Coxiella burnetii-Infected NK Cells Release Infectious Bacteria by Degranulation

Matthiesen, Svea; Zaeck, Luca M.; Franzke, Kati; Jahnke, Rico; Fricke, Charlie; Mauermeir, Michael; Finke, Stefan; Lührmann, Anja; Knittler, Michael R.

doi:10.1128/iai.00172-20

Cited by 8 publications

(6 citation statements)

References 113 publications

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“…In the murine model, NK cells did not intervene in bacterial clearance but participated in the inflammatory response against Q Fever 42 . C. burnetii can infect NK cells, which secrete IFNɣ and release lytic granules containing bacteria via degranulation 67 . Whether this also occurs in goats remains to be investigated.…”

Section: Discussionmentioning

confidence: 99%

Adjuvanting Coxevac® with QuilA® skews Coxiella burnetii-induced inflammatory responses towards a sustained Th1-CD8+-mediated activation and increases protection in an experimental goat model

Mori

Tomaiuolo

Jansen

et al. 2022

Preprint

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Coxevac® is the EMA-approved veterinary vaccine for the protection of cattle and goats against Q Fever, a zoonotic bacterial disease due to Coxiella burnetii. Since Coxevac® reduces bacterial shedding and clinical symptoms but does not prevent infection, novel, ready-to-use vaccine formulations are needed to increase its immunogenicity. Here, a goat vaccination-challenge model was used to evaluate the impact of the commercially available saponin-based QuilA® adjuvant on Coxevac® immunity. Upon challenge, the QuilA®-Coxevac® group showed a stronger immune response reflected in a higher magnitude of total IgG and an increase in circulating and splenic CD8+ T-cells compared to the Coxevac® and challenged-control groups. The QuilA®-Coxevac® group was characterized by a targeted Th1-type response (IFNɣ, IP10) associated with increased transcripts of CD8+ and NK cells in spleens and γδ T cells in bronchial lymph nodes. Coxevac® vaccinated animals presented an intermediate expression of Th1-related genes, whilst the challenged-control group showed an immune response characterized by pro-inflammatory (IL1β, TNFα, IL12), Th2 (IL4 and IL13), Th17 (IL17A) and other immunoregulatory cytokines (IL6, IL10). An intriguing role was observed for γδ T cells, which were of TBX21- and SOX4-types in the QuilA®-Coxevac® and challenged control group, respectively. Overall, the addition of QuilA® resulted in a sustained Th1-type activation associated with increased vaccine protection. QuilA® could be proposed as one readily-applied solution to improve Coxevac® efficacy against C. burnetii infection in field settings.

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Section: Discussionmentioning

confidence: 99%

Adjuvanting Coxevac® with QuilA® skews Coxiella burnetii-induced inflammatory responses towards a sustained Th1-CD8+-mediated activation and increases protection in an experimental goat model

Mori

Tomaiuolo

Jansen

et al. 2022

Preprint

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“…The tandem-di-Tomato (tdTomato) expressing NMII strain was prepared as described previously (Matthiesen et al, 2020): the tdTomato gene (codons optimized for expression in C. burnetii ) was amplified by PCR with Q5 polymerase (New England Biolabs, Frankfurt, Germany) using primers a533 (5’-GATTTAAGAAGGAGATCTGCAGATGGTGTCAAAAGGAG-3’) and a534 (5’-AAGCTTGCATGCCTCAGTCGACTTATTTATAAAGTTCATCCATGC-3’) to attach overhang- sequences for Gibson assembly. The destination vector pJB-CAT-ProD-mCherry (kindly provided by Robert Heinzen and Paul Beare, Rocky Mountain Laboratories, MT, USA) was digested with PstI and SalI.…”

Section: Methodsmentioning

confidence: 99%

Macrophages inhibit Coxiella burnetii by the ACOD1-itaconate pathway for containment of Q fever

Kohl¹,

Siddique²,

Bodendorfer³

et al. 2022

Preprint

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Infection with the intracellular bacterium Coxiella (C.) burnetii can cause chronic Q fever with severe complications and limited treatment options. Here, we identify the enzyme cis- aconitate decarboxylase 1 (ACOD1 or IRG1) and its product itaconate as protective host immune pathway in Q fever. Infection of mice with C. burnetii induced expression of several anti-microbial candidate genes, including Acod1. In macrophages, Acod1 was essential for restricting C. burnetii replication, while other antimicrobial pathways were dispensable. Intratracheal or intraperitoneal infection of Acod1-/- mice caused increased C. burnetii burden, significant weight loss and stronger inflammatory gene expression. Exogenously added itaconate restored pathogen control in Acod1-/- mouse macrophages and blocked replication in human macrophages. In axenic cultures, itaconate directly inhibited growth of C. burnetii. Finally, treatment of infected Acod1-/-mice with itaconate efficiently reduced the tissue pathogen load. Thus, ACOD1-derived itaconate is a key factor in the macrophage-mediated defense against C. burnetii and may be exploited for novel therapeutic approaches in chronic Q fever.

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“…The tandem-di-Tomato (tdTomato) expressing NMII strain was prepared as described previously (Matthiesen et al, 2020): the tdTomato gene (codons optimized for expression in C. burnetii) was amplified by PCR with Q5 polymerase (New England Biolabs, Frankfurt, Germany) using primers a533 (5 0 -GATTTAAGAAGGA GATCTGCAGATGGTGTCAAAAGGAG-3 0 ) and a534 (5 0 -AAGCTTG CATGCCTCAGTCGACTTATTTATAAAGTTCATCCATGC-3 0 ) to attach overhang-sequences for Gibson assembly. The destination vector pJB-CAT-ProD-mCherry (kindly provided by Robert Heinzen and Paul Beare, Rocky Mountain Laboratories, MT, USA) was digested with PstI and SalI.…”

Section: Generation Of Tdtomato-expressing C Burnetiimentioning

confidence: 99%

Macrophages inhibit Coxiella burnetii by the ACOD1 ‐itaconate pathway for containment of Q fever

et al. 2022

Self Cite

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Infection with the intracellular bacterium Coxiella (C.) burnetii can cause chronic Q fever with severe complications and limited treatment options. Here, we identify the enzyme cis‐aconitate decarboxylase 1 (ACOD1 or IRG1) and its product itaconate as protective host immune pathway in Q fever. Infection of mice with C. burnetii induced expression of several anti‐microbial candidate genes, including Acod1. In macrophages, Acod1 was essential for restricting C. burnetii replication, while other antimicrobial pathways were dispensable. Intratracheal or intraperitoneal infection of Acod1−/− mice caused increased C. burnetii burden, weight loss and stronger inflammatory gene expression. Exogenously added itaconate restored pathogen control in Acod1−/− mouse macrophages and blocked replication in human macrophages. In axenic cultures, itaconate directly inhibited growth of C. burnetii. Finally, treatment of infected Acod1−/− mice with itaconate efficiently reduced the tissue pathogen load. Thus, ACOD1‐derived itaconate is a key factor in the macrophage‐mediated defense against C. burnetii and may be exploited for novel therapeutic approaches in chronic Q fever.

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Coxiella burnetii-Infected NK Cells Release Infectious Bacteria by Degranulation

Cited by 8 publications

References 113 publications

Adjuvanting Coxevac® with QuilA® skews Coxiella burnetii-induced inflammatory responses towards a sustained Th1-CD8+-mediated activation and increases protection in an experimental goat model

Adjuvanting Coxevac® with QuilA® skews Coxiella burnetii-induced inflammatory responses towards a sustained Th1-CD8+-mediated activation and increases protection in an experimental goat model

Macrophages inhibit Coxiella burnetii by the ACOD1-itaconate pathway for containment of Q fever

Macrophages inhibit Coxiella burnetii by the ACOD1 ‐itaconate pathway for containment of Q fever

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