- RNA-based mechanisms of virulence control in Enterobacteriaceae. [JOURNAL ARTICLE]
- RNA Biol 2016 Jul 21.:1-17.
Enteric pathogens of the family Enterobacteriaceae colonize various niches within animals and humans in which they compete with intestinal commensals and are attacked by the host immune system. To survive these hostile environments they possess complex, multilayer regulatory networks that coordinate the control of virulence factors, host-adapted metabolic functions and stress resistance. An important part of these intricate control networks are RNA-based control systems that enable the pathogen to fine-tune its responses. Recent next-generation sequencing approaches revealed a large repertoire of conserved and species-specific riboregulators, including numerous cis- and trans-acting non-coding RNAs, sensory RNA elements (RNA thermometers, riboswitches), regulatory RNA-binding proteins and RNA degrading enzymes which regulate colonization factors, toxins, host defense processes and virulence-relevant physiological and metabolic processes. All of which are important cues for pathogens to sense and respond to fluctuating conditions during the infection. This review covers infection-relevant riboregulators of E. coli, Salmonella, Shigella and Yersinia, highlights their versatile regulatory mechanisms, complex target regulons and functions, and discusses emerging topics and future challenges to fully understand and exploit RNA-based control to combat bacterial infections.
- Inhibition of the injectisome and flagellar type III secretion systems by INP1855 impairs Pseudomonas aeruginosa pathogenicity and inflammasome activation. [JOURNAL ARTICLE]
- J Infect Dis 2016 Jul 13.
With the rise of multidrug resistance, Pseudomonas aeruginosa infections require alternative therapeutics. The injectisome (iT3SS) and flagellar (fT3SS) type III secretion systems are two virulence factors associated with poor clinical outcomes. iT3SS translocates toxins, rod, needle or regulator proteins, and flagellin into the host cell cytoplasm and causes cytotoxicity and NLRC4-dependent inflammasome activation, which induces IL-1β release and reduces IL-17 production and bacterial clearance. fT3SS insures bacterial motility, attachment to the host cells, and triggers inflammation. INP1855 is an iT3SS inhibitor identified by in vitro screening using Yersinia pseudotuberculosis Using a mouse model of P. aeruginosa pulmonary infection we show that INP1855 improves survival after infection with an iT3SS-positive strain, reduces bacterial pathogenicity and dissemination, and IL-1β secretion, and increases IL-17 secretion. INP1855 also modified the cytokine balance in mice infected with an iT3SS-negative, fT3SS-positive strain. In vitro, INP1855 impaired iT3SS and fT3SS functionality as evidenced by a reduction in secretory activity and flagellar motility and an increase in ATP levels. As a result, INP1855 decreased cytotoxicity mediated by toxins and by inflammasome activation induced by both laboratory strains and clinical isolates. We conclude that INP1855 acts by dual inhibition of iT3SS and fT3SS, and represents a promising therapeutic approach.
- [Sympatric Speciation of the Plague Microbe Yersinia pestis: Monohostal Specialization in the Host-Parasite Marmot-Flea (Marmota sibirica-Oropsylla silantiewi) System]. [English Abstract, Journal Article]
- Izv Akad Nauk Ser Biol 2016 Mar-Apr; (2):117-27.
An ecological scenario of the origin of the plague microbe that is interpreted in the light of modern Darwinism (synthetic theory of evolution) is presented. It is shown that the plague microbe emerged from a clone of the psychrophilic saprozoonotic pseudotuberculosis microbe Yersinia pseudotuberculosis O:1b in the mountain steppe landscapes of Central Asia in the Sartan time, 22000-15000 years ago, in the monohostal Mongolian marmot (Marmota sibirica)-flea (Oropsylla silantiewi) host-parasite system. It was noted that the evolutionary process described corresponds to the sympatric form of speciation by transition ofthe clone of migrant founders to a new, already-existing ecological niche. It was established that monohostal specialization of the plague microbe was made possible due to heterothermia (5-37 degrees C) of marmots in the hibernation period. The factors of the speciation process--isolation, the struggle for existence, and natural selection--were analyzed.
- Primary cellulitis and cutaneous abscess caused by Yersinia enterocolitica in an immunocompetent host: A case report and literature review. [Journal Article]
- Medicine (Baltimore) 2016 Jun; 95(26):e3988.
Primary extraintestinal complications caused by Yersinia enterocolitica are extremely rare, especially in the form of skin and soft-tissue manifestations, and little is known about their clinical characteristics and treatments. We presented our case and reviewed past cases of primary skin and soft-tissue infections caused by Y enterocolitica. We report a case of primary cellulitis and cutaneous abscess caused by Y enterocolitica in an immunocompetent 70-year-old woman with keratodermia tylodes palmaris progressiva. She presented to an outpatient clinic with redness, swelling, and pain of the left ring finger and left upper arm without fever or gastrointestinal symptoms 3 days before admission. One day later, ulceration of the skin with exposed bone of the proximal interphalangeal joint of the left ring finger developed, and cefditoren pivoxil was described. However, she was admitted to our hospital due to deterioration of symptoms involving the left finger and upper arm. Cefazolin was initiated on admission, then changed to sulbactam/ampicillin and vancomycin with debridement of the left ring finger and drainage of the left upper arm abscess. Wound culture grew Y enterocolitica serotype O:8 and methicillin-sensitive Staphylococcus aureus. Blood cultures were negative and osteomyelitis was ruled out. Vancomycin was switched to ciprofloxacin, then skin and soft-tissue manifestations showed clear improvement within a few days. The patient received 14 days of ciprofloxacin and oral amoxicillin/clavulanate and has since shown no recurrence. We reviewed 12 cases of primary skin and soft-tissue infections caused by Y enterocolitica from the literature. In several past cases, portal entry involved failure of the skin barrier on distal body parts. Thereafter, infection might have spread to the regional lymph nodes from the ruptured skin. Y enterocolitica is typically resistant to aminopenicillins and narrow-spectrum cephalosporins. In most cases, these inefficient antibiotic agents were initially prescribed, but patient conditions rapidly improved after implementing appropriate therapy and drainage. In addition, primary skin and soft-tissue infections occurred even in patients lacking risk factors. Physicians should consider the rare differential diagnosis of Y enterocolitica infection when seeing patients with deteriorating skin lesions under standard treatment, even if the patient is immunocompetent.
- Increased plasmid copy number is essential for Yersinia T3SS function and virulence. [JOURNAL ARTICLE]
- Science 2016 Jun 30.
Pathogenic bacteria have evolved numerous virulence mechanisms that are essential for establishing infections. The enterobacteria Yersinia uses a Type III Secretion System (T3SS), encoded by a 70-kb, low-copy, IncFII-class virulence plasmid. Here, we report a novel virulence strategy in Y. pseudotuberculosis in which this pathogen up-regulates the plasmid copy-number during infection. We show that increased dose of plasmid-encoded genes is indispensable for virulence and substantially elevates the expression and function of the T3SS. Remarkably, we found direct, tight coupling between plasmid replication and T3SS function. This regulatory pathway provides a framework for further exploration of the environmental sensing mechanisms of pathogenic bacteria.
- Yersinia enterocolitica specific infection by bacteriophages TG1 and ϕR1-RT is dependent on temperature regulated expression of the phage host receptor OmpF. [JOURNAL ARTICLE]
- Appl Environ Microbiol 2016 Jun 24.
Bacteriophages present huge potential both as a resource for developing novel tools for bacterial diagnostics and for use in phage therapy. This is also valid for bacteriophages specific for Yersinia enterocolitica. To increase our knowledge on Y. enterocolitica -specific phages we characterized two novel yersiniophages. The genomes of the bacteriophages vB_YenM_TG1 (TG1) and vB_YenM_ϕR1-RT (ϕR1-RT), isolated from pig manure in Canada and from sewage in Finland, consist of linear double-stranded DNA of 162,101 and 168,809 bp respectively. Their genomes encode 262 putative coding sequences and 4 tRNAs genes, and share 91% overall nucleotide identity. Based on phylogenetic analyses of their whole genome sequences and large terminase subunit protein sequences, a genus named Tg1virus within the family Myoviridae is proposed with TG1 and ϕR1-RT as member species. These bacteriophages exhibit a host range restricted to Y. enterocolitica, and display lytic activity against the epidemiologically significant serotypes O:3, O:5,27, and O:9 at and below 25°C. Adsorption analyses of LPS and OmpF mutants demonstrate that these phages use both the LPS inner core heptosyl residues and the outer membrane protein OmpF as phage receptors. Based on RNA-sequencing and quantitative proteomics we also demonstrate the temperature dependent infection is due to strong repression of OmpF at 37°C. In addition, ϕR1-RT was shown to be able to enter into a pseudolysogenic state. All together, this work provides further insight into phage-host cell interactions by highlighting the importance of understanding underlying factors which may affect the abundance of phage host receptors on the cell surface.Only a small number of bacteriophages infecting Y. enterocolitica, the predominant causative agent of yersiniosis, have been previously described. Here, two newly isolated Y. enterocolitica phages were studied in detail with the aim of elucidating the host cell receptors required for infection. Our research further expands the repertoire of phages available for consideration as potential antimicrobial agents or as diagnostic tools for this important bacterial pathogen.
- Paleogenetics and Past Infections: the Two Faces of the Coin of Human Immune Evolution. [Journal Article]
- Microbiol Spectr 2016 Jun; 4(3)
With the advent of next-generation sequencing, paleogenetics has considerably expanded over the past few years and notably encompassed the characterization of the genomes of archaic humans who lived more than 30,000 years ago. These paleogenetics investigations have revealed that admixture between modern and archaic humans occurred, with Neanderthals having contributed to 1.5% to 2.1% of modern Eurasian genomes, and Denisovans to 3% to 6% of modern Melanesian genomes and to approximately 0.2% of modern Asian genomes. Although these contributions are modest, they played a major role in shaping immune gene families, such as the HLA class I genes, for which the archaic alleles now represent more than 50% of the alleles in Europe and Asia. Such a high frequency is consistent with these archaic HLA class I variants having been positively selected because of their protective effect against contagious and devastating epidemics, such as those due to the plague agent Yersinia pestis or to Mycobacterium tuberculosis, which is responsible for deadly tuberculosis. While the exact nature of the infectious agents that contributed to the selection of the archaic variants is unknown, we are entering an exciting period in which paleogenetics and paleomicrobiology data can be integrated to generate a clearer picture of how the immune system of modern populations was shaped and the role admixture and epidemics have played in such evolutions.
- Antimicrobial peptide CAP18 and its effect on Yersinia ruckeri infections in rainbow trout Oncorhynchus mykiss (Walbaum): comparing administration by injection and oral routes. [JOURNAL ARTICLE]
- J Fish Dis 2016 Jun 23.
The antimicrobial peptide CAP18 has been demonstrated to have a strong in vitro bactericidal effect on Yersinia ruckeri, but its activity in vivo has not been described. In this work, we investigated whether CAP18 protects rainbow trout Oncorhynchus mykiss (Walbaum) against enteric red mouth disease caused by this pathogen either following i.p. injection or by oral administration (in feed). It was found that injection of CAP18 into juvenile rainbow trout before exposure to Y. ruckeri was associated with lowered mortality compared to non-medicated fish although it was less effective than the conventional antibiotic oxolinic acid. Oral administration of CAP18 to trout did not prevent infection. The proteolytic effect of secretions on the peptide CAP18 in the fish gastrointestinal tract is suggested to account for the inferior effect of oral administration.
- Cationic host defense peptides; novel antimicrobial therapeutics against Category A pathogens and emerging infections. [JOURNAL ARTICLE]
- Pathog Glob Health 2016 Jun 17.:1-11.
Cationic Host Defense Peptides (HDP, also known as antimicrobial peptides) are crucial components of the innate immune system and possess broad-spectrum antibacterial, antiviral, and immunomodulatory activities. They can contribute to the rapid clearance of biological agents through direct killing of the organisms, inhibition of pro-inflammatory mediators such as lipopolysaccharide, and by modulating the inflammatory response to infection. Category A biological agents and materials, as classified by the United States National Institutes for Health, the US Centers for Disease Control and Prevention, and the US Department of Homeland Security, carry the most severe threat in terms of human health, transmissibility, and preparedness. As such, there is a pressing need for novel frontline approaches for prevention and treatment of diseases caused by these organisms, and exploiting the broad antimicrobial activity exhibited by cationic host defense peptides represents an exciting priority area for clinical research. This review will summarize what is known about the antimicrobial and antiviral effects of the two main families of cationic host defense peptides, cathelicidins, and defensins in the context of Category A biological agents which include, but are not limited to; anthrax (Bacillus anthracis), plague (Yersinia pestis), smallpox (Variola major), tularemia (Francisella tularensis). In addition, we highlight priority areas, particularly emerging viral infections, where more extensive research is urgently required.
- The Functions of Effector Proteins in Yersinia Virulence. [Journal Article, Research Support, Non-U.S. Gov't, Review]
- Pol J Microbiol 2016; 65(1):5-12.
Yersinia species are bacterial pathogens that can cause plague and intestinal diseases after invading into human cells through the Three Secretion System (TTSS). The effect of pathogenesis is mediated by Yersinia outer proteins (Yop) and manifested as down-regulation of the cytokine genes expression by inhibiting nuclear factor-κ-gene binding (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. In addition, its pathogenesis can also manipulate the disorder of host innate immune system and cell death such as apoptosis, pyroptosis, and autophagy. Among the Yersinia effector proteins, YopB and YopD assist the injection of other virulence effectors into the host cytoplasm, while YopE, YopH, YopJ, YopO, and YopT target on disrupting host cell signaling pathways in the host cytosols. Many efforts have been applied to reveal that intracellular proteins such as Rho-GTPase, and transmembrane receptors such as Toll-like receptors (TLRs) both play critical roles in Yersinia pathogenesis, establishing a connection between the pathogenic process and the signaling response. This review will mainly focus on how the effector proteins of Yersinia modulate the intrinsic signals in host cells and disturb the innate immunity of hosts through TTSS.