Comparative Approaches to Identify Host Factors Specifically Targeted by Yersinia pestis During the Infectious Process

ABSTRACTYersinia pestishas evolved many strategies to evade the innate immune system. One of these strategies is the ability to survive within macrophages. Upon phagocytosis,Y. pestisprevents phagolysosome maturation and establishes a modified compartment termed theYersinia-containing vacuole (YCV).Y. pestisactively inhibits the acidification of this compartment, and eventually, the YCV transitions from a tight-fitting vacuole into a spacious replicative vacuole. The mechanisms to generate the YCV have not been defined. However, we hypothesized that YCV biogenesis requiresY. pestisinteractions with specific host factors to subvert normal vesicular trafficking. In order to identify these factors, we performed a genome-wide RNA interference (RNAi) screen to identify host factors required forY. pestissurvival in macrophages. This screen revealed that 71 host proteins are required for intracellular survival ofY. pestis. Of particular interest was the enrichment for genes involved in endosome recycling. Moreover, we demonstrated thatY. pestisactively recruits Rab4a and Rab11b to the YCV in a type three secretion system-independent manner, indicating remodeling of the YCV byY. pestisto resemble a recycling endosome. While recruitment of Rab4a was necessary to inhibit YCV acidification and lysosomal fusion early during infection, Rab11b appeared to contribute to later stages of YCV biogenesis. We also discovered thatY. pestisdisrupts global host endocytic recycling in macrophages, possibly through sequestration of Rab11b, and this process is required for bacterial replication. These data provide the first evidence thatY. pestistargets the host endocytic recycling pathway to avoid phagolysosomal maturation and generate the YCV.IMPORTANCEYersinia pestiscan infect and survive within macrophages. However, the mechanisms that the bacterium use to subvert killing by these phagocytes have not been defined. To provide a better understanding of these mechanisms, we used an RNAi approach to identify host factors required for intracellularY. pestissurvival. This approach revealed that the host endocytic recycling pathway is essential forY. pestisto avoid clearance by the macrophage. We further demonstrate thatY. pestisremodels the phagosome to resemble a recycling endosome, allowing the bacterium to avoid the normal phagolysosomal maturation pathway. Moreover, we show that infection withY. pestisdisrupts normal recycling in the macrophage and that disruption is required for bacterial replication. These findings provide the first evidence thatY. pestistargets the host endocytic recycling pathway in order to evade killing by macrophages.

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Comparative Morphometric Analysis of Experimental Plague Infection Caused by Yersinia pestis Strains with Different Genetic Characteristics

Problems of Particularly Dangerous Infections ◽

10.21055/0370-1069-2008-4(98)-49-53 ◽

2008 ◽

pp. 49-53 ◽

Cited By ~ 2

Author(s):

S. A. Bugorkova ◽

V. E. Kouklev ◽

T. V. Bugorkova ◽

Z. V. Malykhina ◽

V. V. Kutyrev

Keyword(s):

Yersinia Pestis ◽

Morphometric Analysis ◽

Pulmonary Tissue ◽

Genetic Characteristics ◽

Infectious Process ◽

Functional Systems ◽

Process Formation ◽

Immunocompetent Organs ◽

Compensatory Process

Data on adaptive-compensatory process formation in detoxication and adaptation functional systems of test animals during the plague infection modeling were obtained by means of morphometric analysis. The latter included characterization of apudocytes condition in the number of organs. Changes of apudocytes activity and quantity in immunocompetent organs and pulmonary tissue of biomodels were determined. Morphometric indices selected for registration were shown to allow characterizing the severity of experimental infectious process.

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HIV-1 Capsid Core: A Bullet to the Heart of the Target Cell

Frontiers in Microbiology ◽

10.3389/fmicb.2021.652486 ◽

2021 ◽

Vol 12 ◽

Author(s):

Elenia Toccafondi ◽

Daniela Lener ◽

Matteo Negroni

Keyword(s):

Genetic Material ◽

Host Factors ◽

Retroviral Infection ◽

Infectious Process ◽

Infected Cells ◽

Material Translocation ◽

Infectious Cycle ◽

Hiv 1 ◽

Genomic Material

The first step of the intracellular phase of retroviral infection is the release of the viral capsid core in the cytoplasm. This structure contains the viral genetic material that will be reverse transcribed and integrated into the genome of infected cells. Up to recent times, the role of the capsid core was considered essentially to protect this genetic material during the earlier phases of this process. However, increasing evidence demonstrates that the permanence inside the cell of the capsid as an intact, or almost intact, structure is longer than thought. This suggests its involvement in more aspects of the infectious cycle than previously foreseen, particularly in the steps of viral genomic material translocation into the nucleus and in the phases preceding integration. During the trip across the infected cell, many host factors are brought to interact with the capsid, some possessing antiviral properties, others, serving as viral cofactors. All these interactions rely on the properties of the unique component of the capsid core, the capsid protein CA. Likely, the drawback of ensuring these multiple functions is the extreme genetic fragility that has been shown to characterize this protein. Here, we recapitulate the busy agenda of an HIV-1 capsid in the infectious process, in particular in the light of the most recent findings.

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Plague Microbe Aggregation in the Organism of Fleas (Siphonaptera) with Different Vector Ability

Problems of Particularly Dangerous Infections ◽

10.21055/0370-1069-2012-4-15-17 ◽

2012 ◽

pp. 15-17

Author(s):

L. P. Bazanova ◽

A. Ya. Nikitin

Keyword(s):

Yersinia Pestis ◽

Causative Agent ◽

Infectious Process ◽

Block Formation ◽

The Difference

The following factors have been used to characterize 12 species and subspecies of fleas (Siphonaptera) and plague microbe (Yersinia pestis subs. pestis): the proportion of fleas with “blocks”, “blockules” and their ratio, called the index of microbe aggregation. The block formation is registered in 10, whereas formation of blockules are registered in all of the studied species and subspecies of Siphonaptera , the difference between active and passive transmitters according to the last characteristics being unreliable. The fleas, among of which “blocked” ones are not revealed in the experiments, are capable to transmit the causative agent of plague, sometimes with generalization of infectious process in animals, that can provide for continuous transmission of microbe without formation of “blocks” in the proventriculus. Thus, the high value of “rate of block formation” does not reflect the existence of coevolution in the interactions between microbe and its transmitter.

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In Vivo Transcriptional Profiling of Yersinia pestis Reveals a Novel Bacterial Mediator of Pulmonary Inflammation

mBio ◽

10.1128/mbio.02302-14 ◽

2015 ◽

Vol 6 (1) ◽

Cited By ~ 14

Author(s):

Roger D. Pechous ◽

Christopher A. Broberg ◽

Nikolas M. Stasulli ◽

Virginia L. Miller ◽

William E. Goldman

Keyword(s):

Yersinia Pestis ◽

Inflammatory Responses ◽

Severe Pneumonia ◽

Sudden Onset ◽

Host Factors ◽

Respiratory Pathogen ◽

Bacterial Survival ◽

Pneumonic Plague ◽

Content Type

ABSTRACTInhalation ofYersinia pestisresults in primary pneumonic plague, a highly lethal and rapidly progressing necrotizing pneumonia. The disease begins with a period of extensive bacterial replication in the absence of disease symptoms, followed by the sudden onset of inflammatory responses that ultimately prove fatal. Very little is known about the bacterial and host factors that contribute to the rapid biphasic progression of pneumonic plague. In this work, we analyzed thein vivotranscription kinetics of 288 bacterial open reading frames previously shown by microarray analysis to be dynamically regulated in the lung. Using this approach combined with bacterial genetics, we were able to identify five Y. pestis genes that contribute to the development of pneumonic plague. Deletion of one of these genes,ybtX, did not alter bacterial survival but attenuated host inflammatory responses during late-stage disease. Deletion ofybtXin another lethal respiratory pathogen,Klebsiella pneumoniae, also resulted in diminished host inflammation during infection. Thus, ourin vivotranscriptional screen has identified an important inflammatory mediator that is common to two Gram-negative bacterial pathogens that cause severe pneumonia.IMPORTANCEYersinia pestis is responsible for at least three major pandemics, most notably the Black Death of the Middle Ages. Due to its pandemic potential, ease of dissemination by aerosolization, and a history of its weaponization, Y. pestis is categorized by the Centers for Disease Control and Prevention as a tier 1 select agent most likely to be used as a biological weapon. To date, there is no licensed vaccine against Y. pestis. Importantly, an early “silent” phase followed by the rapid onset of nondescript influenza-like symptoms makes timely treatment of pneumonic plague difficult. A more detailed understanding of the bacterial and host factors that contribute to pathogenesis is essential to understanding the progression of pneumonic plague and developing or enhancing treatment options.

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SPECIFICITY OF IMMUNE MODULATING EFFECT OF YERSINIA PESTIS ENDOTOXIN

Journal of microbiology epidemiology immunobiology ◽

10.36233/0372-9311-2016-3-104-112 ◽

2016 ◽

pp. 104-112

Author(s):

V. I. Tynyanova ◽

V. P. Zyuzina ◽

G. V. Demidova ◽

E. P. Sokolova

Keyword(s):

Immune Response ◽

Yersinia Pestis ◽

Chemical Structure ◽

Inflammatory Cytokine ◽

Signal Pathways ◽

Toxic Shock ◽

Temperature Dependent ◽

Infectious Process ◽

Toxic Potential ◽

Pro Inflammatory Cytokines

Literature and own data on mechanisms of realization of lipopolysaccharide (LPS) toxic potential of Yersinia pestis in the conditions of a macroorganism are analyzed. 2 modifications of LPS are examined - temperature dependent changes of chemical structure of polymers and a change in their conformation under the effect of micro- and macroorganism factors. A special attention is paid to comparative study of toxic and immune modulating properties of the specified LPS forms. Both LPS forms are concluded to activate TLR4/MD2 receptor, inducing synthesis of 2 types of cytokines - pro-inflammatory and interferons. However, dominance of their signal pathways and cross-regulation of the transduced signal are mirrored, and as a result the initial form of LPS initiates interferon synthesis, and conformationally changed - pro-inflammatory cytokines. Results of the experiments are summarized in 2 schemes of signal transfer by TLR4/MD2 receptor under the effect of 2 forms of Y. pestis LPS. Variations of cytokine-inducing properties of the initial and conformationally-altered forms of Y. pestis LPS corresponds to the immune response of the organism at each stage of the infectious process: late inflammatory response by interferon type is characteristic for intra-cellular cycle of plague development, and pro-inflammatory cytokine hyper-production is observed at the terminal stage of infection-toxic shock.

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Identification of host factors required for Yersinia pestis macrophage intracellular survival and their impact on vacuole maturation, acidification and trafficking.

10.18297/etd/2378 ◽

2016 ◽

Author(s):

Michael Connor

Keyword(s):

Yersinia Pestis ◽

Intracellular Survival ◽

Host Factors

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A SEARCH FOR NEW MOLECULAR TARGETS FOR OPTIMIZING PLAGUE PREVENTIVE VACCINATION AND THERAPY

Russian Journal of Infection and Immunity ◽

10.15789/2220-7619-snm-1254 ◽

2019 ◽

Author(s):

E. Krasil'nikova ◽

A. Trunyakova ◽

A. Vagaiskaya ◽

T. Svetoch ◽

R. Shaikhutdinova ◽

...

Keyword(s):

Yersinia Pestis ◽

Molecular Targets ◽

World Health ◽

Transport Systems ◽

Resistant Bacteria ◽

Expert Committee ◽

Antibiotic Resistant ◽

Susceptible Host ◽

Infectious Process ◽

Pathogenicity Factors

The causative agent of plague, Yersinia pestis, is a highly virulent bacterial pathogen and a potential bioweapon. Depending on the route of infection, two prevalent forms of the disease – bubonic and pneumonic, are known. The latter is featured by a high fatality rate. Mortality in untreated bubonic plague patients reaches up to 40-60%, whereas untreated pneumonic plague is always lethal. The development of the infectious process in susceptible host is accounted for by a whole set of pathogenicity factors in plaque pathogen displaying various functional modalities being expressed depending on stage of infectious process, providing their coordinated expression. Knocking out any of such factors, in turn, may not either affect microbe virulence or lead to its attenuation. A search for new Yersinia pestis pathogenicity factors and subsequent development of highly effective subunit and live attenuated plague vaccines inducing development of pronounced cellular and humoral immune reactions, and/or assessment of their potential use as molecular targets for plague therapy still remain a pressing issue, as both currently licensed plague vaccines do not meet the WHO requirements, whereas strains of plague microbe isolated in Madagascar are resistant to all drugs recommended for plague antibacterial therapy. Here we summarize an impact of described and newly discovered pathogenicity factors into the virulence of Y. pestis strains and their protective anti-plague activity. An effect of loss of genes encoding regulatory proteins as well as mutations in the genes for various transport systems of Y. pestis on attenuation of virulent strains is described as well. Perspectives for introducing characterized antigens into prototype subunit vaccine as well as some other obtained mutants into prototypes of living attenuating vaccines were assessed. The use of antibiotics for plague treatment has been embraced by the World Health Organization Expert Committee on Plague as the ‘gold standard’ treatment. However, concerns regarding development of antibiotic-resistant Y. pestis strains accounted for further exploring alternatives to plaque therapy. Several research groups continue working on seeking for other alternative approaches, e.g. treatment with inhibitors of pathogenicity factors. Preliminary data attempting to treat plague patients with pathogenicity factor inhibitors are summarized. Аnti-virulence drugs targeting key microbial factors represent new promising therapeutic options in fight against antibiotic-resistant bacteria.

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