Bacterial persistence: some new insights into an old phenomenon

Bigger discovered more than 60 years ago, at the very beginning of the antibiotic era, that populations of antibiotic-sensitive bacteria contained a very small fraction (approximately 10⁻⁶) of antibiotic-tolerant cells (persisters). Persisters are different from antibiotic-resistant mutants in that their antibiotic tolerance is non-heritable and reversible. In spite of its importance as an interesting biological phenomenon and in the treatment of infectious diseases, persistence did not attract the attention of the scientific community for more than four decades since its discovery. The main reason for this lack of interest was the difficulty in isolating sufficient numbers of persister cells for experimentation, since the proportion of persisters in a population of wild-type cells is extremely small. However, with the discovery of high-persister (hip) mutants of Escherichia coli by Moyed and his group in the early 1980s, the phenomenon attracted the attention of many groups and significant progress has occurred since then. It is now believed that persistence is the end result of a stochastic switch in the expression of some toxin-antitoxin (TA) modules (of which the hipA and hipB genes could be examples), creating an imbalance in their intracellular levels. There are also models invoking the involvement of the alarmone (p) ppGpp in the generation of persisters. However, the precise mechanisms are still unknown. Bacterial persistence is part of a wider gamut of phenomena variously called as bistability, multistability, phenotypic heterogeneity, stochastic switching processes, etc. It has attracted the attention of not only microbiologists but also a diverse band of researchers such as biofilm researchers, evolutionary biologists, sociobiologists, etc. In this article, I attempt to present a broad overview of bacterial persistence to illustrate its significance and the need for further exploration.     

Enhanced antibody response to a detergent-soluble antigen in human filariasis after treatment with diethylcarbamazine

An antigen fraction has been isolated from the water insoluble component of cattle filarial parasiteSetaria digitata by detergent NP-40 solubilization, precipitation with ammonium sulphate and fractionation on sephadex G-100. Immunoglobulin G response to the isolated antigenic fraction was selectively suppressed in asymptomatic microfilaraemic people in comparison to the amicrofilaraemic groups of endemic normals and chronic patients. However, treating microfilaraemic people with diethylcarbamazine enhanced the antibody levels by 10-fold. These results suggest that active infection suppresses the response induced by the isolated antigenic fraction which is elevated after clearance of microfilariae.     

Lipid melting and cuticular permeability: new insights into an old problem

The idea that the physical properties of cuticular lipids affect cuticular permeability goes back over 65 years. This proposal has achieved textbook status, despite controversy and the general lack of direct supporting evidence. Recent work supports the standard model, in which lipid melting results in increased cuticular permeability. Surprisingly, although all species studied to date can synthesize lipids that remain in a solid state at environmental temperatures, partial melting often occurs due to the deposition of lipids with low melting points. This will tend to increase water loss; the benefits may include better dispersal of lipids or other compounds across the cuticle or improved communication via cuticular pheromones. In addition, insects with high melting-point lipids are not necessarily less permeable at low temperatures. One likely reason is variation in lipid properties within the cuticle. Surface lipids differ from one region to another, and biophysical studies of model mixtures suggest the occurrence of phase separation between melted and solid lipid fractions. Lipid phase separation may have important implications for insect water balance and chemical communication.     

Genetic epidemiology of lymphatic filariasis in American Samoa after mass drug administration

Over 892 million people in 48 countries are at risk of infection by nematodes that cause lymphatic filariasis. As part of the Global Programme to Eliminate Lymphatic Filariasis, mass drug administration is distributed to communities until surveillance indicates infection rates are below target prevalence thresholds. In some countries, including American Samoa, lymphatic filariasis transmission persists despite years of mass drug administration and/or has resurged after cessation. Nothing is known about the population genetics of Wuchereria bancrofti worms in Polynesia, or whether local transmission is persisting and/or increasing due to inadequate mass drug administration coverage, expansion from residual hotspots, reintroduction from elsewhere, or a combination. We extracted DNA from microfilariae on blood slides collected during prevalence surveys in 2014 and 2016, comprising 31 pools of five microfilariae from 22 persons living in eight villages. We sequenced 1104 bp across three mitochondrial markers (ND4, COI, CYTB). We quantified parasite genetic differentiation using variant calls and estimated haplotypes using principal components analysis, F-statistics, and haplotype networks. Of the variants called, all but eight were shared across the main island of Tutuila, and three of those were from a previously described hotspot village, Fagali’i. Genotypic data did not support population genetic structure among regions or villages in 2016, although differences were observed between worms collected in Fagali’i in 2014 and those from 2016. Because estimated haplotype frequency varied between villages, these statistics suggested genetic differentiation, but were not consistent among villages. Finally, haplotype networks demonstrated American Samoan sequence clusters were related to previously published sequences from Papua New Guinea. These are, to our knowledge, the first reports of W. bancrofti genetic variation in Polynesia. The resurgent parasites circulating on the main island of American Samoa represent a single population. This study is the first step towards investigating how parasite population structure might inform strategies to manage resurgence and elimination of lymphatic filariasis.     

Phytanic acid alpha-oxidation,new insights into an old problem: a review

Phytanic acid (3,7,10,14-tetramethylhexadecanoic acid) is a branched-chain fatty acid which is known to accumulate in a number of different genetic diseases including Refsum disease. Due to the presence of a methyl-group at the 3-position, phytanic acid and other 3-methyl fatty acids can not undergo β-oxidation but are first subjected to fatty acid α-oxidation in which the terminal carboxyl-group is released as CO₂. The mechanism of α-oxidation has long remained obscure but has been resolved in recent years. Furthermore, peroxisomes have been found to play an indispensable role in fatty acid α-oxidation, and the complete α-oxidation machinery is probably localized in peroxisomes. This Review describes the current state of knowledge about fatty acid α-oxidation in mammals with particular emphasis on the mechanism involved and the enzymology of the pathway.     

Angiotensin and its AT2 receptor: new insights into an old system

The AT2 receptor represents a true receptor, but signals and functions in unexpected ways compared to the respective features of the 'classical' AT1 receptor. Moreover, some of the actions of the AT2 receptor are even directly opposed to those of the AT1 receptor, especially concerning the growth- and differentiation-modulating actions of ANG II. The regulation of the AT2 receptor itself by its agonist, as well as by growth factors during ontogenesis, and its acknowledged effects on the regulation of cell growth, differentiation and apoptosis, points towards a role of a program modulator in embryonic development and regeneration.     

Branching morphogenesis of the lung: new molecular insights into an old problem

It has been known for decades that branching morphogenesis of the lung is mediated through reciprocal interactions between the epithelium and its underlying mesenchyme. In recent years, several key players, in particular members of the major signaling pathways that mediate this interaction, have been identified. Here, we review the genetic and molecular studies of these key components, which have provided a conceptual framework for understanding the interactions of these major signaling pathways in branching morphogenesis. The future challenge is to translate understanding of the signaling cascade into knowledge of the cellular responses, including cell proliferation, migration and differentiation, that lead to the stereotyped branching.*     

Phytanic acid alpha-oxidation,new insights into an old problem: a review

Phytanic acid (3,7,10,14-tetramethylhexadecanoic acid) is a branched-chain fatty acid which is known to accumulate in a number of different genetic diseases including Refsum disease. Due to the presence of a methyl-group at the 3-position, phytanic acid and other 3-methyl fatty acids can not undergo beta-oxidation but are first subjected to fatty acid alpha-oxidation in which the terminal carboxyl-group is released as CO(2). The mechanism of alpha-oxidation has long remained obscure but has been resolved in recent years. Furthermore, peroxisomes have been found to play an indispensable role in fatty acid alpha-oxidation, and the complete alpha-oxidation machinery is probably localized in peroxisomes. This Review describes the current state of knowledge about fatty acid alpha-oxidation in mammals with particular emphasis on the mechanism involved and the enzymology of the pathway.     

Aping Jane Goodall: insights into human lymphatic filariasis

The relationship between infection and disease has been a subject of intense debate in human filariasis. Most patients with chronic disease such as lymphedema or elephantiasis are free of demonstrable current infection. Based on cross-sectional data and a few assumptions and presumptions, two models of natural history of filariasis have been in vogue during the past two decades. The only (but arduous) way to understand the sequence of events is to follow up subjects with and without patent infections over a period of several years. This article offers critical comments and highlights the insights acquired from such studies.     

Babesiosis: recent insights into an ancient disease

Ever since the discovery of parasitic inclusions in erythrocytes of cattle in Romania by Victor Babes at the end of the 19th century, newly recognised babesial pathogens continue to emerge around the world and the substantial public health impact of babesiosis on livestock and man is ongoing. Babesia are transmitted by ixodid ticks and infection of the host causes a host-mediated pathology and erythrocyte lysis, resulting in anemia, hyperbilirubinuria, hemoglobinuria, and possibly organ failure. Recently obtained molecular data, particularly for the 18S rRNA gene, has contributed significantly to a better understanding of the sometimes puzzling phylogenetic situation of the genus Babesia and new information has been added to help determine the taxonomic position of many species. Moreover, it seems that owing to higher medical awareness the number of reported cases in humans is rising steadily. Hitherto unknown zoonotic babesias are now being reported from geographical areas where babesiosis was not known to occur and the growing numbers of immunocompromised individuals suggest that the frequency of cases will continue to rise. This review covers recent insights into human babesiosis with regard to phylogeny, diagnostics and treatment in order to provide new information on well known as well as recently discovered parasites with zoonotic potential.     

Heme and innate immunity: new insights for an old molecule

Hemolytic episodes such as sickle cell disease, malaria and ischemia-reperfusion occurrence are often associated to the statement of an inflammatory response which may develop or not to a chronic inflammatory status. Although these pathological states are triggered by distinct etiological agents, all of them are associated to high levels of free heme in circulation. In this review, we aim to focus the very recent achievements that have led to the statement of free heme as a proinflammatory molecule, which may play a central role during the onset and/or persistence of inflammation during these pathologies.     

Molecular insights into the initiation of sporulation in Gram-positive bacteria: new technologies for an old phenomenon

The last decade has witnessed extensive, and widespread, changes in scientific technologies that have impacted significantly upon the study of the life sciences. Arguably, the biggest advances in our comprehension of simple and complex biological processes have come as a consequence of obtaining the complete DNA sequence of organisms. It is likely that we will become accustomed to hearing of quantum leaps in the study and understanding of the biology of higher eukaryotes in the coming years, now that (near) complete genome sequences are available for man, mouse and rat. In this review, we will discuss the impact of genome sequence data, and the use of new scientific technologies that have emerged largely as consequence of the availability of this information, on the study of the master regulator of sporulation, Spo0A, in low G+C Gram-positive endospore-forming bacteria.