Search

Using a novel multi-antigen protein array and diagnostic algorithm the exposure, infection, and disease caused by the emerging tick-borne pathogen Borrelia miyamotoi was investigated in the Netherlands and Sweden throughout different populations at risk of tick-bites over the past decades. ABSTRACT: The impact of the emerging tick-borne pathogen Borrelia miyamotoi is not fully understood. We utilized a protein array to investigate B. miyamotoi seroreactivity in various human populations in the Netherlands and Sweden. The IgM/IgG seroprevalence in Dutch healthy (2·5%, 95%CI 1·5-4·1) and population controls (2·0%, 95%CI 0·9-4·4) was lower (p=0·01 and p=0·01) compared to the tick-bite cohort (6·1%, 95%CI 3·9-9·5). In accordance, the Swedish healthy controls (1·0%, 95%CI 0·1-6·9) revealed a lower (p=0·005 and p<0·001) IgM/IgG seroprevalence compared to the tick-bite (8·9%, 95%CI 5·7-13·7) and fever after tick-bite cohort (16·5%, 95%CI 10·6-24·8). Altogether, 15 of 2,175 individuals had serologic evidence of early B. miyamotoi infection. The risk of infection with B. miyamotoi was 0·7% (95%CI 0·3-1·4) in tick-bitten individuals, and of disease 7·3% (95%CI 2·6-12·8) in those with a febrile illness after tick-bite. Our findings provide insights into the risk of infection and disease with this pathogen in Europe., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Declaration of interests All involved authors declare to have no competing interests., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Artemisinin (ART) and its derivatives are important antimalaria agents and have received increased attention due to their broad biomedical effects, such as anticancer and anti-inflammation activities. Recently, ruthenium-derived complexes have attracted considerable attention as their anticancer potentials were observed in preclinical and clinical studies., Methods: To explore an innovative approach in colorectal cancer (CRC) management, we synthesized ruthenium-dihydroartemisinin complex (D-Ru), a novel metal-based artemisinin derivative molecule, and investigated its anticancer, anti-inflammation, and adaptive immune regulatory properties., Results: Compared with its parent compound, ART, D-Ru showed stronger antiproliferative effects on the human CRC cell lines HCT-116 and HT-29. The cancer cell inhibition of D-Ru comprised G1 cell cycle arrest via the downregulation of cyclin A and the induction of apoptosis. ART and D-Ru downregulated the expressions of pro-inflammatory cytokines IL-1β, IL-6, and IL-8. Although ART and D-Ru did not suppress Treg cell differentiation, they significantly inhibited Th1 and Th17 cell differentiation., Conclusions: Our results demonstrated that D-Ru, a novel ruthenium complexation of ART, remarkably enhanced its parent compound's anticancer action, while the anti-inflammatory potential was not compromised. The molecular mechanisms of action of D-Ru include inhibition of cancer cell growth via cell cycle arrest, induction of apoptosis, and anti-inflammation via regulation of adaptive immunity., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Migratory birds play a dual role as potential reservoirs of tick-borne pathogens, and potential dispersers of pathogen-containing ticks during their migratory journeys. Ixodes ricinus , a prevalent tick species in Northern and Western Europe, serves as a primary vector for Anaplasma phagocytophilum -a bacterium with implications for human and animal health. There is limited information available regarding A. phagocytophilum in birds. Our investigation focused on A. phagocytophilum prevalence in ticks collected from migratory birds in southeastern Sweden. The identification of ticks involved both molecular analyses for species determination and morphological classification to ascertain the developmental stage. The presence of A. phagocytophilum was determined using real-time PCR. Of the 1115 ticks analyzed from 4601 birds, 0.9% ( n = 10), including I. ricinus and Ixodes frontalis , tested positive for A. phagocytophilum . Notably, common blackbirds ( Turdus merula ) yielded the highest number of A. phagocytophilum -infected ticks. The findings suggest that A. phagocytophilum is present in a small proportion of ticks infesting migratory birds in southeastern Sweden. Consequently, the role of birds as hosts for ticks infected with A. phagocytophilum appears to be low, suggesting that birds seem to play a minor indirect role in the geographic dispersal of A. phagocytophilum .

The clinical utility of human interleukin-2 (hIL-2) is limited by its short serum half-life, preferential activation of regulatory T (T Reg ) over immune effector cells, and dose-limiting toxicities. We previously engineered F10 immunocytokine (IC), an intramolecularly assembled cytokine/antibody fusion protein that linked hIL-2 to an anti-IL-2 antibody (denoted F10) that extended IL-2 half-life and augmented the immune effector to T Reg ratio. Here, we leveraged molecular engineering to improve the anti-tumor therapeutic efficacy and tolerability of F10 IC by developing an iteration, denoted F10 IC-CBD (collagen binding domain), designed for intratumoral administration and in situ retention based on collagen affinity. F10 IC-CBD retained IL-2 bioactivity exclusively in the tumor and eliminated IL-2-associated toxicities. Furthermore, F10 IC exhibited potent single-agent therapeutic efficacy and synergy with systemic immune checkpoint blockade and elicited an abscopal response in mouse tumors models. This engineered fusion protein presents a prototype for the design of intratumoral therapies., Competing Interests: Declaration of interests Johns Hopkins University has filed intellectual property (WO2020264321A1) entitled “Methods and materials for targeted expansion of immune effector cells” that covers compound F10 IC as well as related compounds, with J.B.S. as a co-inventor. J.I. is a shareholder of ArrowImmune Inc., which is working on immuno-oncology., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objectives: Lyme serology does not readily discriminate an active Lyme borreliosis (LB) from a previous Borrelia infection or exposure. Here, we aimed to investigate a large number of immunological protein biomarkers to search for an immunological pattern typical for active LB, in contrast to patterns found in healthy blood donors, a proportion of whom were previously exposed to Borrelia., Methods: Serum samples from well-characterised adult patients with ongoing LB and healthy blood donors were included and investigated using a proximity extension assay (provided by Olink®) by which 92 different immune response-related human protein biomarkers were analysed simultaneously., Results: In total, 52 LB patients and 75 healthy blood donors were included. The blood donors represented both previously Borrelia exposed (n = 34) and not exposed (n = 41) based on anti-Borrelia antibody status. Ten of the examined 92 proteins differed between patients and blood donors and were chosen for further logistic regression (p<0.1). Six proteins were statistically significantly different between LB patients and blood donors (p<0.05). These six proteins were then combined in an index and analysed using receiver-operating-characteristic curve analysis showing an area under the curve of 0.964 (p<0.001)., Conclusions: The results from this study suggest that there is an immunological protein pattern that can distinguish a present Borrelia infection from a previous exposure as well as anti-Borrelia antibody negative blood donors. Although this method is not adapted for routine clinical use at this point, the possibility is interesting and may open new diagnostic opportunities improving the laboratory diagnostics of LB., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: IT reports participation in advisory board and personal fees from Pfizer Inc outside the submitted work. AJH has a collaborative research agreement with Abbott Laboratories, Chicago, USA and Reagena Oy, Toivala, Finland. Remaining authors report no conflict of interest., (Copyright: © 2023 Tjernberg et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Lyme neuroborreliosis (LNB), a tick-borne infection caused by spirochetes within the Borrelia burgdorferi sensu lato (s.L.) complex, is among the most prevalent bacterial central nervous system (CNS) infections in Europe and the US. Here we have screened a panel of low-passage B . burgdorferi s.l. isolates using a novel, human-derived 3D blood-brain barrier (BBB)-organoid model. We show that human-derived BBB-organoids support the entry of Borrelia spirochetes, leading to swelling of the organoids and a loss of their structural integrity. The use of the BBB-organoid model highlights the organotropism between B . burgdorferi s.l. genospecies and their ability to cross the BBB contributing to CNS infection., Competing Interests: Disclosures: Outside of the present work: A.M.L. reports speaker’s honorarium/travel grants and advisory board activity from Gilead, GSK, and Pfizer. The other authors declare no competing interests exist. P.E.L. has been an external scientific expert to Valneva Austria GmbH and Pfizer Inc. and received speaker’s honorarium and travel grants., (© 2022.)

Background: Artemisinin (ART) is an anti-malaria natural compound with a moderate anticancer action. As a metabolite of ART, dihydroartemisinin (DHA) may have stronger anti-colorectal cancer (CRC) bioactivities. However, the effects of DHA and ART on CRC chemoprevention, including adaptive immune regulation, have not been systematically evaluated and compared., Methods: Coupled with a newly-established HPLC analytical method, enteric microbiome biotransformation was conducted to identify if the DHA is a gut microbial metabolite of ART. The anti-CRC potential of these compounds was compared using two different human CRC cell lines for cell cycle arrest, apoptotic induction, and anti-inflammation activities. Naive CD4 +  T cells were also obtained for testing the compounds on the differentiation of Treg, Th1 and Th17., Results: Using compound extraction and analytical methods, we observed for the first time that ART completely converted into its metabolites by gut microbiome within 24 h, but no DHA was detected. Although ART did not obviously influence cancer cell growth in the concentration tested, DHA very significantly inhibited the cancer cell growth at relatively low concentrations. DHA included G2/M cell cycle arrest via upregulation of cyclin A and apoptosis. Both ART and DHA downregulated the pro-inflammatory cytokine expression. The DHA significantly promoted Treg cell proliferation, while both ART and DHA inhibited Th1 and Th17 cell differentiation., Conclusions: As a metabolite of ART, DHA possessed stronger anti-CRC activities. The DHA significantly inhibited cell growth via cell cycle arrest, apoptosis induction and anti-inflammation actions. The adaptive immune regulation is a related mechanism of actions for the observed effects., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

The chemokine CXCL13 is used as complement to serology in the diagnostics of Lyme neuroborreliosis (LNB). We evaluated and compared the semi-quantitative, cassette-based ReaScan CXCL13 assay with the quantitative recomBead CXCL13 assay using a collection of 209 cerebrospinal fluid samples. The categorical agreement between results interpreted as negative, grey zone, and positive by the two methods was 87%. The diagnostic sensitivity was higher using the recomBead assay, whereas specificity was higher using ReaScan. Few manual steps, and a short turn-around time with no batching of samples makes the ReaScan CXCL13 assay an attractive complement to serology in the diagnostics of LNB., (© 2021. The Author(s).)

The main tools for clinical diagnostics of Lyme neuroborreliosis (LNB) are based on serology, i.e., detection of antibodies in cerebrospinal fluid (CSF). In some cases, PCR may be used as a supplement, e.g., on CSF from patients with early LNB. Standardisation of the molecular methods and systematic evaluation of the pre-analytical handling is lacking. To increase the analytical sensitivity for detection of Borrelia bacteria in CSF by PCR targeting the 16S rRNA gene, parameters were systematically evaluated on CSF samples spiked with a known amount of cultured Borrelia bacteria. The results showed that the parameters such as centrifugation time and speed, the use of complementary DNA as a template (in combination with primers and a probe aiming at target gene 16S rRNA), and the absence of inhibitors (e.g., erythrocytes) had the highest impact on the analytical sensitivity. Based on these results, a protocol for optimised handling of CSF samples before molecular analysis was proposed. However, no clinical evaluation of the proposed protocol has been done so far, and further investigations of the diagnostic sensitivity need to be performed on well-characterised clinical samples from patients with LNB.