Ferroptosis: Final destination for cancer?

Ferroptosis is a recently defined, non‐apoptotic, regulated cell death (RCD) process that comprises abnormal metabolism of cellular lipid oxides catalysed by iron ions or iron‐containing enzymes. In this process, a variety of inducers destroy the cell redox balance and produce a large number of lipid peroxidation products, eventually triggering cell death. However, in terms of morphology, biochemistry and genetics, ferroptosis is quite different from apoptosis, necrosis, autophagy‐dependent cell death and other RCD processes. A growing number of studies suggest that the relationship between ferroptosis and cancer is extremely complicated and that ferroptosis promises to be a novel approach for the cancer treatment. This article primarily focuses on the mechanism of ferroptosis and discusses the potential application of ferroptosis in cancer therapy.     

自噬和铁死亡的相互联系

自噬是一个保守的细胞内降解系统,在细胞死亡中起着双重作用,可以为细胞在营养缺乏条件下提供一些必要的营养物质促进细胞存活,但是自噬过度发生会导致细胞内一些正常组分被降解从而加速细胞死亡.铁死亡是一种新的细胞死亡调控形式,主要依赖于铁的积累和脂质过氧化.铁死亡在细胞形态、生物化学特征和所涉及的调控因子上都与自噬以及其他类型...     

Type I interferons in regulation of mucosal immunity

The mucosal system is the first line of defense against many pathogens. It is continuously exposed to dietary and microbial antigens, and thus the host must maintain a homeostatic environment between commensal microbiota and pathogenic infections. Following infections and inflammatory events, a rapid innate immune response is evoked to dampen the inflammatory processes. Type I interferons, a family of pleiotropic cytokines and major products of the innate immune response, have a key role in these early immune events at the mucosa, as reviewed here. With the emergence of new discoveries of immune cell types in mucosal tissues and their reactions to commensal and pathogenic organisms, we also review the opportunities for exciting research in this field.     

Fungus-Specific CD4 T Cells as Specific Sensors for Identification of Pulmonary Fungal Infections

Patients with cystic fibrosis (CF) suffer from chronic lung infections, caused by bacterial, viral or fungal pathogens, which determine morbidity and mortality. The contribution of individual pathogens to chronic disease and acute lung exacerbations is often difficult to determine due to the complex composition of the lung microbiome in CF. In particular, the relevance of fungal pathogens in CF airways remains poorly understood due to limitations of current diagnostics to identify the presence of fungal pathogens and to resolve the individual host–pathogen interaction status. T-lymphocytes play an essential role in host defense against pathogens, but also in inappropriate immune reactions such as allergies. They have the capacity to specifically recognize and discriminate the different pathogens and orchestrate a diverse array of effector functions. Thus, the analysis of the fungus-specific T cell status of an individual can in principle provide detailed information about the identity of the fungal pathogen(s) encountered and the actual fungus–host interaction status. This may allow to classify patients, according to appropriate (protective) or inappropriate (pathology-associated) immune reactions against individual fungal pathogens. However, T cell-based diagnostics are currently not part of the clinical routine. The identification and characterization of fungus-specific T cells in health and disease for diagnostic purposes are associated with significant challenges. Recent technological developments in the field of fungus-specific T helper cell detection provide new insights in the host T cell–fungus interaction. In this review, we will discuss basic principles and the potential of T cell-based diagnostics, as well as the perspectives and further needs for use of T cells for improved clinical diagnostics of fungal diseases.     

No effect of Wolbachia on resistance to intracellular infection by pathogenic bacteria in Drosophila melanogaster

Multiple studies have shown that infection with the endosymbiotic bacterium Wolbachia pipientis confers Drosophila melanogaster and other insects with resistance to infection by RNA viruses. Studies investigating whether Wolbachia infection induces the immune system or confers protection against secondary bacterial infection have not shown any effect. These studies, however, have emphasized resistance against extracellular pathogens. Since Wolbachia lives inside the host cell, we hypothesized that Wolbachia might confer resistance to pathogens that establish infection by invading host cells. We therefore tested whether Wolbachia-infected D. melanogaster are protected against infection by the intracellular pathogenic bacteria Listeria monocytogenes and Salmonella typhimurium, as well as the extracellular pathogenic bacterium Providencia rettgeri. We evaluated the ability of flies infected with Wolbachia to suppress secondary infection by pathogenic bacteria relative to genetically matched controls that had been cured of Wolbachia by treatment with tetracycline. We found no evidence that Wolbachia alters host ability to suppress proliferation of any of the three pathogenic bacteria. Our results indicate that Wolbachia-induced antiviral protection does not result from a generalized response to intracellular pathogens.     

病原体调控宿主细胞周期致病机制的研究进展

病原体在长期进化中形成多种策略以利于自身增殖,进而导致多种疾病.这些策略包括干扰宿主免疫反应、调控细胞周期与凋亡等.近年来,人们越来越关注病原体通过干扰宿主细胞周期致病的机制,有助于更好了解病原体与宿主的相互作用.本文综述了病原体引起宿主细胞周期停滞在不同时期的机制,特别是一些细菌分泌毒力因子引起宿主细胞周期紊乱并导致...     

Acanthamoeba Interaction with Extracellular Matrix Glycoproteins: Biological and Biochemical Characterization and Role in Cytotoxicity and Invasiveness

ABSTRACT. Acanthamoeba are free-living amoebae that are dispersed in most environments. Occasionally, Acanthamoeba cause serious human infections, such as keratitis and encephalitis. During the infection process, amoebic adhesion to, and degradation of, host cells and their extracellular matrix (ECM) appear to be important requirements. We examined the interaction of Acanthamoeba with the ECM, and related this event to host cell destruction and tissue invasion. Pathogenic Acanthamoeba culbertsoni differentially attached on the ECM glycoproteins laminin-1, collagen-I, and fibronectin, as compared with non-pathogenic Acanthamoeba astronyxis . Binding to collagen-I and laminin-1 induced A. culbertsoni to become flattened and elongated. Because attachment on laminin-1 was higher in A. culbertsoni , laminin-1 was chosen for further analysis. A 55-kDa laminin-binding protein was identified in pathogenic amoebae, but it was not found in non-pathogenic amoebae. No differential cytotoxicity against distinct cell types was observed between A. culbertsoni incubated with or without ECM. On the other hand, binding on collagen-I or matrigel scaffolds induced a differential effect where A. culbertsoni invaded collagen-I matrices more rapidly. These results indicate that ECM recognition, as an antecedent to tissue invasion, may be a trait characteristic of pathogenic Acanthamoeba .     

Microbial considerations in genetically engineered mouse research

Microbial infections have long been of concern to scientists using laboratory rodents because of their potential to confound and invalidate research. With the explosion of genetically engineered mice (GEM), new concerns over the impact of microbial agents have emerged because these rodents in many cases are more susceptible to disease than their inbred or outbred counterparts. Moreover, interaction between microbe and host and the resulting manifestation of disease conceivably differ between GEM and their inbred and outbred counterparts. As a result, infections may alter the GEM phenotype and confound interpretation of results and conclusions about mutated gene function. In addition, because GEM are expensive to produce and maintain, contamination by pathogens or opportunists has severe economic consequences. This review addresses how microbial infections may influence phenotype, how immunomodulation of the host as the result of induced mutations may modify host susceptibility to microbial infections, how novel host:microbe interactions have led to the development of new animal models for disease, how phenotype changes have led to the discovery of new pathogens, and new challenges associated with prevention and control of microbial infections in GEM. Although the focus is on naturally occurring infections, extensive literature on the use of GEM in studies of microbial pathogenesis also exists, and the reader is referred to this literature if microbial infection is a suspected culprit in phenotype alteration.     

An Experimental Model to Study Tuberculosis-Malaria Coinfection upon Natural Transmission of Mycobacterium tuberculosis and Plasmodium berghei

Coinfections naturally occur due to the geographic overlap of distinct types of pathogenic organisms. Concurrent infections most likely modulate the respective immune response to each single pathogen and may thereby affect pathogenesis and disease outcome. Coinfected patients may also respond differentially to anti-infective interventions. Coinfection between tuberculosis as caused by mycobacteria and the malaria parasite Plasmodium, both of which are coendemic in many parts of sub-Saharan Africa, has not been studied in detail. In order to approach the challenging but scientifically and clinically highly relevant question how malaria-tuberculosis coinfection modulate host immunity and the course of each disease, we established an experimental mouse model that allows us to dissect the elicited immune responses to both pathogens in the coinfected host. Of note, in order to most precisely mimic naturally acquired human infections, we perform experimental infections of mice with both pathogens by their natural routes of infection, i.e. aerosol and mosquito bite, respectively.     

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.     

Chlamydia and apoptosis: life and death decisions of an intracellular pathogen

The chlamydiae are important obligate intracellular prokaryotic pathogens that, each year, are responsible for millions of human infections involving the eye, genital tract, respiratory tract, vasculature and joints. The chlamydiae grow in cytoplasmic vesicles in susceptible host cells, which include the mucosal epithelium, vascular endothelium, smooth muscle cells, circulating monocytes and recruited or tissue-specific macrophages. One important pathogenic strategy that chlamydiae have evolved to promote their survival is the modulation of programmed cell death pathways in infected host cells. The chlamydiae can elicit the induction of host cell death, or apoptosis, under some circumstances and actively inhibit apoptosis under others. This subtle pathogenic mechanism highlights the manner in which these highly successful pathogens take control of infected cells to promote their own survival - even under the most adverse circumstances.     

Influence of human gastrointestinal tract bacterial pathogens on host cell apoptosis

Several pathogenic bacteria are able to trigger apoptosis in the host cell, but the mechanisms by which it occurs differ, and the resulting pathology can take different courses. Induction and/or blockage of programmed cell death upon infection is a result of complex interaction of bacterial proteins with cellular proteins involved in signal transduction and apoptosis. In this review we focus on pro/anti-apoptotic activities exhibited by two enteric pathogens Salmonella enterica, Yersinia spp. and gastric pathogen Helicobacter pylori. We present current knowledge on how interaction between mammalian and bacterial cell relates to the molecular pathways of apoptosis, and what is the role of apoptosis in pathogenesis.     

Immunity against extracellular pathogens

Summary Eukaryotic cells live in a relatively comfortable equilibrium with a wide variety of microbes. However, while many of the cohabiting microorganisms are harmless or even beneficial to the eukaryotic host, a number of prokaryotes have evolved the capacity to invade and replicate within host cells, thereby becoming potentially pathogenic. To be able to cope with potential pathogens, most organisms have developed several host defense mechanisms. First, microbes can be internalized and destroyed by a number of cell types of an innate immune system in a rather aspecific manner. Second, more complex organisms possess additionally an adaptive immune system that is capable of eliminating hazardous microbes in a highly specific manner. This review describes recent progress in our understanding of how pathogens interact with cells of the immune system, resulting in activation of the immune system or, for certain microorganisms, in the evasion of host defense reactions.     

Reprogramming the phagocytic pathway—intracellular pathogens and their vacuoles (Review)

Phagocytic immune cells (particularly macrophages and neutrophils) take up and digest particles that have invaded our bodies. In doing so, they represent a very early line of defence against a microbial attack. During uptake, the particles are wrapped by a portion of the phagocyte's plasma membrane, and a new endocytic compartment, the phagosome, is formed. The typical fate of a phagosome is its fusion with lysosomes to yield a phagolysosome in which the particle is digested. Recent data show that some ‘intracellular microorganisms’ that can cause severe illnesses (tuberculosis, leprosy, legionaire's disease and others) manage to reprogramme the host phagocytes not to deliver them to the lysosomal compartment. This probably results in increased survival of the pathogens. The analysis of the composition of such ‘novel’ compartments and research on the molecular mechanisms underlying the microbial interference with host cell functions are likely to yield important insights into: (1) which endocytic/phagocytic compartments phagocytes employ to handle ingested material in general; (2) how some pathogenic microorganisms can reprogramme the phagocytic pathway; and possibly (3) how infections caused by these microorganisms can be treated more effectively. Here, some studies are presented analysing which compartments intracellular pathogens inhabit and how microbes might be able to reprogramme their host cells.     

Antibody-mediated protective immunity in fungal infections

The host response to fungal infection is the result of a complex interaction between the pathogen and the host's innate and adaptive immune system. Cell-mediated immunity is widely considered to be critical for the successful outcome of fungal infections. However, in recent years numerous studies have established that certain antibodies may play an important role in host immunoprotection against pathogenic fungi, through interaction with different cellular targets, such as mannans, heat shock proteins, capsular polysaccharides, surface proteins, and yeast killer toxin receptors, with mechanisms of action sometimes still undefined. This review summarizes the latest findings on the role of different types of antibodies in the antifungal defense against infections caused by epidemiologically important fungi, such as Candida albicans, Cryptococcus neoformans, Histoplasma capsulatum, and others. New perspectives of antibody-mediated therapy, based on the availability of monoclonal and recombinant antibodies as well as genetically engineered antibody fragments of defined specificity, will be also envisaged and discussed.     

C-ferroptosis is an iron-dependent form of regulated cell death in cyanobacteria

Ferroptosis is an oxidative and iron-dependent form of regulated cell death (RCD) recently described in eukaryotic organisms like animals, plants, and parasites. Here, we report that a similar process takes place in the photosynthetic prokaryote Synechocystis sp. PCC 6803 in response to heat stress. After a heat shock, Synechocystis sp. PCC 6803 cells undergo a cell death pathway that can be suppressed by the canonical ferroptosis inhibitors, CPX, vitamin E, Fer-1, liproxstatin-1, glutathione (GSH), or ascorbic acid (AsA). Moreover, as described for eukaryotic ferroptosis, this pathway is characterized by an early depletion of the antioxidants GSH and AsA, and by lipid peroxidation. These results indicate that all of the hallmarks described for eukaryotic ferroptosis are conserved in photosynthetic prokaryotes and suggest that ferroptosis might be an ancient cell death program.     

Microbial translocation of the blood-brain barrier

A major contributing factor to high mortality and morbidity associated with CNS infection is the incomplete understanding of the pathogenesis of this disease. Relatively small numbers of pathogens account for most cases of CNS infections in humans, but it is unclear how such pathogens cross the blood-brain barrier (BBB) and cause infections. The development of the in vitro BBB model using human brain microvascular endothelial cells has facilitated our understanding of the microbial translocation of the BBB, a key step for the acquisition of CNS infections. Recent studies have revealed that microbial translocation of the BBB involves host cell actin cytoskeletal rearrangements, most likely as the result of specific microbial-host interactions. A better understanding of microbial-host interactions that are involved in microbial translocation of the BBB should help in developing new strategies to prevent CNS infections. This review summarises our current understanding of the pathogenic mechanisms involved in translocation of the BBB by meningitis-causing bacteria, fungi and parasites.     

Regulatory cells and infectious agents: detentes cordiale and contraire

This brief review describes the types of interactions that occur between CD4(+)CD25(+) regulatory T cells (Treg) and microbial pathogens. These interactions range from one of mutual benefit (détente cordiale) such as occurs in Leishmania major infection of resistant mouse strains, to instances where the Treg response appears to mainly favor the pathogen and be detrimental to the host (détente contraire). Examples of the latter include chronic persistent infections with retroviruses, perhaps including HIV, and hepatitis C virus. The Treg response also hampers the effectiveness of immunity against some acute virus infections such as HSV. Evidence is also discussed showing that Treg can play a benevolent role to limit the severity of bystander tissue damage in circumstances where the immune response to pathogens is immunopathological. Finally, emerging approaches are discussed that either blunt or activate Treg and that could be used practically to manage host-pathogen interaction.     

The host cytosol: front-line or home front?

Intracellular pathogens replicate in modified vacuolar compartments or in the cytosol of host cells. Many pathogenic bacterial species have evolved to modify the host vacuolar environment, but little is known about the mammalian cytosol as a medium for bacterial growth. Recent studies indicate that the cytosol is restrictive for the growth of bacteria other than cytosolic pathogens in contrast to earlier research that provided evidence that any bacteria with access to the cytosol can replicate there. Comparison of these studies suggests that the cytosolic contents of various host cell types can be differentially permissive for bacterial growth, and that both host and bacterial factors are important in determining the ability of particular bacteria to replicate in the cytosol.