Enterobacterial adhesins and the case for studying SNPs in bacteria

Single-nucleotide polymorphisms (SNPs) in structural genes can have a dramatic effect on the biology of whole organisms, from bacteria and viruses to mammals. Here, we underscore the importance of SNPs in bacterial genes that contribute to the ability of pathogens to cause disease. SNPs that confer an adaptive advantage for bacterial pathogens have been discovered in the genes encoding the FimH and Dr adhesins of Escherichia coli and, most recently, Salmonella enterica sv. Typhimurium FimH.     

How Do Filamentous Pathogens Deliver Effector Proteins into Plant Cells?

Fungal and oomycete plant parasites are among the most devastating pathogens of food crops. These microbes secrete effector proteins inside plant cells to manipulate host processes and facilitate colonization. How these effectors reach the host cytoplasm remains an unclear and debated area of plant research. In this article, we examine recent conflicting findings that have generated discussion in the field. We also highlight promising approaches based on studies of both parasite and host during infection. Ultimately, this knowledge may inform future broad spectrum strategies for protecting crops from such pathogens.     

Fascination with bacteria-triggered cell death: the significance of Fas-mediated apoptosis during bacterial infection in vivo

Increasing evidence indicates that bacterial pathogens have developed mechanisms to modulate the apoptotic signaling cascade of host cells and thereby cause disease. The Fas death receptor pathway is one of the most extensively investigated apoptotic signaling pathways. In this review we discuss the role of Fas signaling during the interplay between bacterial pathogens and the host in vivo.     

A method using active-site sequence conservation to find functional shifts in protein families: application to the enzymes of central metabolism, leading to the identification of an anomalous isocitrate dehydrogenase in pathogens

We have introduced a method to identify functional shifts in protein families. Our method is based on the calculation of an active-site conservation ratio, which we call the "ASC ratio." For a structurally based alignment of a protein family, this ratio is the average sequence similarity of the active-site region compared to the full-length protein. The active-site region is defined as all the residues within a certain radius of the known functionally important groups. Using our method, we have analyzed enzymes of central metabolism from a large number of genomes (35). We found that for most of the enzymes, the active-site region is more highly conserved than the full-length sequence. However, for three tricarboxylic acid (TCA)-cycle enzymes, active-site sequences are considerably more diverged (than full-length ones). In particular, we were able to identify in six pathogens a novel isocitrate dehydrogenase that has very low sequence similarity around the active site. Detailed sequence-structure analysis indicates that while the active-site structure of isocitrate dehydrogenase is most likely similar between pathogens and nonpathogens, the unusual sequence divergence could result from an extra domain added at the N-terminus. This domain has a leucine-rich motif similar one in the Yersinia pestis cytotoxin and may therefore confer additional pathogenic functions.     

Global drivers of human pathogen richness and prevalence

The differences in the richness and prevalence of human pathogens among different geographical locations have ramifying consequences for societies and individuals. The relative contributions of different factors to these patterns, however, have not been fully resolved. We conduct a global analysis of the relative influence of climate, alternative host diversity and spending on disease prevention on modern patterns in the richness and prevalence of human pathogens. Pathogen richness (number of kinds) is largely explained by the number of birds and mammal species in a region. The most diverse countries with respect to birds and mammals are also the most diverse with respect to pathogens. Importantly, for human health, the prevalence of key human pathogens (number of cases) is strongly influenced by disease control efforts. As a consequence, even where disease richness is high, we might still control prevalence, particularly if we spend money in those regions where current spending is low, prevalence is high and populations are large.     

Bacterial entry into cells: a role for the endocytic machinery

Increasing evidence indicates that pathogens have evolved highly efficient strategies to induce their internalization within host cells. Viruses and bacteria express and expose on their surface, molecules that mimic endogenous ligands to cell receptors, thereby inducing specific intracellular signalling cascades. More recently it has become clear that, as most viruses, bacteria can enter cells via the clathrin-mediated pathway, indicating a key role for endocytosis in pathogens entry into cells. Here we review the pathways followed by Listeria monocytogenes to enter into non-phagocytic cells, as a model for the subversion of cellular functions to induce pathogens internalization.     

Pathogen-endoplasmic-reticulum interactions: in through the out door

A key determinant for the survival of intracellular pathogens is their ability to subvert the cellular processes of the host to establish a compartment that allows replication. Although most microorganisms internalized by host cells are efficiently cleared following fusion with lysosomes, many pathogens have evolved mechanisms to escape this degradation. In this Review, we provide insight into the molecular processes that are targeted by pathogens that interact with the endoplasmic reticulum and thereby subvert the immune response, ensure their survival intracellularly and cause disease. We also discuss how the endoplasmic reticulum 'strikes back' and controls microbial growth.     

Mechanisms of pathogen entry through the endosomal compartments

Several pathogens - bacteria, viruses and parasites - must enter mammalian cells for survival, replication and immune-system evasion. These pathogens generally make use of existing cellular pathways that are designed for nutrient uptake, receptor downregulation and signalling. Because most of these pathways end in lysosomes, an organelle that is capable of killing microorganisms, pathogens have developed remarkable means to avoid interactions with this lytic organelle.     

Effect of microbial pathogens on the diversity of aquatic populations, notably in Europe

The expansion of aquaculture and the demand for ornamental fish have resulted in the large-scale movements of aquatic animals and their pathogens. Here we review the most important non-native fish and shellfish pathogens in European waters and their global impacts on wild fish host populations. The role of theoretical models in the study of the impact of microbial pathogens is discussed, including its integration into risk assessments.     

The H-index as a quantitative indicator of the relative impact of human diseases

Assessment of the relative impact of diseases and pathogens is important for agencies and other organizations charged with providing disease surveillance, management and control. It also helps funders of disease-related research to identify the most important areas for investment. Decisions as to which pathogens or diseases to target are often made using complex risk assessment approaches; however, these usually involve evaluating a large number of hazards as it is rarely feasible to conduct an in-depth appraisal of each. Here we propose the use of the H-index (or Hirsch index) as an alternative rapid, repeatable and objective means of assessing pathogen impact. H-index scores for 1,414 human pathogens were obtained from the Institute for Scientific Information's Web of Science (WOS) in July/August 2010. Scores were compared for zoonotic/non-zoonotic, and emerging/non-emerging pathogens, and across taxonomic groups. H-indices for a subset of pathogens were compared with Disability Adjusted Life Year (DALY) estimates for the diseases they cause. H-indices ranged from 0 to 456, with a median of 11. Emerging pathogens had higher H-indices than non-emerging pathogens. Zoonotic pathogens tended to have higher H-indices than human-only pathogens, although the opposite was observed for viruses. There was a significant correlation between the DALY of a disease and the H-index of the pathogen(s) that cause it. Therefore, scientific interest, as measured by the H-index, appears to be a reflection of the true impact of pathogens. The H-index method can be utilized to set up an objective, repeatable and readily automated system for assessing pathogen or disease impact.     

Microbial quest for food in vivo: ‘Nutritional virulence’ as an emerging paradigm

Microbial access to host nutrients is a fundamental aspect of infectious diseases. Pathogens face complex dynamic nutritional host microenvironments that change with increasing inflammation and local hypoxia. Since the host can actively limit microbial access to nutrient supply, pathogens have evolved various metabolic adaptations to successfully exploit available host nutrients for proliferation. Recent studies have unraveled an emerging paradigm that we propose to designate as ‘nutritional virulence’. This paradigm is based on specific virulence mechanisms that target major host biosynthetic and degradation pathways (proteasomes, autophagy and lysosomes) or nutrient‐rich sources, such as glutathione, to enhance host supply of limiting nutrients, such as cysteine. Although Cys is the most limiting cellular amino acid, it is a metabolically favourable source of carbon and energy for various pathogens that are auxotrophic for Cys but utilize idiosyncratic nutritional virulence strategies to generate a gratuitous supply of host Cys. Therefore, proliferation of some intracellular pathogens is restricted by a host nutritional rheostat regulated by certain limiting amino acids, and pathogens have evolved idiosyncratic strategies to short circuit the host nutritional rheostat. Deciphering mechanisms of microbial ‘nutritional virulence’ and metabolism in vivo will facilitate identification of novel microbialand host targets for treatment and prevention of infectious diseases. Host–pathogen synchronization of amino acid auxotrophy indicates that this nutritional synchronization has been a major driving force in the evolution of many intracellular bacterial pathogens.     

Modulation of mammalian apoptotic pathways by intracellular protozoan parasites

During intracellular parasitic infections, pathogens and host cells take part in a complex web of events that are crucial for the outcome of the infection. Modulation of host cell apoptosis by pathogens attracted the attention of scientists during the last decade. Apoptosis is an efficient mechanism used by the host to control infection and limit pathogen multiplication and dissemination. In order to ensure completion of their complex life cycles and to guarantee transmission between different hosts, intracellular parasites have developed mechanisms to block apoptosis and sustain the viability of their host cells. Here, we review how some of the most prominent intracellular protozoan parasites modulate the main mammalian apoptotic pathways by emphasizing the advances from the last decade, which have begun to dissect this dynamic and complex interaction.     

The role of P2 receptors in controlling infections by intracellular pathogens

A growing number of studies have demonstrated the importance of ATP_e-signalling via P2 receptors as an important component of the inflammatory response to infection. More recent studies have shown that ATP_e can also have a direct effect on infection by intracellular pathogens, by modulating membrane trafficking in cells that contain vacuoles that harbour intracellular pathogens, such as mycobacteria and chlamydiae. A conserved mechanism appears to be involved in controlling infection by both of these pathogens, as a role for phospholipase D in inducing fusion between lysosomes and the vacuoles has been demonstrated. Other P2-dependent mechanisms are most likely operative in the cases of pathogens, such as Leishmania, which survive in an acidic phagolysosomal-like compartment. ATP_e may function as a “danger signal” that alerts the immune system to the presence of intracellular pathogens that damage the host cell, while different intracellular pathogens have evolved enzymes or other mechanisms to inhibit ATP_e-mediated signalling, which should, thus, be viewed as virulence factors for these pathogens.     

Host responses from innate to adaptive immunity after vaccination: Molecular and cellular events

The availability of effective vaccines has had the most profound positive effect on improving the quality of public health by preventing infectious diseases. Despite many successful vaccines, there are still old and new emerging pathogens against which there is no vaccine available. A better understanding of how vaccines work for providing protection will help to improve current vaccines as well as to develop effective vaccines against pathogens for which we do not have a proper means to control. Recent studies have focused on innate immunity as the first line of host defense and its role in inducing adaptive immunity; such studies have been an intense area of research, which will reveal the immunological mechanisms how vaccines work for protection. Toll-like receptors (TLRs), a family of receptors for pathogen-associated molecular patterns on cells of the innate immune system, play a critical role in detecting and responding to microbial infections. Importantly, the innate immune system modulates the quantity and quality of longterm T and B cell memory and protective immune responses to pathogens. Limited studies suggest that vaccines which mimic natural infection and/or the structure of pathogens seem to be effective in inducing long-term protective immunity. A better understanding of the similarities and differences of the molecular and cellular events in host responses to vaccination and pathogen infection would enable the rationale for design of novel preventive measures against many challenging pathogens.     

Plasmodesmata: the battleground against intruders

Plasmodesmata are intercellular channels that establish a symplastic communication pathway between neighboring cells in plants. Owing to this role, opportunistic microbial pathogens have evolved to exploit plasmodesmata as gateways to spread infection from cell to cell within the plant. However, although these pathogens have acquired the capacity to breach the plasmodesmal trafficking pathway, plants are unlikely to relinquish control over a structure essential for their survival so easily. In this review, we examine evidence that suggests plasmodesmata play an active role in plant immunity against viral, fungal and bacterial pathogens. We discuss how these pathogens differ in their lifestyles and infection modes, and present the defense strategies that plants have adopted to prevent the intercellular spread of an infection.     

Functional group/guild modelling of inter-specific pathogen interactions: a potential tool for predicting the consequences of co-infection

Although co-infection is the norm in most human and animal populations, clinicians currently have no practical tool to assist them in choosing the best treatment strategy for such patients. Given the vast range of potential pathogens which may co-infect the host, obtaining such a practical tool may seem an intractable problem. In ecology the joint concepts of functional groups and guilds have been used to conceptually simplify complex ecosystems, in order to understand how their component parts interact and may be manipulated. Here we propose a mechanism by which to apply these concepts to pathogen co-infection systems. Further, we describe how these groups could be incorporated into a mathematical modelling framework which, after validation, could be used as a clinical tool to predict the outcome of any particular combination of pathogens co-infecting a host.     

Mucin dynamics and enteric pathogens

The extracellular secreted mucus and the cell surface glycocalyx prevent infection by the vast numbers of microorganisms that live in the healthy gut. Mucin glycoproteins are the major component of these barriers. In this Review, we describe the components of the secreted and cell surface mucosal barriers and the evidence that they form an effective barricade against potential pathogens. However, successful enteric pathogens have evolved strategies to circumvent these barriers. We discuss the interactions between enteric pathogens and mucins, and the mechanisms that these pathogens use to disrupt and avoid mucosal barriers. In addition, we describe dynamic alterations in the mucin barrier that are driven by host innate and adaptive immune responses to infection.     

Why is sterility virulence most common in sexually transmitted infections? Examining the role of epidemiology

Sterility virulence, or the reduction in host fecundity due to infection, occurs in many host–pathogen systems. Notably, sterility virulence is more common for sexually transmitted infections (STIs) than for directly transmitted pathogens, while other forms of virulence tend to be limited in STIs. This has led to the suggestion that sterility virulence may have an adaptive explanation. By focusing upon finite population models, we show that the observed patterns of sterility virulence can be explained by consideration of the epidemiological differences between STIs and directly transmitted pathogens. In particular, when pathogen transmission is predominantly density invariant (as for STIs), and mortality is density dependent, sterility virulence can be favored by demographic stochasticity, whereas if pathogen transmission is predominantly density dependent, as is common for most directly transmitted pathogens, sterility virulence is disfavored. We show these conclusions can hold even if there is a weak selective advantage to sterilizing.     

Feeding strategies of anthropophilic mosquitoes result in increased risk of pathogen transmission

Vector-borne disease specialists have traditionally assumed that in each egg-laying cycle mosquitoes take a single bloodmeal that is used for egg development and feed on plant sugars for flight and production of energy reserves. Here we review research showing that for two of the most important vectors of human pathogens (Anopheles gambiae and Aedes aegypti) imbibing multiple bloodmeals during a gonotrophic cycle while foregoing sugar feeding is a common behaviour, not an exception. By feeding preferentially and frequently on human blood these species increase their fitness and exponentially boost the basic reproduction rate of pathogens they transmit. Although the epidemiological outcome is similar, there are important differences in processes underlying frequent human contact by these species that merit more detailed investigation.     

Advances in macrocyclic peptide-based antibiotics

Macrocyclic peptide-based natural products have provided powerful new antibiotic drugs, drug candidates, and scaffolds for medicinal chemists as a source of inspiration to design novel antibiotics. While most of those natural products are active mainly against Gram-positive pathogens, novel macrocyclic peptide-based compounds have recently been described, which exhibit potent and specific activity against some of the most problematic Gram-negative ESKAPE pathogens. This mini-review gives an up-date on recent developments.