scale human death and have a major economic impact, influenza virus is one of the most important microbial pathogens. To control influenza virus, both clarification of the mechanisms by which the virus causes disease and the development of effective drugs and other therapies based on these mechanisms are needed. Virus infection often induces cell death, which can play an important role in disease pathogenesis, and influenza virus, in particular, has been shown to induce significant levels of apoptosis in vivo and in vitro. Over the past decade, the mechanisms by which viral and cellular factors modulate apoptosis induction in influenza virus-infected cells have been revealed. Viral proteins such as hemagglutinin, neuraminidase, M1, NS1, and PB1-F2 have been shown to be involved in apoptosis induction through extrinsic or intrinsic apoptotic pathways. On the other hand, several drugs with different mechanisms of action and a neutralizing monoclonal antibody (mAb) are currently used to control influenza virus. A better understanding of both how influenza virus infects host cells and the intracellular signaling pathways that are activated by infection is essential for the development of antiviral drugs and other effective therapies.

Helicobacter pylori (H. pylori) infects the stomach of more than 50% of humans and causes chronic gastritis in most infected individuals. H. pylori has developed mechanisms to survive the harsh gastric environment. In the host infected with H. pylori, various immune cells infiltrate into the infected gastric mucosa and then severe inflammatory responses occur. This severe inflammation, however, is not able to clear H. pylori and the process may contribute to the associated disease pathogenesis. Toll-like receptor 2 (TLR2) and Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) might be essential for activation of innate immunity against H. pylori infections. Type 1 helper T cells and regulatory T cells induced in stomach and Peyer's patches play an important role in the associated chronic inflammation. Recently, vaccines targeting various factors associated with H. pylori infection have been developed. This review provides information on the mechanisms of the host immune system response against H. pylori infections and the characteristics of H. pylori that enable it to evade host defenses.

Visceral leishmaniasis (VL) is the most severe form of leishmaniasis and results from parasitic infection by certain species of the protozoan genus Leishmania. Because VL is often fatal unless treated, rapid and accurate diagnosis of the disease is indispensable for case control. Currently, the gold standard diagnosis of VL is detection of parasites in a spleen or bone marrow aspirate. Because this method is invasive, time-consuming, and not sufficiently sensitive, rendering it inefficient, alternative methods including serological diagnosis have been developed. The 'first generation' serological tests that detect antibodies to Leishmania parasites in peripheral blood, serum or plasma, have utilized crude antigen, e.g., whole parasites or parasite lysate, that often have cross-reactivity / low specificity issues. As a result, efforts have been focused on characterizing antigens for 'second generation' diagnostic tests. The best example of such defined antigens is the recombinant K39 protein, or rK39, which contains a 39-amino acid repeat, and diagnostic tests based on this antigen are now commercially available and used world-wide. This review discusses advances in and the current status on antigen discovery for antibody detection-type diagnostic tests of visceral leishmaniasis.

Virus-like particles (VLPs) are viral coats formed by the self-assembly of the components of viruses excluding their genetic material. These particles may be used as vectors to transport molecules chemically attached on the VLP surface, or as vessels for the systemic delivery of pharmacologically important molecules as drugs, siRNAs, genes, mRNAs, magnetic nanoparticles, quantum dots and other medical-imaging aids. Herein we review the recent advances in heterologous production and purification of VLPs, the current trends in chemical modification of VLPs, and the advances on the application of VLPs as vectors, tools for medical imaging and materials for nanotechnology.

The signaling enzyme Phospholipase D (PLD) has been implicated in numerous cell biological processes, including Ras activation, cell spreading, stress fiber formation, chemotaxis, and vesicular trafficking during neurotransmitter and hormonal release. These observations have been mostly obtained from cell culture experiments using a primary alcohol to inhibit PLD activity or by modulating endogenous expression levels of the PLD1 and PLD2 isoforms. Since modulating PLD levels can have non-specific long-term effects and alcohols have been described to cause PLD-independent deleterious effects, the identification of potent specific small molecule PLD inhibitors is an important advance for the field. In this review, I will highlight the recent identification and characterization of chemical PLD inhibitors and describe their potential therapeutic interest in the treatment of human brain diseases/disorders and cancer metastasis.

Nitric oxide (NO) is involved in many physiological and pathological brain processes. NO is probably the smallest and most versatile bioactive molecule identified. NO signaling in excitable tissues requires rapid and controlled delivery of NO to specific cellular targets. This tight control of NO signaling is largely regulated at the level of its biosynthesis. NO production might lead either to toxicity or to neuroprotection depending on the level of NO, the location of NO production, the extent of oxidative stress and the type of neurodegenerative process. It has been suggested that NO directly acts as an antioxidant. This protective effect is mediated by small fluxes of NO (<1 μmol/L). This is consistent with the fact that NO terminates lipid peroxidation reactions and suggests that the production of NO is a major protective mechanism against oxidative stress in vivo. In fact it has been demonstrated, in vitro as well as in vivo, that during brain insult NO might be part of the physiological response to injury. In general, it is accepted that a normal pathophysiologic response of the damaged tissue may involve controlled NO production and the inhibition of this response may interfere with the normal repair process. Nevertheless, it has been suggested that a high production of NO after the induction of iNOS expression can interact with superoxide anion generated by the mitochondria or by other mechanisms, leading to the formation of the potent oxidant species peroxynitrite. These events would result in cell damage and altered neuronal physiological function. The present review focuses on the role of NO as an important neuromodulator that can exert both neurotoxic and neuroprotective effects in different injuries.