Host cell death machinery as a target for bacterial pathogens

Elimination of infected cells via programmed cell death plays a fundamental role in the defense of multicellular organisms against bacteria, viruses, and parasites. Several pathogens have therefore evolved sophisticated strategies to modulate the host cell death programme for their survival. This review aims to summarize recent findings on how bacterial pathogens interfere with the host cell death apparatus.     

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.     

Remodeling of host glycoproteins during bacterial infection

Protein glycosylation is a common post-translational modification found in all living organisms. This modification in bacterial pathogens plays a pivotal role in their infectious processes including pathogenicity, immune evasion, and host-pathogen interactions. Importantly, many key proteins of host immune systems are also glycosylated and bacterial pathogens can notably modulate glycosylation of these host proteins to facilitate pathogenesis through the induction of abnormal host protein activity and abundance. In recent years, interest in studying the regulation of host protein glycosylation caused by bacterial pathogens is increasing to fully understand bacterial pathogenesis. In this review, we focus on how bacterial pathogens regulate remodeling of host glycoproteins during infections to promote the pathogenesis.     

When ferroptosis meets pathogenic infections

Apoptosis, necrosis, or autophagy are diverse types of regulated cell death (RCD), recognized as the strategies that host cells use to defend against pathogens such as viruses, bacteria, or fungi. Pathogens can induce or block different types of host cell RCD, promoting propagation or evading host immune surveillance. Ferroptosis is a newly identified RCD. Evidence has demonstrated how pathogens regulate ferroptosis to promote their replication, dissemination, and pathogenesis. However, the interaction between ferroptosis and pathogenic infections still needs to be completely elucidated. This review summarizes the advances in the interaction between pathogenic infections and host ferroptotic processes, focusing on the underlying mechanisms of how pathogens exploit ferroptosis, and discussing possible therapeutic measures against pathogen-associated diseases in a ferroptosis-dependent manner.     

Iron uptake mechanisms of pathogenic bacteria

Abstract: Most of the iron in a mammalian body is complexed with various proteins. Moreover, in response to infection, iron availability is reduced in both extracellular and intracellular compartments. Bacteria need iron for growth and successful bacterial pathogens have therefore evolved to compete successfully for iron in the highly iron-stressed environment of the host's tissues and body fluids. Several strategies have been identified among pathogenic bacteria, including reduction of ferric to ferrous iron, occupation of intracellular niches, utilisation of host iron compounds, and production of siderophores. While direct evidence that high affinity mechanisms for iron acquisition function as bacterial virulence determinants has been provided in only a small number of cases, it is likely that many if not all such systems play a central role in the pathogenesis of infection.     

Connexins in respiratory and gastrointestinal mucosal immunity

The mucosal lining forms the physical and chemical barrier that protects against pathogens and hostile particles and harbors its own population of bacteria, fungi and archea, known as the microbiota. The immune system controls tolerance of this population of microorganisms that have proven to be beneficial for its host. Keeping its physical integrity and a correct balance with the microbiota, the mucosa preserves its homeostasis and its protective function and maintains host’s health. However, in some conditions, pathogens may succeed in breaching mucosal homeostasis and successfully infecting the host. In this review we will discuss the role the mucosa plays in the defense against bacterial pathogens by considering the gap junction protein connexins. We will detail their implication in mucosal homeostasis and upon infection with bacteria in the respiratory and the gastrointestinal tracts.     

Inhibition of death receptor signaling by bacterial gut pathogens

Gastrointestinal bacterial pathogens such as enteropathogenic Escherichia coli, Salmonella and Shigella control inflammatory and apoptotic signaling in human intestinal cells to establish infection, replicate and disseminate to other hosts. These pathogens manipulate host cell signaling through the translocation of virulence effector proteins directly into the host cell cytoplasm, which then target various signaling pathways. Death receptors such as TNFR1, FAS and TRAIL-R induce signaling cascades that are crucial to the clearance of pathogens, and as such are major targets for inhibition by pathogens. This review focuses on what is known about how bacterial gut pathogens inhibit death receptor signaling to suppress inflammation and prevent apoptosis.     

Intracellular niche switching as host subversion strategy of bacterial pathogens

Numerous bacterial pathogens “confine” themselves within host cells with an intracellular localization as main or exclusive niche. Many of them switch dynamically between a membrane-bound or cytosolic lifestyle. This requires either membrane damage and/or repair of the bacterial-containing compartment. Niche switching has profound consequences on how the host cell recognizes the pathogens in time and space for elimination. Moreover, niche switching impacts how bacteria communicate with host cells to obtain nutrients, and it affects the accessibility to antibiotics. Understanding the local environments and cellular phenotypes that lead to niche switching is critical for developing new host-targeted antimicrobial strategies, and has the potential to shed light into fundamental cellular processes.     

病原细菌效应蛋白靶向宿主细胞核研究进展*

细胞核是细胞遗传与代谢的控制中心,调控细胞对外界的响应、代谢、生长和分化等细胞活动。在细菌感染宿主细胞过程中,个别细菌来源的效应蛋白能够靶向进入宿主细胞核,影响细胞核内基因的转录、RNA剪切、DNA修复以及染色质重组等生命活动,将这些能够进入细胞核的细菌效应蛋白称之为核调节蛋白。对病原菌分泌的核调节蛋白进入宿主细胞核的方式,以及不同病原菌的核调节蛋白调控宿主细胞的生命过程进行归纳总结,从而为深入探究病原细菌感染宿主细胞的致病机理提供理论基础。     

Superinfection drives virulence evolution in experimental populations of bacteria and plasmids

A prominent hypothesis proposes that pathogen virulence evolves in large part due to a trade‐off between infectiousness and damage to hosts. Other explanations emphasize how virulence evolves in response to competition among pathogens within hosts. Given the proliferation of theoretical possibilities, what best predicts how virulence evolves in real biological systems? Here, I show that virulence evolution in experimental populations of bacteria and self‐transmissible plasmids is best explained by within‐host competition. Plasmids evolved to severely reduce the fitness of their hosts even in the absence of uninfected cells. This result is inconsistent with the trade‐off hypothesis, which predicts that under these conditions vertically transmitted pathogens would evolve to be less virulent. Plasmid virulence was strongly correlated with the ability to superinfect cells containing competing plasmid genotypes, suggesting a key role for within‐host competition. When virulent genotypes became common, hosts evolved resistance to plasmid infection. These results show that the trade‐off hypothesis can incorrectly predict virulence evolution when within‐host interactions are neglected. They also show that symbioses between bacteria and plasmids can evolve to be surprisingly antagonistic.     

The role of microbiota in infectious disease

The intestine harbors an ecosystem composed of the intestinal mucosa and the commensal microbiota. The microbiota fosters development, aids digestion and protects host cells from pathogens - a function referred to as colonization resistance. Little is known about the molecular basis of colonization resistance and how it can be overcome by enteropathogenic bacteria. Recently, studies on inflammatory bowel diseases and on animal models for enteric infection have provided new insights into colonization resistance. Gut inflammation changes microbiota composition, disrupts colonization resistance and enhances pathogen growth. Thus, some pathogens can benefit from inflammatory defenses. This new paradigm will enable the study of host factors enhancing or inhibiting bacterial growth in health and disease.     

In vitro, ex vivo and in vivo models: A comparative analysis of Paracoccidioides spp. proteomic studies

Members of the Paracoccidioides complex are human pathogens that infect different anatomic sites in the host. The ability of Paracoccidioides spp. to infect host niches is putatively supported by a wide range of virulence factors, as well as fitness attributes that may comprise the transition from mycelia/conidia to yeast cells, response to deprivation of micronutrients in the host, expression of adhesins on the cell surface, response to oxidative and nitrosative stresses, as well as the secretion of hydrolytic enzymes in the host tissue. Our understanding of how those molecules can contribute to the infection establishment has been increasing significantly, through the utilization of several models, including in vitro, ex vivo and in vivo infection in animal models. In this review we present an update of our understanding on the strategies used by the pathogen to establish infection. Our results were obtained through a comparative proteomic analysis of Paracoccidioides spp. in models of infection.     

The Role of Autophagy during Group B Streptococcus Infection of Blood-Brain Barrier Endothelium

Bacterial meningitis occurs when bloodborne pathogens invade and penetrate the blood-brain barrier (BBB), provoking inflammation and disease. Group B Streptococcus (GBS), the leading cause of neonatal meningitis, can enter human brain microvascular endothelial cells (hBMECs), but the host response to intracellular GBS has not been characterized. Here we sought to determine whether antibacterial autophagy, which involves selective recognition of intracellular organisms and their targeting to autophagosomes for degradation, is activated in BBB endothelium during bacterial infection. GBS infection resulted in increased punctate distribution of GFP-microtubule-associated protein 1 light chain 3 (LC3) and increased levels of endogenous LC3-II and p62 turnover, two hallmark indicators of active autophagic flux. Infection with GBS mutants revealed that bacterial invasion and the GBS pore-forming β-hemolysin/cytolysin (β-h/c) trigger autophagic activation. Cell-free bacterial extracts containing β-h/c activity induced LC3-II conversion, identifying this toxin as a principal provocative factor for autophagy activation. These results were confirmed in vivo using a mouse model of GBS meningitis as infection with WT GBS induced autophagy in brain tissue more frequently than a β-h/c-deficient mutant. Elimination of autophagy using Atg5-deficient fibroblasts or siRNA-mediated impairment of autophagy in hBMECs led to increased recovery of intracellular GBS. However, electron microscopy revealed that GBS was rarely found within double membrane autophagic structures even though we observed GBS-LC3 co-localization. These results suggest that although autophagy may act as a BBB cellular defense mechanism in response to invading and toxin-producing bacteria, GBS may actively thwart the autophagic pathway.     

Yersinia effectors target mammalian signalling pathways

Animals have an immune system to fight off challenges from both viruses and bacteria. The first line of defence is innate immunity, which is composed of cells that engulf pathogens as well as cells that release potent signalling molecules to activate an inflammatory response and the adaptive immune system. Pathogenic bacteria have evolved a set of weapons, or effectors, to ensure survival in the host. Yersinia spp. use a type III secretion system to translocate these effector proteins, called Yops, into the host. This report outlines how Yops thwart the signalling machinery of the host immune system.     

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.     

Exploitation of the endoplasmic reticulum by bacterial pathogens

The endoplasmic reticulum (ER) has unique properties that are exploited by microbial pathogens. Exotoxins secreted by bacteria take advantage of the host transport pathways that deliver proteins from the Golgi to the ER. Transport to the ER is necessary for the unfolding and translocation of these toxins into the cytosol where their host targets reside. Intracellular pathogens subvert host vesicle transport to create ER-like vacuoles that support their intracellular replication. Investigations on how bacterial pathogens can use the ER during host infection are providing important details on transport pathways involving this specialized organelle.     

Unexpected encounter of the parasitic kind

Both parasitology and stem cell research are important disciplines in their own right. Parasites are a real threat to human health causing a broad spectrum of diseases and significant annual rates morbidity and mortality globally. Stem cell research, on the other hand, focuses on the potential for regenerative medicine for a range of diseases including cancer and regenerative therapies. Though these two topics might appear distant, there are some "unexpected encounters". In this review, we summarise the various links between parasites and stem cells. First,we discuss how parasites' own stem cells represent interesting models of regeneration that can be translated to human stem cell regeneration. Second, we explore the interactions between parasites and host stem cells during the course of infection. Third, we investigate from a clinical perspective, how stem cell regeneration can be exploited to help circumvent the damage induced by parasitic infection and its potential to serve as treatment options for parasitic diseases in the future. Finally, we discuss the importance of screening for pathogens during organ transplantation by presenting some clinical cases of parasitic infection following stem cell therapy.     

Genetics-squared: combining host and pathogen genetics in the analysis of innate immunity and bacterial virulence

The interaction of bacterial pathogens with their hosts’ innate immune systems can be extremely complex and is often difficult to disentangle experimentally. Using mouse models of bacterial infections, several laboratories have successfully applied genetic approaches to identify novel host genes required for innate immune defense. In addition, a variety of creative bacterial genetic schemes have been developed to identify key bacterial genes involved in triggering or evading host immunity. In cases where both the host and pathogen are amenable to genetic manipulation, a combination of host and pathogen genetic approaches can be used. Focusing on bacterial infections of mice, this review summarizes the benefits and limitations of applying genetic analysis to the study of host–pathogen interactions. In particular, we consider how prokaryotic and eukaryotic genetic strategies can be combined, or “squared,” to yield new insights in host–pathogen biology.