Individual bacterial cells can communicate via quorum sensing, cooperate to harvest nutrients from their environment, form multicellular biofilms, compete over resources and even kill one another. When the environment that bacteria inhabit is an animal host, these social behaviours mediate virulence. Over the last decade, much attention has focussed on the ecology, evolution and pathology of bacterial cooperation, and the possibility that it could be exploited or destabilised to treat infections. But how far can we really extrapolate from (...) theoretical predictions and laboratory experiments to make inferences about ‘cooperative’ behaviours in hosts and reservoirs? To determine the likely importance and evolution of cooperation ‘in the wild’, several questions must be addressed. A recent paper that reports the dynamics of bacterial cooperation and virulence in a field experiment provides an excellent nucleus for bringing together key empirical and theoretical results which help us to frame – if not completely to answer – these questions. (shrink)

The host actin nucleation machinery is subverted by many bacterial pathogens to facilitate their entry, motility, replication, and survival. The majority of research conducted in the past primarily focused on exploitation of a host actin nucleator, the Arp2/3 complex, by bacterial pathogens. Recently, new studies have begun to explore the role of formins, another family of host actin nucleators, in bacterial pathogenesis. This review provides an overview of recent advances in the study of the exploitation (...) of the Arp2/3 complex and formins by bacterial pathogens. Secreted bacterial effector proteins seem to manipulate the regulation of these actin nucleators or functionally mimic them to drive bacterial entry, motility and survival within host cells. An enhanced understanding of how formins are exploited will provide us with greater insight into how a fundamental eurkaryotic cellular process is utilized by bacteria and will also advance our knowledge of host‐pathogen interactions. (shrink)

Frederick Griffith was an English bacteriologist at the Pathological Laboratory of the Ministry of Health in London who believed that progress in the epidemiology and control of infectious diseases would come only with more precise knowledge of the identity of the causative microorganisms. Over the years, Griffith developed and expanded a serological technique for identifying pathogenic microorganisms, which allowed the tracing of the sources of infectious disease outbreaks: slide agglutination. Yet Griffith is not remembered for his contributions to the biology (...) and epidemiology of infectious diseases so much as for discovering the phenomenon known as ‘transformation’. Griffith’s discovery, for many, was a pure case of serendipity whose biological relevance had also largely escaped him. In this paper, I argue that the key to understanding the significance of bacterial transformation – and the scientific legacy of Fred Griffith – rests not only on it initiating a cascade of events leading to molecular genetics but also on its implications for epidemiology based on the biology of host–parasite interactions. Looking at Griffith’s entire career, instead of focusing only on the transformation study, we can better appreciate the place of the latter within Griffith’s overall contributions. Presented in this way, Griffith’s experiment on bacterial transformation also ceases to appear as an anomaly, which in turn leads us to rethink some of the most prevalent historical conceptions about his work. (shrink)

Bacterial plasmids are ubiquitous ‘minichromosomes’ that have major importance in clinical microbiology, as agents of pathogenicity and as carriers of antibiotic resistance, and in molecular genetics, through their role as vectors in gene manipulation. Plasmids carry a wide range of dispensable, transiently useful and often bizarre functions.1 Naturally occurring plasmids, in addition to modifying the host cell phenotype, carry genes involved in the control of their own vegetative replication, plasmid copy number2 and stable inheritance. They may also carry determinants (...) for the conjugal transfer of DNA between bacteria.3 Whereas low‐copy‐number plasmids must be partitioned by some active process during cell division, the evidence suggests that multicopy plasmids are distributed randomly between daughter cells. Two independent determinants are necessary for the stable inheritance of multicopy plasmids, and both of these appear to act by maximizing the number of independent plasmid molecules. (shrink)

The H‐NS protein is a major component of the nucleoid in Gram‐negative bacterial cells. It is a global regulator of transcription that affects the expression of many genes, including virulence genes in pathogenic species. At a local level, it facilitates the formation of nucleoprotein structures that repress transcriptional promoter function. H‐NS can form bridges between different DNA molecules or between different sections of the same molecule, allowing it to compact and impose structure on the nucleoid. A recent paper by (...) Dame et al.1 reports new insights into H‐NS‐mediated DNA bridging that were obtained using an optical tweezers device. BioEssays 29: 212–216, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

The Center for Disease Control and Prevention’s Active Bacterial Core Surveillance (CDC ABCs) Program is a collaborative effort betweeen the CDC, state health departments, laboratories, and universities to track invasive bacterial pathogens of particular importance to public health [1]. The year-end surveillance reports produced by this program help to shape public policy and coordinate responses to emerging infectious diseases over time. The ABCs case report form (CRF) data represents an excellent opportunity for data reuse beyond the original (...) surveillance purposes. (shrink)

Bacterial populations are heterogeneous, which in many cases can provide a selective advantage during changes in environmental conditions. In some instances, heterogeneity exists at the genetic level, in which significant allelic variation occurs within a population seeded by a single cell. In other cases, heterogeneity exists due to phenotypic differences within a clonal, genetically identical population. A variety of mechanisms can drive this latter strategy. Stochastic fluctuations can drive differential gene expression, but heterogeneity in gene expression can also be (...) driven by environmental changes sensed by individual cells residing in distinct locales. Utilizing multiple single cell approaches, workers have started to uncover the extent of heterogeneity within bacterial populations. This review will first describe several examples of phenotypic and genetic heterogeneity, and then discuss many single cell approaches that have recently been applied to define heterogeneity within bacterial populations. (shrink)

Although Archaea inhabit the human body and possess some characteristics of pathogens, there is a notable lack of pathogenic archaeal species identified to date. We hypothesize that the scarcity of disease‐causing Archaea is due, in part, to mutually‐exclusive phage and virus populations infecting Bacteria and Archaea, coupled with an association of bacterial virulence factors with phages or mobile elements. The ability of bacterial phages to infect Bacteria and then use them as a vehicle to infect eukaryotes may (...) be difficult for archaeal viruses to evolve independently. Differences in extracellular structures between Bacteria and Archaea would make adsorption of bacterial phage particles onto Archaea (i.e. horizontal transfer of virulence) exceedingly hard. If phage and virus populations are indeed exclusive to their respective host Domains, this has important implications for both the evolution of pathogens and approaches to infectious disease control. (shrink)

The synergies between viral and bacterial infections are well established. Most studies have been focused on the indirect mechanisms underlying this phenomenon, including immune modulation and alterations to the mucosal structures that promote pathogen outgrowth. A growing body of evidence implicates direct binding of virus to bacterial surfaces being an additional mechanism of synergy at the host–pathogen interface. These cross‐kingdom interactions enhance bacterial and viral adhesion and can alter tissue tropism. These bacterial–viral complexes play unique roles (...) in pathogenesis and can alter virulence potential. The bacterial–viral complexes may also play important roles in pathogen transmission. Additionally, the complexes are recognized by the host immune system in a distinct manner, thus presenting novel routes for vaccine development. These synergies are active for multiple species in both the respiratory and gastrointestinal tract, indicating that direct interactions between bacteria and virus to modulate host interactions are used by a diverse array of species. (shrink)

Pathogenic bacteria frequently target the endoplasmic reticulum (ER) and mitochondria in order to exploit host functions. ER‐mitochondria inter‐organelle communication is topologically sub‐compartmentalized at mitochondria‐associated ER membranes (MAMs). MAMs are specific membranous microdomains with unique regulatory functions such as lipid synthesis and trafficking, calcium homeostasis, mitochondrial morphology, inflammasome activation, autophagosome formation, and apoptosis. These important cellular processes are all modulated by pathogens to subvert host functions and promote infection, thus it is tempting to assume that pathogenic bacteria target MAMs to (...) subvert these different pathways in their hosts. First lines of evidence that support this hypothesis come from Legionella pneumophila. This intracellular bacterium secretes an effector that exhibits sphingosine‐1 phosphate lyase activity (LpSpl) that seems to target MAMs to modulate the autophagy response to infection. Here we thus propose the concept that MAMs could be targeted by pathogenic bacteria to undermine key host cellular processes. (shrink)

: This article analyzes German debates on the microbiology of infectious diseases from 1865 to 1875 and asks how and when organic pollution in tissues became noteworthy for aetiology and pathogenesis. It was with Ernst Hallier's pleomorphistic microbiology that the organic character of alien material in tissues came to be regarded as important for pathology. The process that followed saw both vigorous biological critique and a number of medical applications of Hallier's work. Around 1874 contemporaries reached the conclusion that pleomorphous (...) vegetation was most likely of little importance if not accidental in relation to the aetiology of infectious diseases whereas the idea of monomorphous micro-organisms facilitated a causal explanation. It was only then that notions such a pure cultures, bacterial specificity, etc. favored by Ferdinand Julius Cohn and his school became popular in medical circles. (shrink)

The bacterial pathogen Listeria monocytogenes displays the remarkable ability to reorganize the actin cytoskeleton within host cells as a means for promoting cell‐to‐cell transfer of the pathogen, in a manner that evades humoral immunity. In a series of events commencing with the biosynthesis of the bacterial surface protein ActA, host cell actin and many actin‐associated protein self‐assemble to from rocket‐tail structures that continually grow at sites proximal to the bacterium and depolymerize distally. Widespread interest in the underlying molecular (...) mechanism of Listeria locomotion stems from the likelihood that the dynamic remodeling of the host cell actin cytoskeleton at the cell's leading edge involves mechanistically analogous interactions. Recent advances in our understanding of these fundamental cytoskeletal rearrangements have been achieved through a clearer recognition of the central role of oligo‐proline sequence repeats present in ActA, and these findings provide a basis for inferring the role of analogous host cell proteins in the force‐producing and position‐securing steps in pseudopod and lamellipod formation at the peripheral membrane. (shrink)

Phosphatidylinositol 5‐phosphate (PtdIns5P), the least characterized among the three phosphatidylinositol monophosphates, is emerging as a bioactive lipid involved in the control of several cellular functions. Similar to PtdIns3P, it is present in low amounts in mammalian cells, and can be detected at the plasma membrane and endomembranes as well as in the nucleus. Changes in PtdIns5P levels are observed in mammalian cells following specific stimuli or stresses, and in human diseases. Recently, the contribution of several enzymes such as PIKfyve, myotubularins, (...) and type II PtdInsP‐kinases to PtdIns5P metabolism has gained a strong experimental support. Here, we provide a picture emerging from recent studies showing how this lipid can be generated and act as a regulator of membrane and cytoskeleton dynamics, and as a modulator of gene expression. We briefly summarize the current methods and tools for studying PtdIns5P, and discuss how PtdIns5P can integrate and coordinate different functions in a spatiotemporal manner. (shrink)

The rate of human health care-associated infections caused by Acinetobacter baumannii has increased significantly in recent years for its remarkable resistance to desiccation and most antibiotics. Phospholipases, capable of destroying a phospholipid substrate, are heterologous group of enzymes which are believed to be the bacterial virulence determinants. There is a need for in silico studies to identify potential vaccine candidates. A. baumannii phospholipase D role has been proved in increasing organism’s resistance to human serum, destruction of host epithelial cell (...) and pathogenesis in murine model. In this in silico study high potentials of A. baumannii PLD in elicitation of humoral and cellular immunities were elucidated. Thermal stability, long half-life, non-similarity to human and gut flora proteome and non-allergenicity were in a list of A. baumannii PLD positive properties. Potential epitopic sequences were also identified that could be used as peptide vaccines against A. baumannii and various other human bacterial pathogens. (shrink)

Diseases caused by Salmonella species are characterized by bacterial invasion of host cells. Salmonella invasion requires a genetic locus (inv) with homology to bacterial systems involved in specific protein export and organelle assembly. Until recently, the actual Salmonella invasion factors exported or assembled by the inv system remained unidentified. It now appears that Salmonella produces novel appendages upon contact with host cells. These appendages are transient, appearing and disappearing rapidly from the bacterial surface. Appendages are altered in (...) strains unable to invade due to mutations within the inv/spa locus. Therefore, a role for the invasion locus has been identified, providing another example of bacterial pathogens responding to signals provided by the host cell surface. (shrink)

Valuable insights into eukaryotic regulatory circuits can emerge from studying interactions of bacterial pathogens such as Helicobacter pylori with host tissues. H. pylori uses a type IV secretion system (T4SS) to deliver its CagA virulence protein to epithelial cells, where much of it becomes phosphorylated. CagA's phosphorylated and non‐phosphorylated forms each interact with host regulatory proteins to alter cell structure and cell fate. Kwok and colleagues1 showed that CagA destined for phosphorylation is delivered using host integrin as receptor (...) and H. pylori's CagL protein as an integrin‐specific adhesin, and that CagL–integrin‐binding activates the kinase cascade responsible for CagA phosphorylation. This research contributes to understanding infectious disease and the control of cell fates. BioEssays 30:515–520, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

NIK1 is a receptor‐like kinase involved in plant antiviral immunity. Although NIK1 is structurally similar to the plant immune factor BAK1, which is a key regulator in plant immunity to bacterial pathogens, the NIK1‐mediated defenses do not resemble BAK1 signaling cascades. The underlying mechanism for NIK1 antiviral immunity has recently been uncovered. NIK1 activation mediates the translocation of RPL10 to the nucleus, where it interacts with LIMYB to fully down‐regulate translational machinery genes, resulting in translation inhibition of host (...) and viral mRNAs and enhanced tolerance to begomovirus. Therefore, the NIK1 antiviral immunity response culminates in global translation suppression, which represents a new paradigm for plant antiviral defenses. Interestingly, transcriptomic analyses in nik1 mutant suggest that NIK1 may suppress antibacterial immune responses, indicating a possible opposite effect of NIK1 in bacterial and viral infections. (shrink)

Antibiotic resistance in bacteria has become a great threat to global public health. Tigecycline is a next‐generation tetracycline that is the final line of defense against severe infections by pan‐drug‐resistant bacterial pathogens. Unfortunately, this last‐resort antibiotic has been challenged by the recent emergence of the mobile Tet(X) orthologs that can confer high‐level tigecycline resistance. As it is reviewed here, these novel tetracycline destructases represent a growing threat to the next‐generation tetracyclines, and a basic framework for understanding the molecular (...) epidemiology and resistance mechanisms of them is presented. However, further large‐scale epidemiological and functional studies are urgently needed to better understand the prevalence and dissemination of these newly discovered Tet(X) orthologs among Gram‐negative bacteria in both human and veterinary medicine. (shrink)

The type III secretion system (T3SS) is a specialized nanomachine that enables bacteria to secrete proteins in a specific order and directly deliver a specific set of them, collectively known as effectors, into eukaryotic organisms. The core structure of the T3SS is a syringe‐like apparatus composed of multiple building blocks, including both membrane‐associated and soluble proteins. The cytosolic components organize together in a chamber‐like structure known as the sorting platform (SP), responsible for recruiting, sorting, and initiating the substrates destined to (...) engage this secretion pathway. In this article, we provide an overview of recent findings on the SP's structure and function, with a particular focus on its assembly pathway. Furthermore, we discuss the molecular mechanisms behind the recruitment and hierarchical sorting of substrates by this cytosolic complex. Overall, the T3SS is a highly specialized and complex system that requires precise coordination to function properly. A deeper understanding of how the SP orchestrates T3S could enhance our comprehension of this complex nanomachine, which is central to the host‐pathogen interface, and could aid in the development of novel strategies to fight bacterial infections. (shrink)

A pathogenic connection between autoreactive T cells, fungal infection, and carcinogenesis has been demonstrated in studies of human autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy as well as in a mouse model in which kinase-dead Ikkα knock-in mice develop impaired central tolerance, autoreactive T cell–mediated autoimmunity, chronic fungal infection, and esophageal squamous cell carcinoma, which recapitulates APECED. IκB kinase α is one subunit of the IKK complex required for NF-κB activation. IKK/NF-κB is essential for central tolerance establishment by regulating the development of medullary thymic (...) epithelial cells that facilitate the deletion of autoreactive T cells in the thymus. In this review, we extensively discuss the pathogenic roles of inborn errors in the IKK/NF-κB loci in the phenotypically related diseases APECED, immune deficiency syndrome, and severe combined immunodeficiency; differentiate how IKK/NF-κB components, through mTEC, T cells/leukocytes, or epithelial cells, contribute to the pathogenesis of infectious diseases, autoimmunity, and cancer; and highlight the medical significance of IKK/NF-κB in these diseases. IKK/NF-κB regulates the expression of many genes that encode proteins involved in many crucial biological functions, such as immunity, tissue homeostasis, and fungal/bacterial/viral infections. Also, IKKα plays anti-tumor activities in many organs independently of NF-κB pathways. Thus, an inborn error in one of these gene loci can cause severe human diseases through these complicated mechanisms. (shrink)

Drug‐resistant bacterial infections constitute a major threat to global public health. Several key bacteria that are becoming increasingly resistant are among those that are ubiquitously carried by human beings and usually cause no symptoms (i.e. individuals are asymptomatic carriers) until and/or unless a precipitating event leads to symptomatic infection (and thus disease). Carriers of drug‐resistant bacteria can also transmit resistant pathogens to others, thus putting the latter at risk of resistant infections. Accumulating evidence suggests that such transmission occurs (...) not only in hospital settings but also in the general community, although considerably more data are needed to assess the extent of this problem. Asymptomatic carriage of drug‐resistant bacteria raises important ethical questions regarding the appropriate public health response, including the degree to which it would be justified to impose burdens on asymptomatic carriers (and others) in order to prevent transmission. In this paper, we (i) summarize current evidence regarding the carriage of key drug‐resistant bacteria, noting important knowledge gaps; and (ii) explore the particular implications of existing public health ethics frameworks for policy‐making regarding asymptomatic carriers. Inter alia, we argue that the relative burdens imposed by public health measures on healthy carriers (as opposed to sick individuals) warrant careful consideration and should be proportionate to the expected public health benefits in terms of risks averted. We conclude that more surveillance and research regarding community transmission will be needed in order to clarify relevant risks and design proportionate policies, although extensive community surveillance itself would also require careful ethical consideration. (shrink)

Proteinaceous stalks produced by Gram‐negative bacteria are often used to adhere to environmental surfaces. Among them, chaperone‐usher (CU) fimbriae adhesins, related to prototypical type 1 fimbriae, interact in highly specific ways with different ligands at different stages of bacterial infection or surface colonisation. Recent analyses revealed a large number of potential and often “cryptic” CU fimbriae homologues in the genome of commensal and pathogenic Escherichia coli and closely related bacteria. We propose that CU fimbriae form a yet unexplored arsenal (...) of lectins, carbohydrate‐binding proteins involved in various aspects of bacterial surface adhesion and tissue tropism. Combined efforts of molecular and structural biologists will be required to unravel the biological contribution of the bacterial lectome, however, current progress has already opened up new perspectives in the design of novel anti‐infective strategies. (shrink)

Protection against bacterial and viral pathogens by antibodies has always been thought to end at the cell surface. Once inside the cell, a pathogen was understood to be safe from humoral immunity. However, it has now been found that antibodies can routinely enter cells attached to viral particles and mediate an intracellular immune response. Antibody‐coated virions are detected inside the cell by means of an intracellular antibody receptor, TRIM21, which directs their degradation by recruitment of the ubiquitin‐proteasome system. (...) In this article we assess how this discovery alters our view of the way in which antibodies neutralise viral infection. We also consider the antiviral function of TRIM21 in the context of its other reported roles in immune signalling and autoimmunity. Finally, we discuss the conceptual implications of intracellular antibody immunity and how it alters our view of the discrete separation of extracellular and intracellular environments. (shrink)

Commensal and pathogenic organisms employ camouflage and mimicry to mediate mutualistic interactions and predator escape. However, the immune mechanisms accounting for the establishment and maintenance of symbiotic bacterial populations are poorly understood. A promising hypothesis suggests that molecular mimicry, a condition in which different organisms share common antigens, is a mechanism of establishing tolerance between commensals and their hosts. On this view, certain bacteria may mimic the structural features of some of their host’s T-cell receptors (TCRs), namely those that (...) survive thymic selection due to their lack of complementarity to self-antigens. With such “holoimmunity” the mimicking micro-organisms avoid immune recognition as the copied TCRs become mirror images of an extended super-organismal self, consisting of symbiotic and host antigens. Accordingly, analysis of genomic and metagenomic data suggests a tripartite mimicry between TCRs, self-antigens, and commensal antigens that would serve as the basis for immune tolerance between these populations. And conversely, in an autoimmune scenario, both symbiotic microbes and the mimicked host tissue would be targeted for immune destruction. (shrink)

Horizontal gene transfer advances bacterial evolution. To benefit from horizontally acquired genes, enteric bacteria must overcome silencing caused when the widespread heat‐stable nucleoid structuring (H‐NS) protein binds to AT‐rich horizontally acquired genes. This ability had previously been ascribed to both anti‐silencing proteins outcompeting H‐NS for binding to AT‐rich DNA and RNA polymerase initiating transcription from alternative promoters. However, we now know that pathogenic Salmonella enterica serovar Typhimurium and commensal Escherichia coli break down H‐NS when this silencer is not bound (...) to DNA. Curiously, both species use the same protease – Lon – to destroy H‐NS in distinct environments. Anti‐silencing proteins promote the expression of horizontally acquired genes without binding to them by displacing H‐NS from AT‐rich DNA, thus leaving H‐NS susceptible to proteolysis and decreasing H‐NS amounts overall. Conserved amino acid sequences in the Lon protease and H‐NS cleavage site suggest that diverse bacteria degrade H‐NS to exploit horizontally acquired genes. (shrink)

We have synthesized a 582,970-base pair Mycoplasma genitalium genome. This synthetic genome, named M. genitalium JCVI-1.0, contains all the genes of wild-type M. genitalium G37 except MG408, which was disrupted by an antibiotic marker to block pathogenicity and to allow for selection. To identify the genome as synthetic, we inserted "watermarks" at intergenic sites known to tolerate transposon insertions. Overlapping "cassettes" of 5 to 7 kilobases (kb), assembled from chemically synthesized oligonucleotides, were joined by in vitro recombination to produce intermediate (...) assemblies of approximately 24 kb, 72 kb ("1/8 genome"), and 144 kb ("1/4 genome"), which were all cloned as bacterial artificial chromosomes in Escherichia coli. Most of these intermediate clones were sequenced, and clones of all four 1/4 genomes with the correct sequence were identified. The complete synthetic genome was assembled by transformation-associated recombination cloning in the yeast Saccharomyces cerevisiae, then isolated and sequenced. A clone with the correct sequence was identified. The methods described here will be generally useful for constructing large DNA molecules from chemically synthesized pieces and also from combinations of natural and synthetic DNA segments. 10.1126/science.1151721. (shrink)

Beginning in the 1940s, mass production of antibiotics involved the industrial-scale growth of microorganisms to harvest their metabolic products. Unfortunately, the use of antibiotics selects for resistance at answering scale. The turn to the study of antibiotic resistance in microbiology and medicine is examined, focusing on the realization that individual therapies targeted at single pathogens in individual bodies are environmental events affecting bacterial evolution far beyond bodies. In turning to biological manifestations of antibiotic use, sciences fathom material outcomes (...) of their own previous concepts. Archival work with stored soil and clinical samples produces a record described here as ‘the biology of history’: the physical registration of human history in bacterial life. This account thus foregrounds the importance of understanding both the materiality of history and the historicity of matter in theories and concepts of life today. (shrink)

Abstractabstract:Long before COVID-19 made social distancing familiar, people with cystic fibrosis (CF) already practiced such behaviors. CF is held up as a classic example of genetic disease, yet people with CF are also susceptible to bacteria from the environment and from other CF patients. Starting in the 1980s, a bacterial epidemic in the CF population highlighted clashing priorities of connection, physical safety, and environmental protection. Policymakers ultimately called for the physical separation of people with CF from one another via (...) recommendations that reconfigured the CF community. Simultaneously, medical researchers recognized that one highly transmissible CF pathogen called cepacia was being developed for environmental applications and got the EPA to limit cepacia's environmental deployment. Environmental regulations speak to the challenge of useful microbes that harm a minority, but CF cross-infection also involves legal implications for microbial and genetic discrimination, social consequences for CF communities, and ethical questions about balancing autonomy, harms, and benefits. As scientists increasingly study connections between host genetics, microbial genetics, and infectious risks, CF is a vital referent. (shrink)

There is a steadily growing literature on the role of the immune system in psychiatric disorders. So far, these advances have largely taken the form of correlations between specific aspects of inflammation (e.g. blood plasma levels of inflammatory markers, genetic mutations in immune pathways, viral or bacterial infection) with the development of neuropsychiatric conditions such as autism, bipolar disorder, schizophrenia and depression. A fundamental question remains open: why are psychiatric disorders and immune responses intertwined? To address this would require (...) a step back from a historical mind–body dualism that has created such a dichotomy. We propose three contributions of active inference when addressing this question: translation, unification, and simulation. To illustrate these contributions, we consider the following questions. Is there an immunological analogue of sensory attenuation? Is there a common generative model that the brain and immune system jointly optimise? Can the immune response and psychiatric illness both be explained in terms of self-organising systems responding to threatening stimuli in their external environment, whether those stimuli happen to be pathogens, predators, or people? Does false inference at an immunological level alter the message passing at a psychological level (or vice versa) through a principled exchange between the two systems? (shrink)

Eukaryotic gene expression is extensively controlled at the level of mRNA stability and the mechanisms underlying this regulation are markedly different from their archaeal and bacterial counterparts. We propose that two such mechanisms, nonsense‐mediated decay (NMD) and motif‐specific transcript destabilization by CCCH‐type zinc finger RNA‐binding proteins, originated as a part of cellular defense against RNA pathogens. These branches of the mRNA turnover pathway might have been used by primeval eukaryotes alongside RNA interference to distinguish their own messages from (...) those of RNA viruses and retrotransposable elements. We further hypothesize that the subsequent advent of “professional” innate and adaptive immunity systems allowed NMD and the motif‐triggered mechanisms to be efficiently repurposed for regulation of endogenous cellular transcripts. This scenario explains the rapid emergence of archetypical mRNA destabilization pathways in eukaryotes and argues that other aspects of post‐transcriptional gene regulation in this lineage might have been derived through a similar exaptation route. -/- . (shrink)

Many bacteria that cause disease have the capacity to enter into and live within eukaryotic cells such as epithelial cells and macrophages. The mechanisms used by these organisms to achieve and maintain this intracellular lifestyle vary considerably, but most mechanisms involve subversion and exploitation of host cell functions. Entry into non‐phagocytic cells involves triggering host signal transduction mechanisms to induce rearrangement of the host cytoskeleton, thereby facilitating bacterial uptake. Once inside the host cell, intracellular pathogens either remain within (...) membrane bound inclusions or escape to the cytoplasm. Those living in the cytoplasm can further pirate the host actin system, using actin as a mechanism to facilitate movement within and between host cells. Organisms remaining within the vacuole have specialized mechanisms for intracellular survival and growth which involve additional communication with the host cell. Some of the processes involved in the various steps of facultative intracellular parasitism are discussed in the context of subverting the host cell cytoskeleton and signal transduction pathways for bacterial benefit. (shrink)

It is well established that chronic infections can lead to cancer. Almost unknown is that, in contrast, acute brief viral and bacterial infections may have beneficial effects in cases of established neoplastic disease, while exposure to pathogenic products by infection, vaccination, and inhalation can cause prophylactic effects. In the following I will align evidence from case studies of spontaneous regression and from epidemiological studies with recent immunology to conclude that pathogenic substances belonging to the group of “pathogen‐associated molecular patterns” (...) can trigger the innate immune system to establish anti‐neoplastic immune responses. A better understanding of the protective role of the innate immune system might leverage considerable prophylactic potential. (shrink)

The hemolysin toxin (HlyA) is secreted across both the cytoplasmic and outer membranes of pathogenic Escherichia coli and forms membrane pores in cells of the host immune system, causing cell dysfunction and death. The processes underlying the interaction of HlyA with the bacterial and mammalian cell membranes are remarkable. Secretion of HlyA occurs without a periplasmic intermediate and is directed by an uncleaved C‐terminal targetting signal and the HlyB and HlyD translocator proteins, the former being a member of a (...) transporter superfamily central to import and export of a wide range of substrates by prokaryotic and eukaryotic cells. The separate process by which HlyA is targetted to mammalian cell membranes is dependent upon fatty acylation of a non‐toxic precursor, proHlyA. This is achieved by a novel mechanism directed by the activator protein HlyC, which binds to an internal proHlyA recognition sequence and provides specificity for the transfer of fatty acid from cellular acyl carrier protein. (shrink)

Many bacteria respond in a coordinate manner to environmental changes. External stimuli, sensed by receptors, are transduced to regulatory proteins which participate in well defined pathways of gene expression by varying their structure and mode of action. The network of environmental signal transduction is responsible for a fine and continuous communication between the host and the pathogenic bacteria. As a result, the gene expression machinery of the pathogen is modified continuously, in order to establish the optimal conditions for bacterial (...) survival and multiplication. (shrink)

The human intestines are constantly under the influence of numerous pathological factors: enteropathogenic microorganisms, food antigens, physico‐chemical stress associated with digestion and bacterial metabolism, therefore it must be provided with a system of protection against adverse impact. Recent studies have shown that Paneth cells play a crucial role in maintaining homeostasis of the small intestines. Paneth cells perform many vital functions aimed at maintaining a homeostatic balance between normal microbiota, infectious pathogens and the human body, regulate the qualitative (...) composition and number of intestinal microorganisms, prevent the introduction of potentially pathogenic species, and protect stem cells from damage. Paneth cells take part in adaptive and protective‐inflammatory reactions. Paneth cells maintain dynamic balance between microbial populations, and the macroorganism, preventing the development of intestinal infections and cancer. They play a crucial role in gastrointestinal homeostasis and may be key factors in the etiopathological progression of intestinal diseases. (shrink)

Understanding how complex sexual reproduction arose, and why sexual organisms have been more successful than otherwise similar asexual organisms, is a longstanding problem in evolutionary biology. Within this problem, the potential role of endosymbionts or intracellular pathogens in mediating primitive genetic transfers is a continuing theme. In recent years, several remarkable activities of mitochondria have been observed in the germline cells of complex eukaryotes, and it has been found that bacterial endosymbionts related to mitochondria are capable of manipulating (...) diverse aspects of metazoan gametogenesis. An attempt is made here to rationalize these observations with an endosymbiotic model for the evolutionary origins of sex. It is hypothesized that the contemporary life cycle of germline cells has descended from the life cycle of the endosymbiotic ancestor of the mitochondrion. Through an actin‐based motility that drove it from one cell to another, the rickettsial ancestor of mitochondria may have functioned as a primitive transducing particle, the evolutionary progenitor of sperm. BioEssays 26:558–566, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

In the fall of 1950, eleven San Francisco residents were admitted to Berkeley Hospital with rare bacterial infections. Nearly thirty years later, a Senate subcommittee hearing revealed that the military deliberately released Serratia marcescens, a known opportunistic pathogen, from a naval ship in San Francisco Bay just days before the outbreak, which resulted in the death of Edward J. Nevin. Over the next twenty years, a court case and numerous investigations uncovered an alarming truth about the United States biological (...) weapons program. Government and military personnel have repeatedly and publicly defended the safety and ethics of the research program, insisting that the released substances were "harmless simulants", and that their activities did not qualify as human experimentation. These claims contradict not only official project reports, but the knowledge of civilian scientists and the experiences of the exposed populations, which document the widely ignored human dimensions of the project. (shrink)

Um bei einer Wertung der Faktoren, die das Wachstum einer Population beeinflussen, zu einer richtigen Einsicht zu gelangen, empfiehlt es sich, nicht den relativen Wert dieser Faktoren in Bezug auf die in Rede stehende Insektenpopulation auszudrücken, sondern ihre absolute Grösse in Faktoreinheiten zum Ausdruck zu bringen — wie: Wärme in Grad Celsius, Luftfeuchtigkeit in Prozenten, Zahl der im Bevölkerungsmilieu vorgefundenen Raubinsekten oder Parasiten. Auf dieser Grundlage liessen sich Faktoren in folgender Weise aufteilen: Faktoren ersten Grades : Allgemeine Faktoren : Unabhängige (...) Faktoren : nicht mechanische Klimaeinflüsse , chemische Faktoren, Güte der Nahrung. Abhängige Faktoren : die internen Faktoren, die bei einer Zunahme der Dichtigkeit einen Rückgang des Zuwachses bewirken, mit Ausnahme des Kannibalismus, ferner die Menge der Nahrung. Selektive Faktoren : Unabhängige Faktoren : unersättliche Faktoren : mechanische Klimaeinflüsse, weitere mechanische Faktoren, Parasiten und Raubfeinde, die nicht mit töten aufhören, wenn sie gesättigt sind, insofern ihre Bevölkerungsdichte nicht durch die des fraglichen Insektes bedingt wird. ersättliche Faktoren: restliche Raubinsekten und Parasiten, insofern ihre Bevölkerungsdichte nicht durch die des fraglichen Insektes bedingt wird. Abhängige Faktoren : Kannibalismus. Wandelbare Faktoren : Raubinsekten und Parasiten, welche diesem Erfordernis entsprechen, pathogene Pilze und Bakterien. Faktoren zweiten Ranges . Faktoren des dritten Ranges .Afin d'obtenir une notion exacte de la valeur des facteurs qui influencent la croissance d'une population, il vaudra mieux ne pas exprimer ces facteurs en leur valeur relative quant à la population d'insectes en question, mais en unités de facteurs: degrés Celsius, pourcentage de l'humidité de l'air, nombre d'ennemis ou de parasites qui sont présents dans le milieu de la population. Sur cette base on pourra répartir les facteurs de la façon suivante: Facteurs du 1er ordre : Facteurs généraux : influences climatiques non mécaniques , facteurs chimiques, qualité de la nourriture. Facteurs dépendants : les facteurs internes qui font de sorte que la densité de la population diminue quand se présente une plus forte densité, en exceptant le cannibalisme, la quantité de nourriture. Facteurs selectifs ; seule une partie des individus est exposée à leur action; les animaux touchés sont mécaniquement endommagés et, dans la règle, tués. Facteurs indépendants : facteurs insatiables : des influences climatiques mécaniques, d'autres facteurs mécaniques, des parasites et des ennemis qui ne s'arrêtent pas de tuer quand ils sont rassasiés, pour autant que l'intensité de la population de l'insecte en question. facteurs rassasiables: autres ennemis et parasites pour autant que l'intensité de leur population ne se modifie pas sous l'influence de la densité de la population de l'insecte en question. Facteurs indépendants : cannibalisme. Facteurs modifiables : ennemis et parasites qui satisfont à cette exigence, champignons pathogènes, bactéries. Facteurs du 2ième ordre . Facteurs du 3iéme ordre. (shrink)

Bacteria have evolved advanced strategies for surviving during nutritional stress, including expression of specialized enzyme systems that allow them to grow on unusual nutrient sources. Inorganic phosphate (Pi) is limiting in most ecosystems, hence organisms have developed a sophisticated, enzymatic machinery known as carbon‐phosphorus (C‐P) lyase, allowing them to extract phosphate from a wide range of phosphonate compounds. These are characterized by a stable covalent bond between carbon and phosphorus making them very hard to break down. Despite the challenges involved (...) in both synthesizing and catabolizing phosphonates, they are widespread in nature. The enzymes required for the bacterial C‐P lyase pathway have been identified and for the most part structurally characterized. Nevertheless, the mechanistic principles governing breakdown of phosphonate compounds remain enigmatic. In this review, an overview of the C‐P lyase pathway is provided and structural aspects of the involved enzyme complexes are discussed with a special emphasis on the role of ATP‐binding cassette (ABC) proteins. (shrink)

Bacteria have evolved advanced strategies for surviving during nutritional stress, including expression of specialized enzyme systems that allow them to grow on unusual nutrient sources. Inorganic phosphate (Pi) is limiting in most ecosystems, hence organisms have developed a sophisticated, enzymatic machinery known as carbon‐phosphorus (C‐P) lyase, allowing them to extract phosphate from a wide range of phosphonate compounds. These are characterized by a stable covalent bond between carbon and phosphorus making them very hard to break down. Despite the challenges involved (...) in both synthesizing and catabolizing phosphonates, they are widespread in nature. The enzymes required for the bacterial C‐P lyase pathway have been identified and for the most part structurally characterized. Nevertheless, the mechanistic principles governing breakdown of phosphonate compounds remain enigmatic. In this review, an overview of the C‐P lyase pathway is provided and structural aspects of the involved enzyme complexes are discussed with a special emphasis on the role of ATP‐binding cassette (ABC) proteins. (shrink)

This paper aims to offer a new argument in defence bacterial species pluralism. To do so, I shall first present the particular issues derived from the conflict between the non-theoretical understanding of species as units of classification and the theoretical comprehension of them as units of evolution. Secondly, I shall justify the necessity of the concept of species for the bacterial world, and show how medicine and endosymbiotic evolutionary theory make use of different concepts of bacterial species (...) due to their distinctive purposes. Finally, I shall show how my argument provides a new source of defence for bacterial pluralism. (shrink)

Much research has explored behaviours that are linked with disgust sensitivity. Few studies, however, have been devoted to understanding how fixed or variable disgust sensitivity is. We therefore aimed to examine whether disgust sensitivity can change with the environment by repeatedly testing students whose environment was not changing as well as student cadets undergoing intensive training at an army camp. We found that an increase in the perceived harshness of the environment was associated with a decrease in pathogen disgust sensitivity. (...) Our results support the idea that disgust sensitivity is malleable depending on the environment. More specifically, we propose that in a harsh environment, where survival may be more difficult, pathogen disgust sensitivity may decrease to allow the consumption of available resources. (shrink)

It has been argued that people in areas with high pathogen loads will be more likely to avoid outsiders, to be biased in favor of in-groups, and to hold collectivist and conformist values. Cross-national studies have supported these predictions. In this paper we provide new pathogen codes for the 186 cultures of the Standard Cross-Cultural Sample and use them, together with existing pathogen and ethnographic data, to try to replicate these cross-national findings. In support of the theory, we found that (...) cultures in high pathogen areas were more likely to socialize children toward collectivist values (obedience rather than self-reliance). There was some evidence that pathogens were associated with reduced adult dispersal. However, we found no evidence of an association between pathogens and our measures of group bias (in-group loyalty and xenophobia) or intergroup contact. (shrink)

Disgust is reasoned to operate in conjunction with the immune system to help protect the body from illness. However, less is known about the factors that impact the degree to which individuals invest in pathogen avoidance (disgust) versus pathogen management (prophylactic immunological activity). Here, we examine the role that one’s control over pathogen contact plays in resolving such investment trade-offs, predicting that (a) those from low control environments will invest less in pathogen-avoidance strategies and (b) investment in each of these (...) two strategies will occur in a compensatory fashion (i.e. they will be traded off with one other). Across four studies, we found support for these predictions, using a variety of manipulations and measures. By providing novel insights into how one’s control over pathogen exposure influences disgust sensitivity and immune system activity, the current research poses an important contribution to the literature on disgust, pathogen avoidance, and the immune system. (shrink)

Cell‐wall‐less bacterial variants, or L‐forms, have been described in many bacterial species under laboratory conditions, in infected eukaryotic cell cultures and inside animals. Of special interest for human health is the formation of L‐forms as a consequence of specific antibiotic treatments, and the potential involvement of L‐forms in persistent and relapsing infections. An old enigma about L‐forms is how they can divide in the absence of cell wall synthesis, since septum formation is an essential requisite for cell division. (...) However, the classical definition of L‐forms as cell‐wall‐less bacterial variants may need a revision to accomodate recent observations by Richard d'Ari and coworkers:1 genetic and biochemical evidence indicates that E. coli L‐forms induced by β‐lactam antibiotics do contain small amounts of peptidoglycan, essential for their growth and probably required for septum formation. If these observations are extrapolated to all known L‐forms, the very concept of cell‐wall‐less bacteria may need revision, and be restricted to mycoplasmas and their relatives. BioEssays 29:1189–1191, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Within the same pathogen-stress framework as proposed by Fincher & Thornhill (F&T), we argue further that pathogen stress promotes matrilocal rather than patrilocal family ties which, in turn, slow down the process of modernity; and that pathogen stress promotes social learning or copying, including the adoption of foreign religions.

In contrast to the great majority of mycobacterial species that are harmless saprophytes, Mycobacterium tuberculosis and other closely related tubercle bacilli have evolved to be among the most important human and animal pathogens. The need to develop new strategies in the fight against tuberculosis (TB) and related diseases has fuelled research into the evolutionary success of the M. tuberculosis complex members. Amongst the various disciplines, genomics and functional genomics have been instrumental in improving our understanding of these organisms. In (...) this review we will present some of the recent key findings on molecular determinants of mycobacterial pathogenicity and attenuation, the evolution of M. tuberculosis, genome dynamics, antigen mining for improved diagnostic and subunit antigens, and finally the identification of novel drug targets. The genomics revolution has changed the landscape of TB research, and now underpins our renewed efforts to defeat this deadly pathogen. (shrink)

Skin-transmitted pathogens have threatened humans since ancient times. We investigated whether skin-transmitted pathogens were a subclass of disgust stimuli that evoked an emotional response that was related to, but distinct from, disgust and fear. We labelled this response “the heebie jeebies”. In Study 1, coding of 76 participants’ experiences of disgust, fear, and the heebie jeebies showed that the heebie jeebies was elicited by unique stimuli which produced skin-crawling sensations and an urge to protect the skin. In Experiment (...) 2,350 participants’ responses to skin-transmitted pathogen, fear-inducing, and disgust-inducing vignettes showed that the vignettes elicited sensations and urges which loaded onto heebie jeebies, fear, and disgust factors, respectively. Experiment 3 largely replicated findings from Experiment 2 using video stimuli. Results are consistent with the notion that skin-transmitted pathogens are a subclass of disgust stimuli which motivate behaviours that are functionally consistent with disgust yet qualitatively distinct. (shrink)

This essay details a historical crossroad in biochemistry and microbiology in which penicillin was a co-agent. I narrate the trajectory of the bacterial cell wall as the precise target for antibiotic action. As a strategic object of research, the bacterial cell wall remained at the core of experimental practices, scientific narratives and research funding appeals throughout the antibiotic era. The research laboratory was dedicated to the search for new antibiotics while remaining the site at which the mode of (...) action of this new substance was investigated. This combination of circumstances made the bacterial wall an ontology in transit. As invisible as the bacterial wall was for clinical purposes, in the biological laboratory, cellular meaning in regard to the action of penicillin made the bacterial wall visible within both microbiology and biochemistry. As a border to be crossed, some components of the bacterial cell wall and the biochemical destruction produced by penicillin became known during the 1950s and 1960s. The cell wall was constructed piece by piece in a transatlantic circulation of methods, names, and images of the shape of the wall itself. From 1955 onwards, microbiologists and biochemists mobilized new names and associated conceptual meanings. The composition of this thin and rigid layer would account for its shape, growth and destruction. This paper presents a history of biochemical morphology: a chemistry of shape – the shape of bacteria, as provided by its wall – that accounted for biology, for life itself. While penicillin was being established as an industrially-manufactured object, it remained a scientific tool within the research laboratory, contributing to the circulation of further scientific objects. (shrink)