An overview of current Italian studies on bacterial pathogenesis

World Journal of Microbiology and Biotechnology -     

An overview of the mechanisms of mutagenesis and carcinogenesis

Cancer is a genetic disease due to the accumulation of numerous mutations rendering the tumour cell insensitive to control by the local cellular environment and by the whole organism. Analysis of the frequency of appearance of human cancer as a function of age shows that between four and seven mutations in key genes are usually necessary to produce most human cancers. Interesting debates in the literature are concerned with the idea that normal mutation rates followed by selective advantage of mutated clones are enough to produce the numerous mutations found in human cancers. Alternatively, the mutator phenotype hypothesis is based on the idea that the normal mutation rates are insufficient to account for the multiple mutations found in tumours. It is, however, difficult not only to know this exact mutation frequency in cells but also to know the total number of cell divisions giving rise to a cancer. Therefore, during at least one step in the carcinogenic process, a mutator phenotype in target cells may occur due to mutations controlling the fidelity of DNA replication or DNA repair, the apoptosis pathways or the cell cycle checkpoint regulations. Among the multiple mutations found in human cancers such as gene amplification, chromosome alterations and translocations, point mutations are very important and the molecular mechanisms of their production are well documented. I will describe in detail the various mechanisms that a cell can use to produce point mutations due to lower fidelity in the DNA polymerisation step or to inefficient repair pathways. The presence of multiple mutations in human cancer is interesting not only in terms of understanding the carcinogenesis process in humans but also in eventually promoting strategies to decrease the efficiency of this process and to increase cancer therapy regimen.     

Oxidative stress in the pathogenesis of systemic scleroderma: An overview

Systemic sclerosis (SSc) is a rare disorder of the connective tissue characterized by fibrosis of the skin, skeletal muscles and visceral organs. Additional manifestations include activation of the immune system and vascular injury. SSc causes disability and death as the result of end‐stage organ failure. Two clinical subsets of the SSc are accepted: limited cutaneous SSc (lc‐SSc) and diffuse cutaneous SSc (dc‐SSc). At present, the aetiology and pathogenesis of SSc remain obscure, and consequently, disease outcome is unpredictable. Numerous studies suggest that reactive oxidizing species (ROS) play an important role in the pathogenesis of scleroderma. Over the years, several reports have supported this hypothesis for both lc‐SSc and dc‐SSc, although the specific role of oxidative stress in the pathogenesis of vascular injury and fibrosis remains to be clarified. The aim of the present review was to report and comment the recent findings regarding the involvement and role of oxidative stress in SSc pathogenesis. Biomarkers proving the link between ROS and the main pathological features of SSc have been summarized.     

Brain iron uptake and homeostatic mechanisms: An overview

Timely and adequate iron acquisition by the brain is essential to normal neurological function. Despite the numerous cognitive and neurological impairments that are associated with disruptions in brain iron acquisition, including both too much and too little iron, the mechanism and regulation of the mechanisms by which the brain acquires iron are poorly understood. In this article, we review the current state of knowledge regarding expression of iron transport proteins in the brain, brain iron uptake and discuss why a model for brain iron uptake must take into consideration the potentially competing influences on the endothelial cell between the status of iron in the brain versus the systemic iron status.     

The lipid A palmitoyltransferase PagP: molecular mechanisms and role in bacterial pathogenesis

Palmitoylated lipid A can both protect pathogenic bacteria from host immune defences and attenuate the activation of those same defences through the TLR4 signal transduction pathway. A palmitate chain from a phospholipid is incorporated into lipid A by an outer membrane enzyme PagP, which is an 8-stranded antiparallel beta-barrel preceded by an amino-terminal amphipathic alpha-helix. The PagP barrel axis is tilted by 25 degrees with respect to the membrane normal. An interior hydrophobic pocket in the outer leaflet-exposed half of the molecule functions as a hydrocarbon ruler that allows the enzyme to distinguish palmitate from other acyl chains found in phospholipids. Internalization of a phospholipid palmitoyl group within the barrel appears to occur by lateral diffusion from the outer leaflet through non-hydrogen-bonded regions between beta-strands. The MsbA-dependent trafficking of lipids from the inner membrane to the outer membrane outer leaflet is necessary for lipid A palmitoylation in vivo. The mechanisms by which bacteria regulate pagP gene expression strikingly reflect the corresponding pathogenic lifestyle of the bacterium. Variations on PagP structure and function can be illustrated with the known homologues from Gram-negative bacteria, which include pathogens of humans and other mammals in addition to pathogens of insects and plants. The PagP enzyme is potentially a target for the development of anti-infective agents, a probe of outer membrane lipid asymmetry, and a tool for the synthesis of lipid A-based vaccine adjuvants and endotoxin antagonists.     

Molecular mechanisms of LL-37-induced receptor activation: An overview

The human cathelicidin peptide LL-37 plays a crucial role in the immune system on many levels, from the first line of defense in epithelial cells to restoring the tissue after infection. On host cells, the majority of the LL-37-induced effects are mediated via the direct or indirect activation of several structurally unrelated cell surface receptors or intracellular targets. How LL-37 is able to affect multiple receptors is currently not well understood. So far, the mechanistic details underlying receptor activation are poorly investigated and evidence for a conventional ligand/receptor interaction is scarce. Over the past few decades, a large number of studies have reported on the activation of a receptor and/or components of the downstream signal transduction pathway induced by LL-37. This review summarizes the current knowledge on molecular mechanisms underlying LL-37-induced receptor activation.     

Translocation of bacterial proteins--an overview

Recent progress in the understanding of the nature of the extraordinary variety of protein translocation systems, mainly in Gram negative bacteria, is reviewed. This takes us from the insertion of proteins into the inner membrane via the sophisticated Sec apparatus, the lethal injection of Type III proteins into host cells and on to the beautiful machine that assembles the flagellum. Attempts are made to establish some order, some common principles that might explain the variety and the complexity of some systems. The fundamentals considered are the nature of different transport signals, the nature of translocons (a wide variety of inner membrane types, outer membrane translocons are more conserved), the process of docking to translocons, the role of chaperones and the folding of transported proteins, the energetics of translocation, and prospects for future advances.     

Towards understanding molecular mechanisms of action of homeopathic drugs: An overview

The changes in the contents of cyclic AMP, cyclic GMP, ATP, ADP, AMP and fructose-2,6-bisphosphate that occur in the mantle tissue of the mussel Mytilus galloprovincialis Lmk were analysed with regard to the annual gametogenic cycle. Throughout 2 years, the lowest contents of AMP, ADP and ATP were detected during late winter-spring, whereas the maximum appeared in the autumn months. During the second year, fructose-2,6-bisphosphate and cAMP showed a very similar behaviour. The levels of both compounds rose throughout the year until a maximum in September. Their behaviour was also similar to that observed during the first year, but displaced in time. Both in 1998 and in 1999, the highest level of cGMP was detected during the spring-summer months. The results obtained suggest that the glycolytic pathway, with regard to the breeding cycle, might be regulated by fructose-2,6-bisphosphate and cyclic AMP through the activation of 6-phosphofructo-1-kinase, which is the main regulating enzyme of the glycolysis in mantle of M. galloprovincialis.     

Spongiform encephalopathies and prions: An overview of pathology and disease mechanisms

Abstract The etiology of spongiform encephalopathies has been sharply contested for decades. At the heart of the issue is the question of disease origin: Are prion diseases representative of primary neurodegenerative genetic disorders, or are they bona fide infectious diseases? This article provides a brief outline of the progress made in the elucidation of prion disease mechanisms in the context of pathological support of the 'protein only' hypothesis. The answer to the above question appears to be that spongiform encephalopathies are uniquely both infectious and genetic neurodegenerative diseases.     

Liver glucokinase: An overview on the regulatory mechanisms of its activity

Blood glucose is the primary cellular substrate and in vivo must be tightly maintained. The liver plays a key role in glucose homeostasis increasing or decreasing glucose output and uptake during fasting and feeding. Glucokinase (GCK) is central to this process. Its activity is modulated in a coordinated manner via a complex set of mechanisms: in the postprandial period, the simultaneous rise in glucose and insulin increases GCK activity by enhanced gene expression, changes in cellular location, and interaction with regulatory proteins. Conversely, in the fasting state, the combined decrease in glucose and insulin concentrations and increase in glucagon concentrations, halt GCK activity. Herein we summarize the current knowledge regarding the regulation of hepatic GCK activity.     

Structural biology of bacterial pathogenesis

Recent years have seen a rapid increase in structural information on proteins implicated in bacterial pathogenesis. The different modes by which bacteria establish contact with their host tissues are exemplified by the structures of bacterial adhesins in complex with their cognate host receptor. A more detailed structural understanding of the various Gram-negative secretion systems has emerged with the determination of the structures of type I and type IV secretion system components, and with the elucidation of the mechanism of fibre formation in the chaperone-usher pathway of pilus biogenesis. Finally, the structures of complexes of secreted virulence factors bound to their host targets have unravelled the mechanisms by which bacterial pathogens exploit cellular processes to their advantage.     

Obesity: overview of pathogenesis and treatment

This paper presents an overview of selected current concepts of the pathogenesis and treatment of obesity. It has been estimated using the 1981 Canada Fitness Survey data that 14.1% of Canadian adult men and 20.6% of women are greater than 20% above reference table weight. Recent advances in adipocyte metabolism and control have shown that hyperplastic obesity can occur at any age and that there are differences in the replicative rate of adipocyte precursor cells from the massively obese. Furthermore, a number of the complications of obesity, including hypertension, have been related to regional body fat distribution, independent of total body fat. It is suggested that some of the controversy on the relationship between body weight/weight loss and hypertension may be due to failure to account for this. There is now suggestive evidence that abnormalities in diet-induced thermogenesis and (or) brown adipose tissue may result in human obesity. The roles of the major treatment modalities (diet, behaviour therapy, and exercise) are reviewed as are the potential hazards of the weight loss process.     

Structural overview of the bacterial injectisome

The bacterial injectisome is a specialized protein-export system utilized by many pathogenic Gram-negative bacteria for the delivery of virulence proteins into the hosts they infect. This needle-like molecular nanomachine comprises >20 proteins creating a continuous passage from bacterial to host cytoplasm. The last few years have witnessed significant progress in our understanding of the structure of the injectisome with important contributions from X-ray crystallography, NMR and EM. This review will present the current state of the structure of the injectisome with particular focus on the molecular structures of individual components and how these assemble together in a functioning T3SS.     

Self-compartmentalized bacterial proteases and pathogenesis

Protein degradation is required for homeostasis of all living organisms. Self-compartmentalized ATP-dependent proteases are required for virulence of several pathogenic bacteria. Among the proteases implicated are ClpP and Lon, as well as the more recently identified bacterial proteasome. It is generally assumed that when a pathogen invades a host, microbial proteins become irreversibly damaged and need to be degraded. However, recent data suggest that proteolysis is also essential for virulence gene regulation. In this review, we will discuss what is known about the relationship between ATP-dependent proteolysis and pathogenesis. In addition, we will propose other potential roles these chambered proteases may have in bacterial virulence. Importantly, these proteases show promise as targets for antimicrobial therapy.     

Flow cytometry and bacterial pathogenesis

Our understanding of microbial adaptations to diverse and threatening environments is limited by the assumption that the behavior of individual bacteria can be accurately determined by measuring the behavior of populations. Recent advances in gene expression reporter systems, fluorescence microscopy and flow cytometry allow microbiologists to explore the complex interactions between bacteria and their environment with single cell resolution. The application of these technologies has been particularly useful in systems, such as host-pathogen interactions, where genetic analysis is often cumbersome. Recently, flow cytometry is increasingly being applied to study host-pathogen interactions.