Ticks are hematophagous arthropods that use a complex mixture of salivary proteins to evade host defenses while taking a blood meal. Little is known about the immunological and physiological consequences of tick feeding on humans. Here, we performed the first bulk and single-nucleus RNA sequencing (snRNA-seq) of skin and blood of four persons presenting with naturally acquired, attached Ixodes scapularis ticks. Pathways and individual genes associated with innate and adaptive immunity were identified based on bulk RNA sequencing, including interleukin-17 signaling and platelet activation pathways at the site of tick attachment or in peripheral blood. snRNA-seq further revealed that the Hippo signaling, cell adhesion, and axon guidance pathways were involved in the response to an I. scapularis bite in humans. Features of the host response in these individuals also overlapped with that of laboratory guinea pigs exposed to I. scapularis and which acquired resistance to ticks. These findings offer novel insights for the development of new biomarkers for I. scapularis exposure and anti-tick vaccines for human use.

• MeSH
• klíště * genetika   MeSH
• kousnutí klíštětem * MeSH
• lidé MeSH
• morčata MeSH
• RNA malá jaderná MeSH
• sekvence nukleotidů MeSH
• stravovací zvyklosti fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• morčata MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

It is becoming increasingly clear that the communities of microorganisms that populate the surfaces exposed to the external environment, termed microbiota, are key players in the regulation of pathogen-host cross talk affecting the onset as well as the outcome of infectious diseases. We have performed a multicenter, prospective, observational study in which nasal and oropharyngeal swabs were collected for microbiota predicting the risk of invasive fungal infections (IFIs) in patients with hematological malignancies. Here, we demonstrate that the nasal and oropharyngeal microbiota are different, although similar characteristics differentiate high-risk from low-risk samples at both sites. Indeed, similar to previously published results on the oropharyngeal microbiota, high-risk samples in the nose were characterized by low diversity, a loss of beneficial bacteria, and an expansion of potentially pathogenic taxa, in the presence of reduced levels of tryptophan (Trp). At variance with oropharyngeal samples, however, low Trp levels were associated with defective host-derived kynurenine production, suggesting reduced tolerance mechanisms at the nasal mucosal surface. This was accompanied by reduced levels of the chemokine interleukin-8 (IL-8), likely associated with a reduced recruitment of neutrophils and impaired fungal clearance. Thus, the nasal and pharyngeal microbiomes of hematological patients provide complementary information that could improve predictive tools for the risk of IFI in hematological patients.

• MeSH
• Bacteria MeSH
• invazivní mykotické infekce * MeSH
• lidé MeSH
• mikrobiota * MeSH
• nos mikrobiologie   MeSH
• prospektivní studie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• pozorovací studie MeSH
• práce podpořená grantem MeSH

The ability to predict invasive fungal infections (IFI) in patients with hematological malignancies is fundamental for successful therapy. Although gut dysbiosis is known to occur in hematological patients, whether airway dysbiosis also contributes to the risk of IFI has not been investigated. Nasal and oropharyngeal swabs were collected for functional microbiota characterization in 173 patients with hematological malignancies recruited in a multicenter, prospective, observational study and stratified according to the risk of developing IFI. A lower microbial richness and evenness were found in the pharyngeal microbiota of high-risk patients that were associated with a distinct taxonomic and metabolic profile. A murine model of IFI provided biologic plausibility for the finding that loss of protective anaerobes, such as Clostridiales and Bacteroidetes, along with an apparent restricted availability of tryptophan, is causally linked to the risk of IFI in hematologic patients and indicates avenues for antimicrobial stewardship and metabolic reequilibrium in IFI.

• MeSH
• antifungální látky farmakologie   terapeutické užití   MeSH
• farynx mikrobiologie   MeSH
• hematologické nádory komplikace   MeSH
• hodnocení rizik MeSH
• krevní nemoci komplikace   MeSH
• lidé MeSH
• metagenom MeSH
• metagenomika metody   MeSH
• mikrobiota * MeSH
• modely nemocí na zvířatech MeSH
• mykózy diagnóza   farmakoterapie   etiologie   MeSH
• myši MeSH
• pneumonie diagnóza   farmakoterapie   etiologie   MeSH
• rizikové faktory MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH

Syphilis is a bacterial infection caused by Treponema pallidum subsp. pallidum Infection with T. pallidum subsp. pallidum and its dissemination lead to the synthesis of proinflammatory cytokines triggered by the interaction of bacterial lipoproteins with Toll-like receptor 2 (TLR2). TLR2 contains several nonsynonymous single-nucleotide polymorphisms that may impact the activation of its signaling cascade and alter the responsiveness to, or the course of, various infectious diseases, including those caused by pathogenic spirochetes. To investigate whether TLR2 polymorphism may influence susceptibility to syphilis, 221 healthy individuals with no history of syphilis (controls) and 137 patients diagnosed with syphilis (cases) were screened for the presence of the Arg753Gln polymorphism in the TLR2 gene (2258G→A; rs5743708). The Arg753Gln variant occurs at a significantly lower frequency in syphilis patients (4 of 137 [3%]) than in controls (24 of 221 [10.9%]). These data suggest that TLR2 Arg753Gln may protect from the development of syphilis due to reduced signaling.

• MeSH
• alely MeSH
• dospělí MeSH
• frekvence genu MeSH
• genetická predispozice k nemoci * MeSH
• genotyp MeSH
• jednonukleotidový polymorfismus * MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• studie případů a kontrol MeSH
• substituce aminokyselin * MeSH
• syfilis epidemiologie   etiologie   MeSH
• toll-like receptor 2 genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Slovenská republika MeSH

Quantitative and microscopic tracking of Borrelia afzelii transmission from infected Ixodes ricinus nymphs has shown a transmission cycle different from that of Borrelia burgdorferi and Ixodes scapularisBorrelia afzelii organisms are abundant in the guts of unfed I. ricinus nymphs, and their numbers continuously decrease during feeding. Borrelia afzelii spirochetes are present in murine skin within 1 day of tick attachment. In contrast, spirochetes were not detectable in salivary glands at any stage of tick feeding. Further experiments demonstrated that tick saliva is not essential for B. afzelii infectivity, the most important requirement for successful host colonization being a change in expression of outer surface proteins that occurs in the tick gut during feeding. Spirochetes in vertebrate mode are then able to survive within the host even in the absence of tick saliva. Taken together, our data suggest that the tick gut is the decisive organ that determines the competence of I. ricinus to vector B. afzelii We discuss possible transmission mechanisms of B. afzelii spirochetes that should be further tested in order to design effective preventive and therapeutic strategies against Lyme disease.

• MeSH
• arachnida jako vektory mikrobiologie   fyziologie   MeSH
• Borrelia burgdorferi komplex fyziologie   MeSH
• klíště mikrobiologie   fyziologie   MeSH
• lidé MeSH
• lymeská nemoc mikrobiologie   přenos   MeSH
• myši inbrední C3H MeSH
• myši MeSH
• nymfa mikrobiologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The airway epithelium restricts the penetration of inhaled pathogens into the underlying tissue and plays a crucial role in the innate immune defense against respiratory infections. The whooping cough agent, Bordetella pertussis, adheres to ciliated cells of the human airway epithelium and subverts its defense functions through the action of secreted toxins and other virulence factors. We examined the impact of B. pertussis infection and of adenylate cyclase toxin-hemolysin (CyaA) action on the functional integrity of human bronchial epithelial cells cultured at the air-liquid interface (ALI). B. pertussis adhesion to the apical surface of polarized pseudostratified VA10 cell layers provoked a disruption of tight junctions and caused a drop in transepithelial electrical resistance (TEER). The reduction of TEER depended on the capacity of the secreted CyaA toxin to elicit cAMP signaling in epithelial cells through its adenylyl cyclase enzyme activity. Both purified CyaA and cAMP-signaling drugs triggered a decrease in the TEER of VA10 cell layers. Toxin-produced cAMP signaling caused actin cytoskeleton rearrangement and induced mucin 5AC production and interleukin-6 (IL-6) secretion, while it inhibited the IL-17A-induced secretion of the IL-8 chemokine and of the antimicrobial peptide beta-defensin 2. These results indicate that CyaA toxin activity compromises the barrier and innate immune functions of Bordetella-infected airway epithelia.

• MeSH
• adenylátcyklasový toxin genetika   metabolismus   toxicita   MeSH
• AMP cyklický metabolismus   MeSH
• Bordetella pertussis genetika   metabolismus   MeSH
• bronchy cytologie   metabolismus   mikrobiologie   MeSH
• cytoskelet metabolismus   MeSH
• epitelové buňky metabolismus   mikrobiologie   MeSH
• interleukin-6 metabolismus   MeSH
• lidé MeSH
• mucin 5AC metabolismus   MeSH
• pertuse genetika   metabolismus   mikrobiologie   MeSH
• signální transdukce účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The Campylobacter jejuni-host interaction may be affected by the host's gut microbiota through competitive exclusion, metabolites, or modification of the immune response. To understand this interaction, C. jejuni colonization and local immune responses were compared in chickens with different gut microbiota compositions. Birds were treated with an antibiotic cocktail (AT) (experiments 1 and 2) or raised under germfree (GF) conditions (experiment 3). At 18 days posthatch (dph), they were orally inoculated either with 104 CFU of C. jejuni or with diluent. Cecal as well as systemic C. jejuni colonization, T- and B-cell numbers in the gut, and gut-associated tissue were compared between the different groups. Significantly higher numbers of CFU of C. jejuni were detected in the cecal contents of AT and GF birds, with higher colonization rates in spleen, liver, and ileum, than in birds with a conventional gut microbiota (P < 0.05). Significant upregulation of T and B lymphocyte numbers was detected in cecum, cecal tonsils, and bursa of Fabricius of AT or GF birds after C. jejuni inoculation compared to the respective controls (P < 0.05). This difference was less clear in birds with a conventional gut microbiota. Histopathological gut lesions were observed only in C. jejuni-inoculated AT and GF birds but not in microbiota-colonized C. jejuni-inoculated hatchmates. These results demonstrate that the gut microbiota may contribute to the control of C. jejuni colonization and prevent lesion development. Further studies are needed to identify key players of the gut microbiota and the mechanisms behind their protective role.

• MeSH
• antibakteriální látky farmakologie   MeSH
• B-lymfocyty imunologie   mikrobiologie   MeSH
• bursa Fabricii účinky léků   imunologie   mikrobiologie   MeSH
• Campylobacter jejuni účinky léků   imunologie   patogenita   MeSH
• cékum účinky léků   imunologie   mikrobiologie   MeSH
• gnotobiologické modely imunologie   MeSH
• ileum účinky léků   imunologie   mikrobiologie   MeSH
• interakce hostitele a patogenu imunologie   MeSH
• játra účinky léků   imunologie   mikrobiologie   MeSH
• kampylobakterové infekce imunologie   mikrobiologie   veterinární   MeSH
• kur domácí MeSH
• mikrobiální interakce imunologie   MeSH
• nemoci drůbeže imunologie   mikrobiologie   MeSH
• počet mikrobiálních kolonií MeSH
• slezina účinky léků   imunologie   mikrobiologie   MeSH
• střevní mikroflóra imunologie   MeSH
• T-lymfocyty imunologie   mikrobiologie   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The adenylate cyclase toxin-hemolysin (CyaA, ACT, or AC-Hly) of Bordetella pertussis targets phagocytic cells expressing the complement receptor 3 (CR3, Mac-1, αMβ2 integrin, or CD11b/CD18). CyaA delivers into cells an N-terminal adenylyl cyclase (AC) enzyme domain that is activated by cytosolic calmodulin and catalyzes unregulated conversion of cellular ATP into cyclic AMP (cAMP), a key second messenger subverting bactericidal activities of phagocytes. In parallel, the hemolysin (Hly) moiety of CyaA forms cation-selective hemolytic pores that permeabilize target cell membranes. We constructed the first B. pertussis mutant secreting a CyaA toxin having an intact capacity to deliver the AC enzyme into CD11b-expressing (CD11b(+)) host phagocytes but impaired in formation of cell-permeabilizing pores and defective in cAMP elevation in CD11b(-) cells. The nonhemolytic AC(+) Hly(-) bacteria inhibited the antigen-presenting capacities of coincubated mouse dendritic cells in vitro and skewed their Toll-like receptor (TLR)-triggered maturation toward a tolerogenic phenotype. The AC(+) Hly(-) mutant also infected mouse lungs as efficiently as the parental AC(+) Hly(+) strain. Hence, elevation of cAMP in CD11b(-) cells and/or the pore-forming capacity of CyaA were not required for infection of mouse airways. The latter activities were, however, involved in bacterial penetration across the epithelial layer, enhanced neutrophil influx into lung parenchyma during sublethal infections, and the exacerbated lung pathology and lethality of B. pertussis infections at higher inoculation doses (>10(7) CFU/mouse). The pore-forming activity of CyaA further synergized with the cAMP-elevating activity in downregulation of major histocompatibility complex class II (MHC-II) molecules on infiltrating myeloid cells, likely contributing to immune subversion of host defenses by the whooping cough agent.

• MeSH
• adenylátcyklasový toxin metabolismus   MeSH
• AMP cyklický metabolismus   MeSH
• antigeny CD11b metabolismus   MeSH
• Bordetella pertussis patogenita   MeSH
• buněčná membrána metabolismus   MeSH
• dendritické buňky imunologie   MeSH
• fagocyty imunologie   MeSH
• hemolyziny metabolismus   MeSH
• makrofágový antigen 1 metabolismus   MeSH
• myši inbrední BALB C MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• pertuse mikrobiologie   MeSH
• plíce mikrobiologie   patologie   MeSH
• T-lymfocyty imunologie   MeSH
• virulence MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Tick saliva contains a number of effector molecules that inhibit host immunity and facilitate pathogen transmission. How tick proteins regulate immune signaling, however, is incompletely understood. Here, we describe that loop 2 of sialostatin L2, an anti-inflammatory tick protein, binds to annexin A2 and impairs the formation of the NLRC4 inflammasome during infection with the rickettsial agent Anaplasma phagocytophilum Macrophages deficient in annexin A2 secreted significantly smaller amounts of interleukin-1β (IL-1β) and IL-18 and had a defect in NLRC4 inflammasome oligomerization and caspase-1 activation. Accordingly, Annexin a2-deficient mice were more susceptible to A. phagocytophilum infection and showed splenomegaly, thrombocytopenia, and monocytopenia. Providing translational support to our findings, better binding of annexin A2 to sialostatin L2 in sera from 21 out of 23 infected patients than in sera from control individuals was also demonstrated. Overall, we establish a unique mode of inflammasome evasion by a pathogen, centered on a blood-feeding arthropod.

• MeSH
• Anaplasma phagocytophilum genetika   imunologie   MeSH
• annexin A2 chemie   genetika   imunologie   MeSH
• arachnida jako vektory chemie   genetika   imunologie   MeSH
• cystatiny chemie   genetika   imunologie   MeSH
• ehrlichióza imunologie   mikrobiologie   patologie   MeSH
• Escherichia coli genetika   metabolismus   MeSH
• imunitní únik * MeSH
• inflamasomy genetika   imunologie   MeSH
• interleukin-18 genetika   imunologie   MeSH
• interleukin-1beta genetika   imunologie   MeSH
• kaspasa 1 genetika   imunologie   MeSH
• kaspasy genetika   imunologie   MeSH
• klíště chemie   genetika   imunologie   MeSH
• lidé MeSH
• makrofágy imunologie   mikrobiologie   MeSH
• molekulární modely MeSH
• myši MeSH
• protein - isoformy chemie   genetika   imunologie   MeSH
• proteiny regulující apoptózu chemie   genetika   imunologie   MeSH
• proteiny vázající vápník chemie   genetika   imunologie   MeSH
• regulace genové exprese MeSH
• rekombinantní proteiny chemie   genetika   imunologie   MeSH
• sekvence aminokyselin MeSH
• signální transdukce MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Th17 cells constitute a subset of CD4(+) T lymphocytes that play a crucial role in protection against extracellular bacteria and fungi. They are also associated with tissue injury in autoimmune and inflammatory diseases. Here, we report that serpin from the tick Ixodes ricinus, IRS-2, inhibits Th17 differentiation by impairment of the interleukin-6 (IL-6)/STAT-3 signaling pathway. Following activation, mature dendritic cells produce an array of cytokines, including the pleiotropic cytokine IL-6, which triggers the IL-6 signaling pathway. The major transcription factor activated by IL-6 is STAT-3. We show that IRS-2 selectively inhibits production of IL-6 in dendritic cells stimulated with Borrelia spirochetes, which leads to attenuated STAT-3 phosphorylation and finally to impaired Th17 differentiation. The results presented extend the knowledge about the effect of tick salivary serpins on innate immunity cells and their function in driving adaptive immune responses.

• MeSH
• Borrelia imunologie   MeSH
• buněčná diferenciace účinky léků   MeSH
• buňky Th17 účinky léků   fyziologie   MeSH
• dendritické buňky účinky léků   fyziologie   MeSH
• interleukin-6 antagonisté a inhibitory   metabolismus   MeSH
• klíště MeSH
• myši inbrední C57BL MeSH
• serpiny metabolismus   MeSH
• signální transdukce účinky léků   MeSH
• transkripční faktor STAT3 antagonisté a inhibitory   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH