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BETA
Härtlova, Anetta
Alternative names
Publications (7 of 7) Show all publications
Putzova, D., Panda, S., Härtlova, A., Stulík, J. & Gekara, N. O. (2017). Subversion of innate immune responses by Francisella involves the disruption of TRAF3 and TRAF6 signalling complexes. Cellular Microbiology, 19(11), Article ID e12769.
Open this publication in new window or tab >>Subversion of innate immune responses by Francisella involves the disruption of TRAF3 and TRAF6 signalling complexes
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2017 (English)In: Cellular Microbiology, ISSN 1462-5814, E-ISSN 1462-5822, Vol. 19, no 11, article id e12769Article in journal (Refereed) Published
Abstract [en]

The success of pathogens depends on their ability to circumvent immune defences. Francisella tularensis is one of the most infectious bacteria known. The remarkable virulence of Francisella is believed to be due to its capacity to evade or subvert the immune system, but how remains obscure. Here, we show that Francisella triggers but concomitantly inhibits the Toll-like receptor, RIG-I-like receptor, and cytoplasmic DNA pathways. Francisella subverts these pathways at least in part by inhibiting K63-linked polyubiquitination and assembly of TRAF6 and TRAF3 complexes that control the transcriptional responses of pattern recognition receptors. We show that this mode of inhibition requires a functional type VI secretion system and/or the presence of live bacteria in the cytoplasm. The ability of Francisella to enter the cytosol while simultaneously inhibiting multiple pattern recognition receptor pathways may account for the notable capacity of this bacterium to invade and proliferate in the host without evoking a self-limiting innate immune response.

Place, publisher, year, edition, pages
Hoboken: Wiley-Blackwell, 2017
Keywords
inflammatory responses, listeria monocytogenes, murine macrophages, tularensis lvs, cytosolic dna, in vitro, system, infection, activation, trif
National Category
Cell and Molecular Biology
Research subject
Immunology
Identifiers
urn:nbn:se:umu:diva-139636 (URN)10.1111/cmi.12769 (DOI)000412834200008 ()28745813 (PubMedID)
Funder
Swedish Research Council, 2013-8621Swedish Research Council, 2015-02857
Available from: 2017-09-19 Created: 2017-09-19 Last updated: 2019-03-15Bibliographically approved
Erttmann, S. F., Härtlova, A., Sloniecka, M., Raffi, F. A. M., Hosseinzadeh, A., Edgren, T., . . . Gekara, N. O. (2016). Loss of the DNA Damage Repair Kinase ATM Impairs Inflammasome-Dependent Anti-Bacterial Innate Immunity. Immunity, 45(1), 106-118
Open this publication in new window or tab >>Loss of the DNA Damage Repair Kinase ATM Impairs Inflammasome-Dependent Anti-Bacterial Innate Immunity
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2016 (English)In: Immunity, ISSN 1074-7613, E-ISSN 1097-4180, Vol. 45, no 1, p. 106-118Article in journal (Refereed) Published
Abstract [en]

The ATM kinase is a central component of the DNA damage repair machinery and redox balance. ATM dysfunction results in the multisystem disease ataxia-telangiectasia (AT). A major cause of mortality in AT is respiratory bacterial infections. Whether ATM deficiency causes innate immune defects that might contribute to bacterial infections is not known. Here we have shown that loss of ATM impairs inflammasome- dependent anti-bacterial innate immunity. Cells from AT patients or Atm(-/-) mice exhibited diminished interleukin-1 beta (IL-1 beta) production in response to bacteria. In vivo, Atm(-/-) mice were more susceptible to pulmonary S. pneumoniae infection in a manner consistent with inflammasome defects. Our data indicate that such defects were due to oxidative inhibition of inflammasome complex assembly. This study reveals an unanticipated function of reactive oxygen species (ROS) in negative regulation of inflammasomes and proposes a theory for the notable susceptibility of AT patients to pulmonary bacterial infection.

National Category
Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-125590 (URN)10.1016/j.immuni.2016.06.018 (DOI)000380749000014 ()27421701 (PubMedID)
Available from: 2016-09-23 Created: 2016-09-13 Last updated: 2018-06-07Bibliographically approved
Härtlova, A., Erttmann, S. F., Raffi, F. A. M., Schmalz, A. M., Resch, U., Anugula, S., . . . Gekara, N. O. (2015). DNA Damage Primes the Type I Interferon System via the Cytosolic DNA Sensor STING to Promote Anti-Microbial Innate Immunity. Immunity, 42(2), 332-343
Open this publication in new window or tab >>DNA Damage Primes the Type I Interferon System via the Cytosolic DNA Sensor STING to Promote Anti-Microbial Innate Immunity
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2015 (English)In: Immunity, ISSN 1074-7613, E-ISSN 1097-4180, Vol. 42, no 2, p. 332-343Article in journal (Refereed) Published
Abstract [en]

Dysfunction in Ataxia-telangiectasia mutated (ATM), a central component of the DNA repair machinery, results in Ataxia Telangiectasia (AT), a cancer-prone disease with a variety of inflammatory manifestations. By analyzing AT patient samples and Atm(-/-) mice, we found that unrepaired DNA lesions induce type I interferons (IFNs), resulting in enhanced anti-viral and anti-bacterial responses in Atm(-/-) mice. Priming of the type I interferon system by DNA damage involved release of DNA into the cytoplasm where it activated the cytosolic DNA sensing STING-mediated pathway, which in turn enhanced responses to innate stimuli by activating the expression of Toll-like receptors, RIG-I-like receptors, cytoplasmic DNA sensors, and their downstream signaling partners. This study provides a potential explanation for the inflammatory phenotype of AT patients and establishes damaged DNA as a cell intrinsic danger signal that primes the innate immune system for a rapid and amplified response to microbial and environmental threats.

National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-101396 (URN)10.1016/j.immuni.2015.01.012 (DOI)000349916400016 ()25692705 (PubMedID)
Available from: 2015-07-02 Created: 2015-03-30 Last updated: 2018-06-07Bibliographically approved
Fabrik, I., Link, M., Härtlova, A., Dankova, V., Rehulka, P. & Stulik, J. (2014). Application of SILAC labeling to primary bone marrow-derived dendritic cells reveals extensive GM-CSF-dependent arginine metabolism. Journal of Proteome Research, 13(2), 752-762
Open this publication in new window or tab >>Application of SILAC labeling to primary bone marrow-derived dendritic cells reveals extensive GM-CSF-dependent arginine metabolism
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2014 (English)In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 13, no 2, p. 752-762Article in journal (Refereed) Published
Abstract [en]

Although dendritic cells (DCs) control the priming of the adaptive immunity response, a comprehensive description of their behavior at the protein level is missing. The introduction of the into the field of DC research would therefore be highly beneficial. quantitative proteomic technique of metabolic labeling (SILAC) To achieve this, we applied SILAC labeling to primary bone marow-derived DCs (BMDCs). These cells combine both biological relevance and experimental feasibility, as their in vitro generation permits the use of C-13/N-15-labeled amino acids.. Interestingly, BMDCs appear to exhibit a very active arginine metabolism. Using standard cultivation conditions, similar to 20% of all protein-incorporated proline was a byproduct of heavy arginine degradation. In addition, the dissipation of N-15 from labeled arginine to the whole proteome was observed. The latter decreased the mass accuracy in MS and affected the natural isotopic distribution of peptides. SILAC-connected metabolic issues were shown to be enhanced by GM-CSF, which is used for the differentiation of DC progenitors. Modifications of the cultivation procedure suppressed the arginine-related effects, yielding cells with a proteome labeling efficiency of >= 90%. Importantly, BMDCs generated according to the new cultivation protocol preserved their resemblance to inflammatory DCs in vivo, as evidenced by their response to LPS treatment.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-87174 (URN)10.1021/pr4007798 (DOI)000331164100036 ()
Available from: 2014-03-31 Created: 2014-03-24 Last updated: 2018-06-08Bibliographically approved
Härtlova, A., Link, M., Balounova, J., Benesova, M., Resch, U., Straskova, A., . . . Stulik, J. (2014). Quantitative proteomics analysis of macrophage-derived lipid rafts reveals induction of autophagy pathway at the early time of Francisella tularensis LVS infection. Journal of Proteome Research, 13(2), 796-804
Open this publication in new window or tab >>Quantitative proteomics analysis of macrophage-derived lipid rafts reveals induction of autophagy pathway at the early time of Francisella tularensis LVS infection
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2014 (English)In: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 13, no 2, p. 796-804Article in journal (Refereed) Published
Abstract [en]

Francisella tularensis is a highly infectious intracellular pathogen that has evolved an efficient strategy to subvert host defense response to survive inside the host. The molecular mechanisms regulating these host-pathogen interactions and especially those that are initiated at the time of the bacterial entry via its attachment to the host plasma membrane likely predetermine the intracellular fate of pathogen. Here, we provide the evidence that infection of macrophages with F. tularensis leads to changes in protein composition of macrophage-derived lipid rafts, isolated as detergent-resistant membranes (DRMs). Using SILAC-based quantitative proteomic approach, we observed the accumulation of autophagic adaptor protein p62 at the early, stages of microbe-host cell interaction. We confirmed the colocalization of the p62 with ubiquitinated and LC3-decorated intracellular F. tularensis microbes with its maximum at 1 h postinfection. Furthermore, the infection of p62-knockdown host cells led to the transient increase in the intracellular number of microbes up to 4 h after in vitro infection. Together, these data suggest that the activation of the autophagy pathway in F. tularensis infected macrophages, which impacts the early phase of microbial proliferation, is subsequently circumvented by ongoing infection.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-87175 (URN)10.1021/pr4008656 (DOI)000331164100040 ()
Available from: 2014-03-31 Created: 2014-03-24 Last updated: 2018-06-08Bibliographically approved
Fabrik, I., Härtlova, A., Rehulka, P. & Stulik, J. (2013). Serving the new masters: dendritic cells as hosts for stealth intracellular bacteria. Cellular Microbiology, 15(9), 1473-1483
Open this publication in new window or tab >>Serving the new masters: dendritic cells as hosts for stealth intracellular bacteria
2013 (English)In: Cellular Microbiology, ISSN 1462-5814, E-ISSN 1462-5822, Vol. 15, no 9, p. 1473-1483Article in journal (Refereed) Published
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-80034 (URN)10.1111/cmi.12160 (DOI)000322885000003 ()
Available from: 2013-09-16 Created: 2013-09-09 Last updated: 2018-06-08Bibliographically approved
Cerveny, L., Straskova, A., Dankova, V., Hartlova, A., Ceckova, M., Staud, F. & Stulik, J. (2013). Tetratricopeptide Repeat Motifs in the World of Bacterial Pathogens: Role in Virulence Mechanisms. Infection and Immunity, 81(3), 629-635
Open this publication in new window or tab >>Tetratricopeptide Repeat Motifs in the World of Bacterial Pathogens: Role in Virulence Mechanisms
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2013 (English)In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 81, no 3, p. 629-635Article, review/survey (Refereed) Published
Abstract [en]

The tetratricopeptide repeat (TPR) structural motif is known to occur in a wide variety of proteins present in prokaryotic and eukaryotic organisms. The TPR motif represents an elegant module for the assembly of various multiprotein complexes, and thus, TPR-containing proteins often play roles in vital cell processes. As the TPR profile is well defined, the complete TPR protein repertoire of a bacterium with a known genomic sequence can be predicted. This provides a tremendous opportunity for investigators to identify new TPR-containing proteins and study them in detail. In the past decade, TPR-containing proteins of bacterial pathogens have been reported to be directly related to virulence-associated functions. In this minireview, we summarize the current knowledge of the TPR-containing proteins involved in virulence mechanisms of bacterial pathogens while high-lighting the importance of TPR motifs for the proper functioning of class II chaperones of a type III secretion system in the pathogenesis of Yersinia, Pseudomonas, and Shigella.

Place, publisher, year, edition, pages
American Society for Microbiology, 2013
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-68485 (URN)10.1128/IAI.01035-12 (DOI)000316313200003 ()
Available from: 2013-04-26 Created: 2013-04-22 Last updated: 2018-06-08Bibliographically approved
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