• bacterial pathogenesis
• protein sequence analyses
• glycobiology
• pathogens
• bacteriology

• Salmonella typhi/genetics
• Salmonella typhi/pathogenicity
• Animals
• Mice
• Virulence/genetics
• Polysaccharides, Bacterial/genetics
• Polysaccharides, Bacterial/biosynthesis
• Polysaccharides, Bacterial/metabolism
• Mutation, Missense
• Bacterial Capsules/genetics
• Bacterial Capsules/metabolism
• Typhoid Fever/microbiology
• Humans
• Bacterial Proteins/genetics
• Bacterial Proteins/metabolism
• Virulence Factors/genetics
• Virulence Factors/metabolism
• Female
• Whole Genome Sequencing

• R01 AI139625 NIAID NIH HHS
• R01 AI141514 NIAID NIH HHS
• AI139625 U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)
• AI141514 U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)
• U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID)

• E. coli
• bacteria biofilm
• ccdAB
• persistent infection
• recurrent urinary tract infection
• toxin-antitoxin systems

• aging
• germinal center reaction
• pathogen-specific immune response
• regulatory T cells
• vaccination

• Aged
• Aged, 80 and over
• Aging
• Animals
• Antibodies, Viral
• Humans
• Mice
• T-Lymphocytes, Regulatory
• Vaccination/methods
• Vaccines

• Horizon 2020 Framework Programme
• Deutsche Forschungsgemeinschaft

• CCR2+ cells
• Salmonella
• chronic
• granuloma
• host response
• infection
• inflammatory monocyte
• pathogenesis
• persistent

Regulatory T cells (Tregs) are the major determinant of peripheral immune tolerance. Many Treg subsets have been described, however thymus-derived and peripherally induced Tregs remain the most important subpopulations. In multiple sclerosis, a prototypical autoimmune disorder of the central nervous system, Treg dysfunction is a pathogenic hallmark. In contrast, induction of Treg proliferation and enhancement of their function are central immune evasion mechanisms of infectious pathogens. In accordance, Treg expansion is compartmentalized to tissues with high viral replication and prolonged in chronic infections. In friend retrovirus infection, Treg expansion is mainly based on excessive interleukin-2 production by infected effector T cells. Moreover, pathogens seem also to enhance Treg functions as shown in human immunodeficiency virus infection, where Tregs express higher levels of effector molecules such as cytotoxic T-lymphocyte-associated protein 4, CD39 and cAMP and show increased suppressive capacity. Thus, insights into the molecular mechanisms by which intracellular pathogens alter Treg functions might aid to find new therapeutic approaches to target central nervous system autoimmunity. In this review, we summarize the current knowledge of the role of pathogens for Treg function in the context of autoimmune neuroinflammation. We discuss the mechanistic implications for future therapies and provide an outlook for new research directions.

• T cells
• autoimmunity
• immunometabolomics
• microbiome
• microorganism
• neuroinflammation
• pathogens
• regulatory T cells

• metabolites
• microbiota
• molecular mechanism
• postbiotics
• preterm
• probiotics

• Adolescent
• Adult
• Dysbiosis/microbiology
• Extraembryonic Membranes/metabolism
• Female
• Gestational Age
• Humans
• Infant, Newborn
• Microbiota
• Pregnancy
• Premature Birth/epidemiology
• Premature Birth/metabolism
• Premature Birth/microbiology
• Risk Factors
• Young Adult

• NRF-2020R1A2C3011850 National Research Foundation of Korea

• Aspergillus
• Escherichia coli
• Infectious diseases
• Penicillium
• Pseudomonas aeruginosa
• Staphylococcus aureus

• Salmonella Typhimurium
• bactericidal activity
• lysophosphatidylcholine
• macrophage
• phagosome maturation
• reactive oxygen species

• Animals
• Lysophosphatidylcholines/metabolism
• Macrophages/metabolism
• Macrophages/microbiology
• Male
• Mice
• Mice, Inbred BALB C
• NF-KappaB Inhibitor alpha/metabolism
• NF-kappa B/metabolism
• Phagosomes/metabolism
• Phosphorylation
• RAW 264.7 Cells
• Reactive Oxygen Species/metabolism
• Salmonella Infections/metabolism
• Salmonella typhimurium/growth & development
• Salmonella typhimurium/physiology
• Signal Transduction

• antibiotic persisters
• antimicrobial resistance
• persistent infections
• persisters

• Antimicrobial defense
• Helicobacter pylori (H. pylori)
• plasticity
• stem cells
• stomach

Salmonella enterica is a pathogenic bacterium that causes foodborne illness. One of the vehicle foods of S. enterica are chicken eggs. Efficient collection of the bacterium is necessary to detect it specifically. We developed a method to detect S. enterica by PCR on a microfluidic disc device using a fluorescent probe. Salmonella enterica cells were isolated in the microchambers on the device, followed by thermal lysis and PCR targeting with the invA gene, a gene specific to S. enterica, were observed by measurement of the fluorescent signal that resulted from gene amplification. However, the developed method was unable to discriminate viable cells from dead cells. Consequently, in this study, magnetic beads modified with anti-Salmonella antibody were utilized to detect viable Salmonella cells from egg yolk prior to PCR on the device. While using the antibody-modified beads, egg yolk components, which inhibit PCR, were removed. The collected cells were subsequently detected by PCR of the invA gene on a microfluidic disc device. This method enabled the detection of viable cells without the inhibition of PCR by any egg component. S. enterica was detected at 5.0×10⁴ cells mL⁻¹ or at a higher concentration of egg yolk within 6 h including the sampling time.

• PCR
• Salmonella enterica
• egg yolk
• immunomagnetic beads
• invA

• Helicobacter pylori
• autophagy
• genetic plasticity
• immune evasion
• immune tolerance
• persistent infection

• Salmonella
• Wnt/β-catenin
• cancer
• dysbiosis
• infection
• inflammation
• microbiome

• K01 DK075386 NIDDK NIH HHS
• R01 DK105118 NIDDK NIH HHS
• R01 DK114126 NIDDK NIH HHS
• R03 DK089010 NIDDK NIH HHS

• Hen
• Iron
• Iron distribution
• Salmonella Typhimurium
• Spleen

• Animals
• Chickens
• Female
• Iron/blood
• Iron/metabolism
• Iron/pharmacokinetics
• Iron, Dietary/administration & dosage
• Iron, Dietary/blood
• Iron, Dietary/pharmacokinetics
• Iron, Dietary/pharmacology
• Liver/drug effects
• Liver/metabolism
• Oviposition/drug effects
• Random Allocation
• Salmonella Infections, Animal/blood
• Salmonella Infections, Animal/metabolism
• Spleen/drug effects
• Spleen/metabolism
• Tissue Distribution/drug effects

Salmonella enterica serovar Typhi (S. Typhi) and S. Paratyphi, namely typhoidal Salmonellae, are the cause of (para) typhoid fever, which is a devastating systemic infectious disease in humans. In addition, the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) S. Typhi in many low and middle-income countries poses a significant risk to human health. While currently available typhoid vaccines and therapeutics are efficacious, they have some limitations. One important limitation is the lack of controlling individuals who chronically carry S. Typhi. However, due to the strict host specificity of S. Typhi to humans, S. Typhi research is hampered. As a result, our understanding of S. Typhi pathogenesis is incomplete, thereby delaying the development and improvement of prevention and treatment strategies. Nonetheless, to better combat and contain S. Typhi, it is vital to develop a vaccine and therapy for controlling both acutely and chronically infected individuals. This review discusses how scientists are trying to combat typhoid fever, why it is so challenging to do so, which approaches show promise, and what we know about the pathogenesis of S. Typhi chronic infection.

• Salmonella Typhi
• chronic infections
• healthy carriers
• typhoid fever
• typhoidal Salmonellae
• vaccines
• virulence

Pathogenic bacteria cause various infections worldwide, especially in immunocompromised and other susceptible individuals, and are also associated with high infant mortality rates in developing countries. MicroRNAs (miRNAs), small non-coding RNAs with evolutionarily conserved sequences, are expressed in various tissues and cells that play key part in various physiological and pathologic processes. Increasing evidence implies roles for miRNAs in bacterial infectious diseases by modulating inflammatory responses, cell penetration, tissue remodeling, and innate and adaptive immunity. This review highlights some recent intriguing findings, ranging from the correlation between aberrant expression of miRNAs with bacterial infection progression to their profound impact on host immune responses. Harnessing of dysregulated miRNAs in bacterial infection may be an approach to improving the diagnosis, prevention and therapy of infectious diseases.

Changes in production of tiny cellular RNAs in response to bacterial infection could guide the development of better diagnostics and therapies. MicroRNAs regulate other genes by binding to messenger RNA strands and controlling their translation into proteins. Xikun Zhou, Min Wu and colleagues of the University of North Dakota have now reviewed current knowledge about how microRNA levels shift during infection with various bacterial pathogens. These microRNAs can modulate the immune response as well as pathways that influence metabolic activity and cell survival. Increasing studies have indicated that shifts in microRNA levels in response to different infections could provide a potential bacterial ‘fingerprint’ for achieving accurate diagnosis. With deeper insight into how different microRNAs influence infection, it might one day day become possible to target these molecules with ‘antisense’ or ‘agonist’ drugs that modulate their activity.

• Salmonella
• gut microbiota
• host metabolism during infection
• host-microbe interaction
• microbial metabolism

• Animals
• Anti-Bacterial Agents/pharmacology
• Butyric Acid/metabolism
• Clostridium/growth & development
• Dysbiosis/microbiology
• Female
• Fermentation
• Gastroenteritis/microbiology
• Gastroenteritis/pathology
• Gastrointestinal Microbiome/drug effects
• Intestinal Mucosa/microbiology
• L-Lactate Dehydrogenase/antagonists & inhibitors
• Lactic Acid/metabolism
• Male
• Mice
• Mice, Inbred C57BL
• PPAR gamma/agonists
• Salmonella Infections/pathology
• Salmonella typhimurium/growth & development
• Salmonella typhimurium/metabolism
• Triglycerides/pharmacology

• R01 AI118807 NIAID NIH HHS
• R21 AI128151 NIAID NIH HHS
• R01 DK070855 NIDDK NIH HHS
• T32 AI007520 NIAID NIH HHS
• R21 AI103248 NIAID NIH HHS
• Howard Hughes Medical Institute
• T32 GM109776 NIGMS NIH HHS

Salmonella enterica subspecies enterica serovar Typhi is the aetiological agent of typhoid or enteric fever. In a subset of individuals, S. Typhi colonizes the gallbladder causing an asymptomatic chronic infection. Nonetheless, these asymptomatic carriers provide a reservoir for further spreading of the disease. Epidemiological studies performed in regions where S. Typhi is endemic, revealed that the majority of chronically infected carriers also harbour gallstones, which in turn, have been indicated as a primary predisposing factor for the onset of gallbladder cancer (GC). It is now well recognised, that S. Typhi produces a typhoid toxin with a carcinogenic potential, that induces DNA damage and cell cycle alterations in intoxicated cells. In addition, biofilm production by S. Typhi may represent a key factor for the promotion of a persistent infection in the gallbladder, thus sustaining a chronic local inflammatory response and exposing the epithelium to repeated damage caused by carcinogenic toxins. This review aims to highlight the putative connection between the chronic colonization by highly pathogenic strains of S. Typhi capable of combining biofilm and toxin production and the onset of GC. Considering the high risk of GC associated with the asymptomatic carrier status, the rapid identification and profiling of biofilm production by S. Typhi strains would be key for effective therapeutic management and cancer prevention.

• DNA Damage Response
• Salmonella Typhi
• biofilm
• gallbladder cancer
• gallstone
• infection
• inflammation
• skin manifestations
• toxin

• Animals
• Biofilms/growth & development
• Gallbladder Neoplasms/metabolism
• Gallbladder Neoplasms/microbiology
• Gallbladder Neoplasms/pathology
• Gallbladder Neoplasms/prevention & control
• Humans
• Salmonella typhi/physiology
• Typhoid Fever/metabolism
• Typhoid Fever/pathology
• Typhoid Fever/therapy

The adaptation of Salmonella enterica to the eukaryotic host is a key process that enables the bacterium to survive in a hostile environment. Salmonella have evolved an intimate relationship with its host that extends to their cellular and molecular levels. Colonization, invasion, and replication of the bacteria in an appropriate host suggest that modification of host functions is central to pathogenesis. Intuitively, this subversion of the cell must be a complex process, since hosts are not inherently programmed to provide an environment conducive to pathogens. Hosts have evolved countermeasures to pathogen invasion, establishment, and replication through two types of defenses: resistance and tolerance. Resistance functions to control pathogen invasion and reduce or eliminate the invading pathogen. Research has primarily concentrated on resistance mechanisms that are mediated by the immune system. On the other hand, tolerance is mediated by different mechanisms that limit the damage caused by a pathogen’s growth without affecting or reducing pathogen numbers or loads. The mechanisms of tolerance appear to be separated into those that protect host tissues from the virulence factors of a pathogen and those that limit or reduce the damage caused by the host immune and inflammatory responses to the pathogen. Some pathogens, such as Salmonella, have evolved the capacity to survive the initial robust immune response and persist. The persistent phase of a Salmonella infection in the avian host usually involves a complex balance of protective immunity and immunopathology. Salmonella is able to stay in the avian ceca for months without triggering clinical signs. Chronic colonization of the intestinal tract is an important aspect of persistent Salmonella infection because it results in a silent propagation of bacteria in poultry stocks due to the impossibility to isolate contaminated animals. Data from our lab promote the hypothesis that Salmonella have evolved a unique survival strategy in poultry that minimizes host defenses (disease resistance) during the initial infection and then exploits and/or induces a dramatic immunometabolic reprogramming in the cecum that alters the host defense to disease tolerance. Unfortunately, this disease tolerance results in the ongoing human food safety dilemma.

• Salmonella enterica
• chickens
• disease resistance
• disease tolerance
• immunometabolism

• Antibiotic persistence
• Dormancy
• Efflux pumps
• Passive and active defense

• Helicobacter
• Campylobacter
• pathogen
• innate immunity
• bacterial defences

• Animals
• Campylobacter/immunology
• Campylobacter/pathogenicity
• Campylobacter Infections/immunology
• Campylobacter Infections/microbiology
• Helicobacter/immunology
• Helicobacter/pathogenicity
• Helicobacter Infections/immunology
• Helicobacter Infections/microbiology
• Immunity, Innate/immunology
• Immunity, Innate/physiology
• Mammals/immunology
• Mammals/microbiology
• Nitrosative Stress/immunology
• Oxidative Stress/immunology

• MOP84224 CIHR

Spores of Bacillus anthracis, the causative agent of anthrax, are known to persist in the host lungs for prolonged periods of time, however the underlying mechanism is poorly understood. In this study, we demonstrated that BclA, a major surface protein of B. anthracis spores, mediated direct binding of complement factor H (CFH) to spores. The surface bound CFH retained its regulatory cofactor activity resulting in C3 degradation and inhibition of downstream complement activation. By comparing results from wild type C57BL/6 mice and complement deficient mice, we further showed that BclA significantly contributed to spore persistence in the mouse lungs and dampened antibody responses to spores in a complement C3-dependent manner. In addition, prior exposure to BclA deletion spores (ΔbclA) provided significant protection against lethal challenges by B. anthracis, whereas the isogenic parent spores did not, indicating that BclA may also impair protective immunity. These results describe for the first time an immune inhibition mechanism of B. anthracis mediated by BclA and CFH that promotes spore persistence in vivo. The findings also suggested an important role of complement in persistent infections and thus have broad implications.

We discovered an immune modulatory mechanism of Bacillus anthracis mediated by the spore surface protein BclA. We showed for the first time that BclA mediated the binding of complement factor H, a major negative regulator of complement, to the surface of spores. The binding led to the down-regulation of complement activities in vitro and in an animal model. Using mice deficient in complement components, we further showed that BclA promoted spore persistence in the mouse lungs and impaired antibody responses against spores in a complement-dependent manner. We further provided evidence suggesting a role of BclA in the development of protective immunity against lethal B. anthracis challenges. These findings draw attention to a previously understudied aspect of the complement system. They suggest that in addition to conferring resistance to complement-mediated killing and phagocytosis, complement inhibition by pathogens have long-term consequences with respect to persistent infections and development of protective immunity. Considering a growing list of microbial pathogens capable of modulating complement activities, our findings have broad implications.

• Animals
• Asymptomatic Infections
• Communicable Diseases/microbiology
• Intestines/microbiology
• Macrophages/microbiology
• Mice
• Mutagens/toxicity
• Salmonella typhimurium/pathogenicity
• Typhoid Fever/microbiology
• Virulence

• BCG
• human regulatory T-cells
• infection
• leprosy
• pathogens
• regulatory T-cells
• tuberculosis
• vaccination

In this review, we discussed the findings and concepts underlying the potential role of Helicobacter pylori (H. pylori) infections in the initiation, development or persistence of atherosclerosis and coronary heart disease (CHD). This Gram-negative bacterium was described by Marshall and Warren in 1984. The majority of infected subjects carries and transmits H. pylori with no symptoms; however, in some individuals these bacteria may cause peptic ulcers, and even gastric cancers. The widespread prevalence of H. pylori infections and the fact that frequently they remain asymptomatic may suggest that, similarly to intestinal microflora, H. pylori may deliver antigens that stimulate not only local, but also systemic inflammatory response. Recently, possible association between H. pylori infection and extragastric disorders has been suggested. Knowledge on the etiology of atherosclerosis together with current findings in the area of H. pylori infections constitute the background for the newly proposed hypothesis that those two processes may be related. Many research studies confirm the indirect association between the prevalence of H. pylori and the occurrence of CHD. According to majority of findings the involvement of H. pylori in this process is based on the chronic inflammation which might facilitate the CHD-related pathologies. It needs to be elucidated, if the infection initiates or just accelerates the formation of atheromatous plaque.

• Helicobacter pylori
• Coronary heart disease
• Inflammation
• Microbiota
• Lipopolysaccharide

We recently found that Yersinia pseudotuberculosis can be used as a model of persistent bacterial infections. We performed in vivo RNA-seq of bacteria in small cecal tissue biopsies at early and persistent stages of infection to determine strategies associated with persistence. Comprehensive analysis of mixed RNA populations from infected tissues revealed that Y. pseudotuberculosis undergoes transcriptional reprogramming with drastic down-regulation of T3SS virulence genes during persistence when the pathogen resides within the cecum. At the persistent stage, the expression pattern in many respects resembles the pattern seen in vitro at 26oC, with for example, up-regulation of flagellar genes and invA. These findings are expected to have impact on future rationales to identify suitable bacterial targets for new antibiotics. Other genes that are up-regulated during persistence are genes involved in anaerobiosis, chemotaxis, and protection against oxidative and acidic stress, which indicates the influence of different environmental cues. We found that the Crp/CsrA/RovA regulatory cascades influence the pattern of bacterial gene expression during persistence. Furthermore, arcA, fnr, frdA, and wrbA play critical roles in persistence. Our findings suggest a model for the life cycle of this enteropathogen with reprogramming from a virulent to an adapted phenotype capable of persisting and spreading by fecal shedding.

To establish infection and colonize within a host, infecting pathogens have to cope with a variety of destructive surroundings. The food-borne pathogen Y. pseudotuberculosis can cause persistent infection in mice. Upon infection, Y. pseudotuberculosis passes the anti-microbial gastrointestinal milieu and finally remains associated with lymphoid follicles in cecal tissue surrounded by polymorphonuclear leukocytes, indicating that the bacteria are exposed to multiple environmental cues. We performed complex RNA-seq of small cecal biopsies of infected mice to reveal Y. pseudotuberculosis gene expression in vivo. We found that Y. pseudotuberculosis underwent reprogramming from a virulent phenotype, expressing virulence genes during early infection, to an adapted phenotype capable of persisting in the harsh cecal environment. Persistence was characterized by a novel expression pattern with down-regulation of virulence genes and up-regulation of genes involved in anaerobiosis, chemotaxis, and protection against oxidative and acidic stress. Mutagenesis of selected genes revealed that the regulator rovA was critical for the establishment of infection, and that arcA, fnr, frdA, and wrbA play critical roles in maintaining infection for long periods of time. Our study shows the power of RNA deep sequencing, which can be used to reveal the in vivo expression patterns of small amounts of bacteria in complex intestinal environments.