Overview of vaccines and vaccination

Of the 80-plus known infectious agents pathogenic for humans, there are now more than 30 vaccines against 26 mainly viral and bacterial infections and these greatly minimize subsequent disease and prevent death after exposure to those agents. This article describes the nature of the vaccines, from live attenuated agents to subunits, their efficacy and safety, and the kind of the immune responses generated by those vaccines, which are so effective. To date, all licensed vaccines generate especially specific antibodies, which attach to the infectious agent and therefore can very largely prevent infection. These vaccines have been so effective in developed countries in preventing mortality after a subsequent infection that attempts are being made to develop vaccines against many of the remaining infectious agents. Many of the latter are difficult to manipulate; they can cause persisting infections or show great antigenic variation. A range of new approaches to improve selected immune responses, such as immunization with DNA or chimeric live vectors, viral or bacterial, are under intense scrutiny, as well as genomic analysis of the agent.     

Antifungal Distribution Into Cerebrospinal Fluid,Vitreous Humor,Bone, and Other Difficult Sites

The incidence of invasive fungal infections continues to increase, especially in patients with immune dysfunction. Fungal infections are often difficult to treat, requiring therapy for weeks or months to eradicate infection. Although fungal infections of the central nervous system, eye, and bones occur less frequently than infections at other sites, it is necessary to assess the utility of the currently available antifungal agents in treating these infections. Unfortunately, information regarding drug distribution to these sites is often scarce and limited to a few animal studies or case reports. This review summarizes information about commonly used antifungal agents and their penetration into the central nervous system, eye, and bone.     

Substances involved in the natural resistance of fish to infection–A review

Natural‘antibodies’are substances found in the blood of animals that have not been immunised against infective agents. However, exposure to these agents or to cross-reacting antigens may well have taken place. Fish contain naturally-occurring, relatively nonspecific, lectin-like proteins or glycoproteins, which are distinct from immunoglobulins, and which react with a wide variety of antigens and may confer some degree of immunity against natural infection. In most cases the cause of the antigenic stimulus is not obvious although the formation of these‘antibodies’may have been brought about by exposure to various micro-organisms. Many of these antibody-like molecules behave in a similar manner to immune antibodies or immunoglobulins and cross-react with specific carbohydrate moieties on the cell walls of bacteria, erythrocytes and certain other cellular antigens, due to the presence of similar antigenic determinants. It is difficult to ascribe an appropriate definition to the term‘natural antibody’. In fish, these‘antibodies’have been so designated on the basis of functional rather than structural criteria. Such naturally-occurring, low grade, antibody-like‘immune’substances include‘acute phase’proteins, lysozyme and chitinase, interferon, agglutinins, lysins, complement and properdin, precipitins, and non-immunoglobulin, lectin-like molecules. In addition to the above non-immunoglobulin materials, natural immunoglobulins identifiable as IgM have also been reported in fish. Furthermore, mucus contains many biochemical agents capable of reaction against infective organisms and thus providing the host with an immediate or a first line of defence mechanism. This review compiles some of the relevant information in the literature concerned with natural‘immune’substances, present in the serum and mucus of fish, involved in protection against pathogens. Wherever possible the basic physicochemical properties of these substances are indicated and their potential immunobiological functions discussed.     

细菌感染显像剂的研究进展

细菌感染显像剂是利用一些示踪基团(如放射性核素及荧光染料)标记对细菌具有特异性识别作用的导向物,通过检测示踪信号定位细菌感染部位。到目前为止,针对细菌内的特异性位点(如细胞壁、酶、受体等)研制和开发了一系列细菌感染显像剂(包括核素标记的抗生素、噬菌体、抗菌肽、核苷及荧光染料标记的糖类等),这些显像剂能在细菌感染部位高度特异性聚集,有望应用于临床早期诊断细菌感染。本文对这些细菌感染显像剂的种类、浓集机制及研究现状进行了概述,并在此基础上,总结了理想细菌感染显像剂所应具有的特征,为进一步研究和开发新的细菌感染显像剂提供参考。     

Antifungal Penetration into the Nail and New Topicals for Onychomycosis

Onychomycosis is a common and difficult to treat infection, owing predominately to the limited penetration of topical drugs to the site of infection. Systemic drugs are not an option for all patients due to adverse events and drug-drug interactions. In this article, we review the nail penetration and clinical efficacy data of topical drugs, including older agents such as ciclopirox and amorolfine, as well as the newer agents, efinaconazole and tavaborole. Additionally, we describe some unresolved questions in the management of onychomycosis.     

Adventive eriophyoid mites: a global review of their impact, pathways, prevention and challenges

Eriophyoids have high potential as adventive mite species (AMS) because their small size make them difficult to detect, and can be easily distributed in world trade. Economic, social and environmental impact from adventive eriophyoid mites has been significant. Considerable attention has been given to adventive insect species while adventive mites have received little attention and little information is available for eriophyoids. This paper summarizes information on adventive eriophyoid mites, their impact, and the history of some important invasions. The status of adventive species of eriophyoids introduced as biological control agents of weeds is presented. A list of eriophyoid mites reported as invasive species worldwide is given. Pathways of concern and biosecurity actions to reduce the risk of eriophyoid mites are discussed. The need to raise public awareness of the risk and importance of these tiny organisms as AMS is emphasized. Scientific and technical challenges to deal with adventive eriophyoids are discussed.     

Soilborne Plant Diseases Caused by Pythium spp.: Ecology,Epidemiology, and Prospects for Biological Control

Soilborne root diseases caused by plant pathogenic Pythium species cause serious losses in a number of agricultural production systems, which has led to a considerable effort devoted to the development of biological agents for disease control. In this article we review information on the ecology and biological control of these pathogens with the premise that a clear understanding of the ecology of the pathogen will assist in the development of efficacious biocontrol agents. The lifecycles of the pathogens and etiology of host infection also are reviewed, as are epidemiological concepts of inoculum-disease relationships and the influence of environmental factors on pathogen aggressiveness and host susceptibility. A number of fungal and bacterial biocontrol agents are discussed and parallels between their ecology and that of the target pathogens highlighted. The mechanisms by which these microbial agents suppress diseases caused by Pythium spp., such as interference with pathogen survival, disruption of the process of plant infection, and induced host resistance, are evaluated. The possibilities for enhancement of efficacy of specific biological control agents by genetic manipulation or deployment tactics are discussed, as are conceptual suggestions for consideration when developing screening programs for antagonists.     

Bisphosphonated fluoroquinolone esters as osteotropic prodrugs for the prevention of osteomyelitis

Osteomyelitis is a difficult to treat bacterial infection of the bone. Delivering antibacterial agents to the bone may overcome the difficulties in treating this illness by effectively concentrating the antibiotic at the site of infection and by limiting the toxicity that may result from systemic exposure to the large doses conventionally used. Using bisphosphonates as osteophilic functional groups, different forms of fluoroquinolone esters were synthesized and evaluated for their ability to bind bone and to release the parent antibacterial agent. Bisphosphonated glycolamide fluoroquinolone esters were found to present a profile consistent with effective and rapid bone binding and efficient release of the active drug moiety. They were assessed for their ability to prevent bone infection in vivo and were found to be effective when the free fluoroquinolones were not.     

Nosocomial lung infections in adult intensive care units

Nosocomial respiratory tract infections are the leading type of nosocomial infections. Despite the development of new antibiotic therapies, they are associated with an increased morbidity and mortality. Patients with comorbidities are especially predisposed to acquire these infections, as are patients exposed to respiratory therapy. Aspiration of colonized secretions from the oropharynx is the main mechanism of infection development. Barrier techniques to reduce aspiration and antimicrobial agents to alter bacterial flora are important in preventing pneumonia episodes. The initial institution of an adequate antibiotic regimen is a determinant of outcome. Nosocomial pneumonias are often difficult to treat due to antibiotic-resistant bacteria. Antibiotic policies are crucial in avoiding a progression in antibiotic resistance.     

Chromatographic benefits of elevated temperature for the proteomic analysis of membrane proteins

Integral membrane proteins (IMPs) perform crucial cellular functions and are the primary targets for most pharmaceutical agents. However, the hydrophobic nature of their membrane-embedded domains and their intimate association with lipids make them difficult to handle. Numerous proteomic platforms that include LC separations have been reported for the high-throughput profiling of complex protein samples. However, there are still many challenges to overcome for proteomic analyses of IMPs, especially as compared to their soluble counterparts. In particular, considerations for the technical challenges associated with chromatographic separations are just beginning to be investigated. Here, we review the benefits of using elevated temperatures during LC for the proteomic analysis of complex membrane protein samples.     

Infection Spreading in a Population with Evolving Contacts

We study the spreading of an infection within an SIS epidemiological model on a network. Susceptible agents are given the opportunity of breaking their links with infected agents. Broken links are either permanently removed or reconnected with the rest of the population. Thus, the network coevolves with the population as the infection progresses. We show that a moderate reconnection frequency is enough to completely suppress the infection. A partial, rather weak isolation of infected agents suffices to eliminate the endemic state.     

Diseases and causes of death in European bats: dynamics in disease susceptibility and infection rates

Background

Bats receive increasing attention in infectious disease studies, because of their well recognized status as reservoir species for various infectious agents. This is even more important, as bats with their capability of long distance dispersal and complex social structures are unique in the way microbes could be spread by these mammalian species. Nevertheless, infection studies in bats are predominantly limited to the identification of specific pathogens presenting a potential health threat to humans. But the impact of infectious agents on the individual host and their importance on bat mortality is largely unknown and has been neglected in most studies published to date.

Methodology/Principal Findings

Between 2002 and 2009, 486 deceased bats of 19 European species (family Vespertilionidae) were collected in different geographic regions in Germany. Most animals represented individual cases that have been incidentally found close to roosting sites or near human habitation in urban and urban-like environments. The bat carcasses were subjected to a post-mortem examination and investigated histo-pathologically, bacteriologically and virologically. Trauma and disease represented the most important causes of death in these bats. Comparative analysis of pathological findings and microbiological results show that microbial agents indeed have an impact on bats succumbing to infectious diseases, with fatal bacterial, viral and parasitic infections found in at least 12% of the bats investigated.

Conclusions/Significance

Our data demonstrate the importance of diseases and infectious agents as cause of death in European bat species. The clear seasonal and individual variations in disease prevalence and infection rates indicate that maternity colonies are more susceptible to infectious agents, underlining the possible important role of host physiology, immunity and roosting behavior as risk factors for infection of bats.     

Invasive fungal infections in critically ill patients: different therapeutic options and a uniform strategy

The high morbidity, mortality, and healthcare costs associated with the invasive fungal infections, especially in the critical care setting, is of importance since the prophylactic, empiric, and pre-emptive therapy interventions, based on early identification of risk factors, is of common occurrence. In the last years alone there have been important developments in antifungal pharmacotherapy. Evidence-based studies using new antifungal agents are now emerging as important players in the pharmacotherapy of invasive fungal infections in seriously ill and difficult patients. However, data on critically ill patients are more limited and usually recovered from general studies. This study shows the benefits obtained by the new antifungal agents on different clinical situations in critical care units. The increasing number of non-C. albicans species and the high mortality rates in these settings suggest that the application of early de-escalation therapy in critically ill patients with fungal infection should be mandatory. The possibility of using antifungal combination therapy in these types of patients should be considered.     

Allosteric transinhibition by specific antagonists in CCR2/CXCR4 heterodimers

Chemokine receptors are presently used as targets for candidate drugs in the frame of inflammatory diseases and human immunodeficiency virus infection. They were shown to dimerize, but the functional relevance of dimerization in terms of drug action remains poorly understood. We reported previously the existence of negative binding cooperativity between the subunits of CCR2/CCR5 heterodimers. In the present study, we extend these observations to heterodimers formed by CCR2 and CXCR4, which are more distantly related. We also show that specific antagonists of one receptor inhibit the binding of chemokines to the other receptor as a consequence of their heterodimerization, both in recombinant cell lines and primary leukocytes. This resulted in a significant functional cross-inhibition in terms of calcium mobilization and chemotaxis. These data demonstrate that chemokine receptor antagonists regulate allosterically the functional properties of receptors on which they do not bind directly, with important implications on the effects of these potential therapeutic agents.     

Community behavior and amyloid-associated phenotypes among a panel of uropathogenic E. coli

Uropathogenic Escherichia coli (UPEC) are the major causative agents of urinary tract infection and engage in a coordinated genetic and molecular cascade to colonize the urinary tract. Disrupting the assembly and/or function of virulence factors and bacterial biofilms has emerged as an attractive target for the development of new therapeutic strategies to prevent and treat urinary tract infection, particularly in the era of increasing antibiotic resistance among human pathogens. UPEC vary widely in their genetic and molecular phenotypes and more data are needed to understand the features that distinguish isolates as more or less virulent and as more robust biofilm formers or poor biofilm formers. Curli are extracellular functional amyloid fibers produced by E. coli that contribute to pathogenesis and influence the host response during urinary tract infection (UTI). We have examined the production of curli and curli-associated phenotypes including biofilm formation among a specific panel of human clinical UPEC that has been studied extensively in the mouse model of UTI. Motility, curli production, and curli-associated biofilm formation attached to plastic were the most prevalent behaviors, shared by most clinical isolates. We discuss these results in the context on the previously reported behavior and phenotypes of these isolates in the murine cystitis model in vivo.     

Bacteriocins: perspective for the development of novel anticancer drugs

Antimicrobial peptides (AMPs) from prokaryotic source also known as bacteriocins are ribosomally synthesized by bacteria belonging to different eubacterial taxonomic branches. Most of these AMPs are low molecular weight cationic membrane active peptides that disrupt membrane by forming pores in target cell membranes resulting in cell death. While these peptides known to exhibit broad-spectrum antimicrobial activity, including antibacterial and antifungal, they displayed minimal cytotoxicity to the host cells. Their antimicrobial efficacy has been demonstrated in vivo using diverse animal infection models. Therefore, we have discussed some of the promising peptides for their ability towards potential therapeutic applications. Further, some of these bacteriocins have also been reported to exhibit significant biological activity against various types of cancer cells in different experimental studies. In fact, differential cytotoxicity towards cancer cells as compared to normal cells by certain bacteriocins directs for a much focused research to utilize these compounds as novel therapeutic agents. In this review, bacteriocins that demonstrated antitumor activity against diverse cancer cell lines have been discussed emphasizing their biochemical features, selectivity against extra targets and molecular mechanisms of action.

     

Using Antifungal Pharmacodynamics to Improve Patient Outcomes

In vitro and in vivo studies of available and investigational antifungals have broadened our understanding of the pharmacodynamics of these agents as well as the pharmacokinetic/pharmacodynamic characteristics that are associated with efficacy. These data are increasingly being used as surrogate means to answer questions about dosing and administration of antimicrobial agents in order to improve outcomes in patients with invasive fungal infections, as these questions are difficult to answer in clinical trials. The objective of this article is to review the pharmacodynamic activity of widely used classes of antifungal agents, including the azoles, amphotericin B, and the echinocandins, discuss the pharmacokinetic/pharmacodynamic parameters associated with efficacy of these agents in preclinical studies, and describe how this information is being translated into the clinical arena to optimize patient outcomes.     

The living strategy of nematophagous fungi

The infection structures, trophism, and ecological character of nematophagous fungi are reviewed in this article on the basis of data extracted from the literature and the most recent experiments conducted in this area. Traditionally, nematophagous fungi are classified into four groups according to their modes of attacking nematodes: nematode-trapping fungi using adhesive or mechanical hyphal traps, endoparasitic fungi using their spores, eggparasitic fungi invading nematode eggs or females with their hyphal tips, and toxin-producing fungi immobilizing nematodes before invasion. In the present review, we focus on the first two groups. The living strategies of these nematophagous fungi depend on the diversity of their infection structures, such as different traps and spore types, which determine the modes of infecting nematodes. The diversity of trophic modes of nematophagous fungi is an important prerequisite for fungal survival and activity in soil. The abundance and activity of Hirsutella rhossiliensis and H. minnesotensis, representatives of endoparasites and potential biocontrol agents against nematodes, are highly dependent on environmental factors. Comprehensive understanding of the survival and activity of nematophagous fungi in soil is fundamental for the exploitation of these fungi as successful biocontrol agents.     

Phenotypic and Functional Characterization of Monoclonal Antibodies with Specificity for Rhesus Macaque CD200, CD200R and Mincle

Lectin-like molecules and their receptors are cell surface molecules that have been shown to play a role in either facilitating infection or serving as transporters of HIV/SIV in vivo. The role of these lectin-like molecules in the pathogenesis of HIV/SIV infection continues to be defined. In efforts to gain further insight on the potential role of these lectin-like molecules, our laboratory generated monoclonal antibodies (mAb) against the human analogs of rhesus macaque CD200, CD200R and Mincle, since the rhesus macaques are accepted as the most reliable animal model to study human HIV infection. The characterization of the cell lineages from the blood and various tissues of rhesus macaques that express these lectin-like molecules are described herein. Among the mononuclear cells, the cells of the myeloid lineage of rhesus macaques are the predominant cell lineages that express readily detectable levels of CD200, CD200R and Mincle that is similar to the expression of Siglec-1 and Siglec-3 reported by our laboratory earlier. Subset analysis revealed that a higher frequency of the CD14⁺/CD16^- subset from normal rhesus macaques express CD200, CD200R and Mincle. Differences in the frequencies and density of expression of these molecules by the gated population of CD14⁺ cells from various tissues are noted with PBMC and bone marrow expressing the highest and the mononuclear cells isolated from the colon and ileum expressing the lowest levels. While a significant frequency of pDCs and mDCs express Siglec-1/Siglec-3, a much lower frequency expresses CD200, CD200R and Mincle in PBMCs from rhesus macaques. The mAb against CD200 and CD200R but not Mincle appear to inhibit the infection of macrophage tropic SIV/SHIV in vitro. We conclude that these mAbs may have potential to be used as adjunctive therapeutic agents to control/inhibit SIV/HIV infection.