24 research outputs found
Functional characterization of "Bartonella" effector protein - BepE during "in vivo" and "in vitro" infection
No full textThe bartonellae is a family of gram-negative, fastidious, facultative intracellular, zoonotic bacteria. Most of the Bartonella species are highly adapted to establish asymptomatic bacteremia of their reservoir host within which the bacteria colonize erythrocytes as privileged host niche and develop long-lasting persistent infections. Bartonella uses a VirB type IV secretion system (T4SS) to translocate Bartonella effector proteins (Beps) into the infected cells. By using such a tool box it subverts host cellular functions in order to establish a safe niche for replication and survival.
This thesis aimed to elucidate the role of one of the effector proteins – BepE in the establishment of Bartonella infection by using in vivo and in vitro infection models. Started in December 2006, my primary aim was to establish a suitable model for pathogen - natural host interaction. In order to closely mimic the reservoir host infection by BartonelIa, I have adapted the rat intra-venous (i.v.) to intra-dermal (i.d.) infection model, inoculation of B. tribocorum (Btr) in the ear dermis of the animal. This route of infection reflects the natural way of Bartonella transmission by arthropods when the bacteria are inoculated in the skin of a mammal via the feces of a vector after animal scratches. The Btr wild-type i.d. infected animals developed blood stage infection, which started around 7-8 days post infection and lasted for 10 weeks. It was a long-term bacteremic infection without obvious clinical manifestations, a hallmark of the reservoir host infection by Batonellae. The time delay that Btr took to appear in blood could correspond to the way that bacteria need to pass from the derma to the lymphatic-blood system and to the possible interaction with the innate immune system. In summary, the rat i.d. model enabled us to distinguish Bartonella factors involved on two different phases of the infection: early phase, prior seeding into the blood and the blood stage. On those two stages bacteria have different environment to interact with, and assumably different strategies to cope with the host immune system. The rat i.d. infection model revealed BepE as a critical factor in the establishment of reservoir host bacteremia. The expression of BepEBtr could rescue the abacteremic phenotype of Btr ΔbepDE mutant and enabled the strain to reach the blood. Heterologous complementation of Btr ΔbepDE phenotype with BepEBhe suggests that this function of BepE is conserved between different species of Bartonellae. Even more, I could demonstrate that the C-terminal BID domains are having the specific function but putative phosphotyrosine-containing N-term of BepE does not play an essential role in the establishment of long-term bacteremic infection of the natural host by Bartonella.
Another phenotype of BepE but in vitro was observed during the infection of primary endothelial cells HUVECs with Bhe ΔbepE (and ΔbepDEF) mutant(s). Besides erythrocytes, endothelial cells represent another major target cell type for Bartonellae demonstrated as bacillary angiomatoses within the incidental host environment, mostly in immunocompromized human patients. HUVECs infected with Bhe stain that lacked BepEBhe revealed disturbed rear edge detachment during migration and followed with the fragmentation of cell body. This phenomenon was inhibited by pbepEBhe expression in Bhe ΔbepE (and ΔbepDEF) as well as, by T4SS independent expression of pbepEBhe in HUVECs by transfection prior the infection with Bhe ΔbepE (and ΔbepDEF). We found that the cell fragmentation of infected HUVECs is T4SS dependent and is a secondary effect of translocated Beps, potentially the Beps involved in the invasome formation. Further we conclude that the C-terminal BID domains of BepEBhe are sufficient to interfere with the cells fragmentation process. From this we could hypothesize that primary infected cells in i.d. infection model of rats may also undergo fragmentation or impaired migration when infected with Btr ΔbepDE and then Bartonella does not succeed to reach the blood system and colonize red blood cells.
Further, I introduced the i.d. in vivo infection of Rosa 26-loxP-egfp Balb/c mice and in vitro infection of mouse Bone Marrow-derived Dendritic Cells (BMDCs) with B. birtlesii (Bbi) strain that is expressing Cre-BID fusion protein. The in vitro model showed for the first time a Bartonella effector protein translocation in primary immune cells of the reservoir host. This finding builds a strong basis for the hypothesis that primary infected cells in vivo may be the DCs (Langerhance cells or dermal DCs) in the skin of infected animal. DCs are the sentinels of the immune system that constantly sample the environment for the “danger signal”. Thus, they represent one of the candidate cells in the derma to be targeted by Bartonella after inoculation of the bacteria from the feces of arthropod vector. Infected DCs could serve as Trojan horses to carry and disseminate Bartonella from derma to lymphatic–blood system
Meta-Disciplinarity of Digital Education and Communication
No full textDynamic transformation of the knowledge economy, enhanced by Industry 4.0/5.0 development and rise of the networked society in the Digital Age, emergency digitization of all social communicative spheres due to pandemic measures have imposed dramatic changes onto transdisciplinary overlap in different areas of human knowledge and experience, induced by the cross-sectorial job market demands of university level education, curriculum design and learning outcomes.
The Covid-19 pandemic induced amplified digitalization measures in the higher education sphere. This end-to end digital shift in the educational processes (communication, content, outcomes and outputs, skills) heralded the introduction of meta-disciplinary dimensions of learning – digital, hybrid and, blended. These meta-disciplinary dimensions can be considered conduits of vertical (endocentric) and horizontal (exocentric) transdisciplinary of digital education as a communicative system.
Applied meta-disciplinary lens contributes to the solution of holistic modeling of processes and results of updating models and mechanisms of the highly dynamic communication system of education in the digital environment as a whole and its individual formats in the emergency digitization measures of different types
Transdisciplinary Communication in the Meta-Framework of Digital Education
No full textDynamic transformation of the knowledge economy, enhanced by Industry 4.0/5.0 development and rise of the networked society in the Digital Age, emergency digitization of all social communicative spheres due to pandemic measures have imposed dramatic changes onto transdisciplinary overlap in different areas of human knowledge and experience, induced by the cross-sectorial job market demands of university level education, curriculum design and learning outcomes.
The global pandemic and subsequent warfare in Ukraine induced amplified digitalization measures in the higher education sphere. This end-to end digital shift in the educational processes (communication, content, outcomes and outputs, skills) heralded the introduction of meta-disciplinary dimensions of learning – digital, hybrid and, blended. These meta-disciplinary dimensions can be considered conduits of vertical (endocentric) and horizontal (exocentric) transdisciplinary of digital education as a communicative system.
Applied trans-disciplinary lens of the phenomenological approach contributes to the solution of holistic modeling of processes and results of updating models and mechanisms of the highly dynamic communication system of education in the digital environment as a whole and its individual formats in dynamic sustainable and emergency digitization contexts
PRAGMATIC FUNCTIONS AND SOME LINGUISTIC CHARACTERISTICS OF THE DIALOGUE IN THE LITERARY TEXT /ACCORDING THE EXAMPLES FROM G. DOCHANASHVILI’S STORIES/
No full textკონფერენცია მიძღვნილია აკადემიკოს კოტე წერეთლის 100 წლის იუბილესადმი/ DEDICATED TO THE 100TH ANNIVERSARY OF ACADEMICIAN KONSTANTINE TSERETELIDialogues are one of the most complicated widely used forms of human
communication. Indeed, modern time linguistics is mostly interested
in real-time spontaneous dialogues, but the dialogues from the prosaic
literary pieces are also very interesting. They represent one of the most
dynamic means of interpretation and description of the interrelations, behaviour
and varieties of the actions of the literary characters. The diversification and character of the dialogues are conditioned by the contents they
are delivering and the aims of the author. Differences between the real and
modelled by a writer dialogue are evident, but their main linguistic features
do not diff er very much.
The specifics of any dialogue building and its linguistic style depend
on social status, interrelations of the communicants and the situation in
which the given communication takes place, but a real, everyday style dialogue
is spontaneous, not previously prepared and as for the fiction, it is
modelled, a fiction which subordinates to the author’s idea.
In the pieces of the different Georgian writers both types of dialogues
– official and non-official are represented as multisided by their content,
language or structure; especially, symmetric and asymmetric dialogues are
very interesting; their division by types is based on the social characteristic
features and mutual estimation and relations of the participants.
We have studied the dialogues in some literary pieces by Guram Dochanashvili
and we discovered a lot of varieties among them. The virtuosity
of the writer is clear; sometimes, a story begins with a dialogue from the
very beginning; talk is going on not only the participants, but the author
often uses his remarks to appeal to a reader and makes them a participant of the given story. Especially interesting, from that point, is the story “Water(
po)loo or the Recovery Work.”
The so-called dialogue signals have to also be named– structural-compositional
and content-modification ones. Asymmetric dialogues are also
very interesting; they contain phatic lexical units. One more interesting example
is also the case of asymmetrical dialogue when a personage of one
story (“Johannes Sebastian Bach”) utters some phrases in Megrelian, and
this is used as a means of expressing the estrangement by the author.
We have discussed the dialogues from the following literature pieces
by Guram Dochanashvili, with their linguistic characteristics: “The Case”,
“The Man Who Loved Literature Very Much,”
“The Love of One Thing that Needs Hiding,” “Johannes Sebastian Bach”
and “Water(po)loo or the Recovery Work”
Nina Gabrielian's Carousel - Text and Translation
No full textThe Georgian translations of five poems by Rusudan Chanturishvili of
the Russian-speaking Armenian poet, Nina Gabrielian was published in the
2011 collection of translated poems Unquenchable Colors. The poems were
taken from the collected works, Pomegranate Seeds published in 1992.
From the poems presented in the collection, we took The Carousel for
consideration, which is a text loaded with content and poetic means of expression.
N. Gabrielian’s title The Carousel is a major marker of the poetics of
the verse and, on the one hand, presents the model of the world and, on
the other, the poet’s views on the world. N. Gabrielian’s Carousel is a text
containing a musical component, as evidenced by the musical term Tocata
enclosed in parentheses after the title. The title’s relation to the music
is compositionally completed and manifested in the dedication / epigraph
– “to K. S. Khachaturian”. As a matter of fact, the poem was written in the
1980s under the impression of Karen Khachaturian’s sonata, which is why
the author tries to repeat the rhythm of its second part - Tokata - performed
at a fast pace. In her translation, Rusudan Chanturishvili strictly follows the
original’s title, remark and dedication / epigraph.
Nina Gabrieliani’s Carousel, according to the author, is a conventional
astrophic poem consisting of 21 lines irregular in syllabic arrangement; Rusudan
Chanturishvili’s translation is also an astrophic rhythmic verse without
fixed number of syllables per line.
One of the most pronounced organizing means of the structure of Nina
Gabrieliani’s poem is repetition, which the poet uses to enhance the artistic
effect and repeats the same word, phrase, line throughout the poem. The
alliteration and assonance coefficient is also high, which, in addition to the
phonetic sound, also regulates its rhythmic structure.
The anaphora represented by the verbs in the present tense serves the
cause of organizing the poem’s rhythm. The poet also uses the refrain.
The translation is to a certain extent accurate in repeating individual
words, phrases and lines. Alliteration, groups of sounds, tautograms, and assonances
are translated “conditionally according to the specific capabilities
of the language.” However, where it is impossible to replicate the original
elements, R. Chanturishvili uses the right strategy and replaces them with words of effective, expressive power in translation. The same is true about
the anaphora and refrain.
R. Chanturishvili’s translation preserves the original accelerated
rhythm, intonation and mood of the lyrical hero, “although sometimes adherence
to them leads to sacrificing the intellectual accuracy of the original.”
Modified or new lexical items, lines appear (or are omitted) in the translation,
“which plays a certain role in the poem’s rhythm-intonational organization
and the sound.”
The paper discusses examples of synonymous expansion, decrease,
increase, replacement in translation and draws relevant conclusions
New Research by German Kartvelologist about the Merit of Academician Akaki Shanidze
No full textეძღვნება თსუ-ს ემერიტუს პროფესორ ლელი ბარამიძის დაბადებიდან 90-ე წლისთავს/ Dedicated to the 90th Birthday of Emeritus Professor of TSU Leli BaramidzeA new book by well-known kartvelologist prof. Heinz Fähnrich has been published
in Germany; it is dedicated to the life and diverse activities of Georgian Academician
Akaki Shanidze. Title: “Akaki Shanidze in service of science and Georgian nation” (Düren:
Shaker, 2021) (Fähnrich 2021).
Heinz Fähnrich has had much merite to Kartvelian linguistics and philology. At the
beginning of his work, he was interested in archeology and was doing his work in this
field but since 1960 he got interested in Caucasian studies and began to study it at Jena.
In 1969 Fähnrich had his first dissertation paper (Promotion) defense; then he arrived to
Georgia, became Akaki Shanidze’s postgraduate student and in 1971 he had his
dissertation paper (Habilitation) defense at Tbilisi State University, in Georgian language.
He translated Akaki Shanidze’s book “Old Georgian Grammar” (Shanidze 1982). He also
founded the yearly German- language scientific journal “Georgica” and was its editor-inchief
(1978-2006), he worked as the head of Department of Caucasiology (Caucasian
Studies) at Friedrich Schiller University of Jena (1986-2006); from 1996 he is a foreign
member of the Georgian National Academy of Sciences, the author of many scientific
works, among them, the dictionaries, also a translator of Georgian literary pieces and
folklore.
The new book by prof. Heinz Fähnrich introduces to the readers the life and work
of prof. Akaki Shanidze, great Georgian linguist, Academician of Georgian Academy of
sciences (1941) and describes his great merit towards the linguistics as a science. The
book consists of the following paragraphs:
• The road of life before the Doctor dissertation;
• Shanidze’s scientific activities in the field of the New Georgian language;
• Old Georgian language;
• Observations about Kartvelian languages;
• Researches in the field of Georgian dialects;
• His works in Rustvelology;
• Publishing of the Old Georgian manuscripts;
• Researches in lexis;
• Reading the ancient Georgian inscriptions;
• Albanian script and language;
• Selective bibliography of Akaki Shanidze’s works.
At the end there is the list of works edited under the title “Caucasian series” in
1991-2017 (some works of the undergraduate german students of the Caucasiology
specialty among them).
In the introduction, H. Fähnrich remembers the remarkable date, the year 1968,
when Akaki Shanidze was given the honorary title of the doctor of philosophy at the
philosophy faculty of Friedrich Schiller University of Jena.
The part in which A. Shanidze’s biography is given, tells about his difficult but very
interesting and meaningful life; his merit in the comlex job of foundation of Tbilisi State University is underlined; in this part, the author also writes about importance of Akaki
Shanidze’s first dissertation work for the Doctor degree (it was A. Shanidze’s work on
the person marks of the verb in Old Georgian), the special work of the scholar done in
the sphere of Kartvelology and Caucasiology in general, is underlined; his researches on
grammatical structures, his great deal in the process of Georgian and Caucasian
languages investigations, also in the job of development of the Georgian language
studying within the school programs and at the Universities of Georgia are also precious.
In the chapters of his book, the author discusses Akaki Shanidze's fundamental
researches in the fields of the New Georgian and Old Georgian, in Georgian dialects, in
rustvelology, in the lexical sphere, in the process of Old Georgian manuscripts’
researches, in discovering and systematization of the Alban language manuscripts, in
proper reading and dating of the Old Georgian inscriptions, in Kartvelology; special
attention is paid to the fundamental works: “Georgian dialects in the Mountain regions”
from 1915 (Shanidze 1981); “Basics of the Georgian language grammar” (Shanidze
1973); “Grammar of the Old Georgian Language” (Shanidze 1976); “Sinai Polycephalion
of the year 864” (Shanidze was the editor of this fundamental work) (Shanidze 1959),
“Symphony of “Vepxistkaosani” (The Knight in the Panther's Skin) (1956), he also edited
the Georgian folk poetry and others.
The author underlines also Akaki Shanidze’s tribute to the studying of the noun
and verb categories in Georgian, his great deal in work on the system of series and
tense-mood forms (mtskrives) in Georgian verb conjugation; in showing agglutination
and synthesis in the Georgian verb structure. Basing on Akaki Shanidze’s works, the
author suggests 25 verb components (personal marks, marks of tense-mood forms,
morphological markers of the verb categories – chains of prefixes and suffixes which can
be separated out in the verb forms (e.g.ze-cạ -mo-i-čṛ -a, da-gv-a-tvalier-eb-in-eb-d-nen
and others the like).
Besides, prof. Heinz Fähnrich discusses in details the importance of the Georgian
inscriptions in Georgia and abroad (the Georgian inscriptions of Bolnisi, Urbnisi,
Ukangori, Palestine). In this part of the book, along with the great work by Akaki
Shanidze, the important stages are shown in the history of Georgian literary language
development such as main changes and gradual language formation basing on which
Akaki Shanidze reached the main and important goal of phasing the process of Georgian
language development.
Tao-Klarjeti school is mentioned in his work with the manuscripts written there,
also the activities taking place in Gelati and Ikhalto ancient academies, other places
abroad where Georgian language educational activities are mentioned.
Heinz Fähnrich's book about Akaki Shanidze is an a really important acquisition for
Kartvelology
Reported Speech: Classification and Means of Expression’s in Georgian
No full textThe author of a text or the narrator (in the oral speech), besides their own words, can deliver the other people’s narration, to deliver which, the different languages all over the world use for their own language-particular means, and on this point, all the languages reveal large varieties. Generally, among the kinds of other people’s words (someone else's speech), the direct and indirect (or reported) kinds of speech are most usual and known. Besides that, free indirect speech and dialogue are also sorted out as the kinds of indirect speech. The given article discusses the classification of the other people’s words (someone else's speech) and the grammatical and lexical means of their delivering in the modern Georgian. Also, the history of studying the mentioned phenomenon in the different grammar books of the Georgian language (XIX-XX centuries) are studied and shown in Georgian linguistics. Special attention is paid to the valuable work done by P. Ioseliani who was the first linguist in Georgia to study this phenomenon in his Grammar Book edited in 1849 and who sorted out its two types. We should also mention the grammar books by T. Jordania, A. Benashvili, S, Khundadze, M. Janashvili, A. Kutateladze, D. Karichashvili and M. Kelendjeridze, in which the phenomenon of the direct and indirect (reported) speech is discussed and the efforts to create appropriate terminology for this phenomenon are evidenced. The bulk of the empiric material to be analyzed is taken mainly from the corpus of the Georgian language (GNC), and some material – from the Georgian dialectic corpus (GDC). The descriptive methods used in the process of study are as follow: descriptive, comparative, statistical and corpus methods. It is very important to discuss the opinions of the Georgian linguists of the 20th century as relating to the classification of the someone else's speech (or other people’s words) (A. Shanidze, L. Kvachadze, W. Boeder, Zh. Peikrishvili, A. Arabuli, L. Geguchadze, R. Kurdadze…). The opinion expressed by A. Arabuli, concerning the other people’s word which should be discussed as one of the kinds of the indirect (reported) speech, not the direct speech, as it was classified earlier, is especially interesting for us. The additional argument to support this opinion is that despite the similarity with the samples of the direct speech, (repeating the person, number and tense of the verb unchangeable), such phrases reflect neither direct communication (eye-to-eye contact) nor direct appeal to the addressee and only repeats something that already happened in the past, something that was said or thought by somebody, just as it is the characteristic feature for the indirect speech. Terminology of such phenomena should be studied and adjusted in order to specify the explanation of the term “other people’s words, as in reality it denotes not only something said by people earlier, who at the given moment are not participating in the talk, but the words expressing the opinions and thoughts of the person who is participating in the given dialogue at the given time. In such cases the quotative particles “-metki” (< me vtkvi– ‘I said’) and “-tko” (from “tkva”), are used, that makes it possible to maintain the verb forms in the indirect speech. Besides the particle “-meutxari” (from “me vutxari” ‘I told him’), which became very usual and is used in everyday speech, should be also mentioned, as it is used quite often when delivering the dialogue which took place earlier (this suggestion was expressed by the author in their papers (Zekalashvili 2004; 2010; 2020). The mentioned particle has not yet been discussed as a particle in the literary language but is used only in colloquial speech, when delivering the conversation taken place earlier then the dialogue. The article shows the results of the study of necessary transformation which takes place in the process of delivering the indirect (reported) speech from its direct original. Such transformations are usual in the process of delivering several kinds of the narrative, interrogative and imperative sentences in the indirect speech (reported speech, reported questions, reported requests or reported orders). The words of the author are transferred as the main sentence in the structure of the complex subordinate sentence. It is introduced as the direct object and starts within the narrative sentence, with help of the conjunction “rom” - ‘that’; and in case of the interrogative sentence – “tu ara” – ‘or (if) not’, or in case of such pronouns or other words which are by their meaning interrogative, namely (“vin” ‘who’, “ra” ‘what’, “rodis” ‘when’, “sad” ‘where’…); in the imperative sentence with help of the particle “unda” – ‘must’ plus other phrases such as: ‘it must be so’, ‘it is necessary’, ‘mandatory’ and so on…; the negative particles such as “ar” – ‘do not’ or “nu” – ‘you must (should) not do it’ and other means added to the verb forms (“ar” + Subjunctive, “nu” + Present/Futur). Basing on the language corpus, several statistic data are gathered showing the results of measuring the frequency of usage of the quotative particles, such as “metki” – ‘I said’ (or ‘I thought’) and the data, as it was expected, show us that the particle -metki overwhelms the cases with the particle “-tko”. This is because of the fact that its usage is limited by its inner content – transferring the words of the first person to the other person through the speech of the second person. As for the particle “-o”, it is the most frequently used one, it can be met with any of the parts of speech, but sometimes it is a prosodic vowel (in poetry). The particle -o is acknowledged mostly with the words which have particles “titkos” – ‘as if’, and “neta” – ‘wish’, expressing strong dream, desire in the sentences expressing the wish or dream (e. g. “ise šemomxeda, titkos ṗirvelad mxedavso” - ‘she (he) looked at me as if he saw me for the first time’); “važma inaṭra, neṭa is ulamazesi gogo gamacnoo” – ‘the young man dreamed about somebody’ or ‘some situation helped him to know that prettiest girl’). There are the verbs sorted out in the examples chosen to analyze, which are followed by word-by-word (quotative) particles, such as “-metki”, “-tko”, “-o”. As it was expected, those are the verbs out of the ‘speech’ and ‘thinking’ circles, in the different personal and tense forms: “ambobs/tkva” (iṭq̇vis, utkvams) – ‘says/said/is known that ‘he said’, “eubneba” (eṭq̇vis, utxra) ‘tells’, ‘says’ (‘will tell, say’, ‘told, said’); also: “uambobs” ‘retells’, ‘told’, “moaxsenebs” ‘reports’, “elaṗaraḳeba/esaubreba” ‘speaks to’, “uq̇viris” ‘shouts at’, “cạ moiӡaxebs” ‘shouts out’, “evedreba/exvecẹ ba” ‘begs’, “ečurčuleba” ‘whispers’, “ebuṭbuṭeba” ‘murmurs’, “ebuzγuneba” ‘growls’, “naṭrobs” ‘wishes’, “eḳamateba/edaveba” ‘discusses’, “pikrobs” ‘thinks’, “ocnebobs” ‘dreams about’, etc. As about the generalized personal forms, without showing persons: “natkvamia, tkmula” ‘as its said’, “(rogorc) amboben” ‘they say so’, (rogorc) iṭq̇vian” ‘they say’, “cnobilia” ‘as it is known’ ‘it is said’ and the like, they are comparatively rare, but it is generally known that such forms maintain the general sayings with the end-particle -o and are met in the proverbs
A novel mechanism-based pharmacokinetic-pharmacodynamic (PKPD) model describing ceftazidime/avibactam efficacy against β-lactamase-producing Gram-negative bacteria
No full textBACKGROUND: Diazabicyclooctanes (DBOs) are an increasingly important group of non β-lactam β-lactamase inhibitors, employed clinically in combinations such as ceftazidime/avibactam. The dose finding of such combinations is complicated using the traditional pharmacokinetic/pharmacodynamic (PK/PD) index approach, especially if the β-lactamase inhibitor has an antibiotic effect of its own.OBJECTIVES: To develop a novel mechanism-based pharmacokinetic-pharmacodynamic (PKPD) model for ceftazidime/avibactam against Gram-negative pathogens, with the potential for combination dosage simulation.METHODS: Four β-lactamase-producing Enterobacteriaceae, covering Ambler classes A, B and D, were exposed to ceftazidime and avibactam, alone and in combination, in static time-kill experiments. A PKPD model was developed and evaluated using internal and external evaluation, and combined with a population PK model and applied in dosage simulations.RESULTS: The developed PKPD model included the effects of ceftazidime alone, avibactam alone and an 'enhancer' effect of avibactam on ceftazidime in addition to the β-lactamase inhibitory effect of avibactam. The model could describe an extensive external Pseudomonas aeruginosa data set with minor modifications to the enhancer effect, and the utility of the model for clinical dosage simulation was demonstrated by investigating the influence of the addition of avibactam.CONCLUSIONS: A novel mechanism-based PKPD model for the DBO/β-lactam combination ceftazidime/avibactam was developed that enables future comparison of the effect of avibactam with other DBO/β-lactam inhibitors in simulations, and may be an aid in translating PKPD results from in vitro to animals and humans.</p
A translocated effector required for bartonella dissemination from derma to blood safeguards migratory host cells from damage by co-translocated effectors
No full textNumerous bacterial pathogens secrete multiple effectors to modulate host cellular functions. These effectors may interfere with each other to efficiently control the infection process. Bartonellae are Gram-negative, facultative intracellular bacteria using a VirB type IV secretion system to translocate a cocktail of Bartonella effector proteins (Beps) into host cells. Based on in vitro infection models we demonstrate here that BepE protects infected migratory cells from injurious effects triggered by BepC and is required for in vivo dissemination of bacteria from the dermal site of inoculation to blood. Human endothelial cells (HUVECs) infected with a ΔbepE mutant of B. henselae (Bhe) displayed a cell fragmentation phenotype resulting from Bep-dependent disturbance of rear edge detachment during migration. A ΔbepCE mutant did not show cell fragmentation, indicating that BepC is critical for triggering this deleterious phenotype. Complementation of ΔbepE with BepEBhe or its homologues from other Bartonella species abolished cell fragmentation. This cyto-protective activity is confined to the C-terminal Bartonella intracellular delivery (BID) domain of BepEBhe (BID2.EBhe). Ectopic expression of BID2.EBhe impeded the disruption of actin stress fibers by Rho Inhibitor 1, indicating that BepE restores normal cell migration via the RhoA signaling pathway, a major regulator of rear edge retraction. An intradermal (i.d.) model for B. tribocorum (Btr) infection in the rat reservoir host mimicking the natural route of infection by blood sucking arthropods allowed demonstrating a vital role for BepE in bacterial dissemination from derma to blood. While the Btr mutant ΔbepDE was abacteremic following i.d. inoculation, complementation with BepEBtr, BepEBhe or BIDs.EBhe restored bacteremia. Given that we observed a similar protective effect of BepEBhe on infected bone marrow-derived dendritic cells migrating through a monolayer of lymphatic endothelial cells we propose that infected dermal dendritic cells may be involved in disseminating Bartonella towards the blood stream in a BepE-dependent manner
