The antimicrobial role of human MAIT cells

MAIT cells are unconventional T cells that have characteristics of both innate and adaptive immunity. Their fast mobilization and wide distribution in tissues make them part of the first line of defense against infection. MAIT cells recognize riboflavin-related metabolites produced by bacteria and presented by MR1. However, they can also sense viral infection through non-specific activation by cytokines. MAIT cells respond rapidly with secretion of cytokines and degranulation of cytolytic molecules, and play an important role in immune defense. This thesis work aimed to further explore the function of MAIT cells in different contexts. First, we explored the interaction between humoral IgG responses and MAIT cells in antibacterial immunity. Here, MAIT cell responses to IgG-opsonized bacteria were compared to responses against non-opsonized bacteria. MAIT cell responses against opsonized Escherichia coli were stronger, with an increased magnitude and faster kinetics. Furthermore, MAIT cells were activated at lower bacterial doses when opsonized. We deciphered the mechanism responsible for the MAIT cell boost of function and showed that FcγR triggering by the opsonized bacteria was essential to increase MR1 antigen presentation. The boost of function was validated in a vaccine setting, where we used sera from individuals before and after vaccination against Streptococcus pneumoniae to opsonize one vaccine strain. MAIT cell functions were boosted when stimulated with S. pneumoniae opsonized with sera drawn after vaccination. In the second project, we investigated the cytolytic mechanisms used by MAIT cells against E. coli. Interestingly, MAIT cells not only killed E. coli-infected cells but also controlled cell-associated bacterial load through degranulation. More precisely, Granzyme B (GzmB), Granulysin (Gnly), and perforin were involved in the killing. MAIT cell activity was maintained against carbapenem-resistant E. coli (CREC). CREC strains use two main mechanisms of resistance: production of carbapenemases that inactivate carbapenem antibiotics, and membrane impermeability by porin-loss or over-expression of efflux pumps that block antibiotic penetration in the bacteria. Interestingly, MAIT cell- derived Gnly and GzmB were able to damage the membrane of free-living CREC. This effect was further enhanced by the addition of carbapenem antibiotic, suggesting a synergy between the cytotoxic proteins and the antibiotic. This also implied that MAIT cells may overcome the impermeability mechanism of resistance of CREC. In the third project, we investigated if some bacteria can adapt to escape from MAIT cell responses through immune evasion mechanisms. Staphylococcus aureus produces the pore-forming toxin leukotoxin ED (LukED) that binds to CCR5. We found that MAIT cells were hypersensitive to LukED and this was due to very high expression of CCR5 on MAIT cells. Within the T cell pool, MAIT cells were the most severely depleted population indicating that LukED secretion constitutes an immune evasion mechanism from MAIT cell recognition. In conclusion, these findings indicate that MAIT cell responses are boosted against IgG- opsonized pathogens. Furthermore, MAIT cell cytolytic activity is maintained against CREC, and GzmB and Gnly synergize with carbapenem antibiotics to kill free-living CREC. Finally, some bacteria have developed means to evade MAIT cell responses, and this includes LukED secretion by S. aureus, which strongly targets MAIT cells. Overall, this thesis work enhances our understanding of MAIT cells as important antimicrobial immune cells

Lyme borreliosis in dogs

La maladie de Lyme est caractérisée chez le Chien par une arthrite induisant une boiterie, de l’anorexie, de la fièvre, une léthargie, une adénomégalie et parfois une glomérulonéphrite fatale. En absence de mise en évidence de Borrelia dans les prélèvements, le diagnostic repose essentiellement sur un faisceau d’arguments épidémiologique, clinique, sérologique et thérapeutique, après exclusion des autres causes aboutissant au même tableau clinique. La thérapeutique s’appuie sur une antibiothérapie principalement à base de doxycycline. La prévention passe par l’utilisation d’acaricides contre Ixodes spp., vecteurs des Borrelia et éventuellement l’administration d’un vaccin.Lyme disease is characterized in dogs by fever, arthritis that induces lameness, anorexia, lethargy, adenomegaly and sometimes fatal glomerulonephritis. In the absence of direct evidence of Borrelia in the samples, the diagnosis is mainly based on a bundle of epidemiological, clinical, serological and therapeutic arguments, after exclusion of the other causes leading to the same symptoms. Therapy is based on antibiotic like doxycycline. Acaricides against Ixodes spp., vectors of Borrelia, are the main tool for prevention. Vaccines are also possibly available

Vessel wall MR imaging for the detection of intracranial inflammatory vasculopathies

Intracranial vasculopathies are routinely investigated by lumen-based modalities such as magnetic resonance angiography (MRA), computed tomography angiography (CTA), and digital subtraction angiography (DSA). These techniques are useful to analyze the vessel lumen, allowing to detect vessel stenosis or occlusion. However, the primum movins of the disease, i.e., an abnormal thickening of the vessel wall, remains within the arterial wall. The vasculopathy can moreover be present without always narrowing the lumen or modifying its regularity. Hence, there is a need to detect directly and analyze vessel wall abnormalities. Development of 3D high-resolution black blood sequences for intracranial vessel wall MR imaging (VW-MRI) enabled routine clinical applications not only vasculitis, but also of intracranial atherosclerotic disease (ICAD), intracranial dissections, reversible intracranial dissections, reversible cerebral vasoconstriction syndrome (RCVS), Moyamoya disease, and intracranial aneurysms. This high-resolution intracranial VW- MRI approach is increasingly used on a clinical basis at many centers to solve diagnostic problems, especially in patients with ischemic stroke or intracranial hemorrhage. An expert consensus Guideline from the American Society of Neuroradiology provides recommendations for clinical implementation of intracranial vessel wall MRI. There are several technical aspects needed to be considered when implementing VW-MRI in intracranial vessels, including flow suppression, both in blood and cerebrospinal fluid (CSF), spatial resolution and signal-to-noise ratio (SNR). In this article, we review the technical aspects of VW-MRI, and recommend applications for vascular diseases including non-occlusive intracranial vasculopathies, Moyamoya disease, and identifying culprit plaques. We also give a focus on the utility of VW-MRI for determining stroke etiology in adults and in children and young adults

Remote Training of Neurointerventions by Audiovisual Streaming

Telemedicine; Neuroendovascular training; StrokeTelemedicina; Formación neuroendovascular; IctusTelemedicina; Formació neuroendovascular; IctusBackground Remote access of trainees to training centers via video streaming (tele-observership, e‑fellowship) emerges as an alternative to acquire knowledge in endovascular interventions. Situational awareness is a summary term that is also used in surgical procedures for perceiving and understanding the situation and projecting what will happen next. A high situational awareness would serve as prerequisite for meaningful learning success during tele-observerships. We hypothesized that live perception of the angiographical procedures using streaming technology is feasible and sufficient to gain useful situational awareness of the procedure. Methods During a European tele-observership organized by the European Society of Minimally Invasive Neurological Therapy (ESMINT) and its trainee association (EYMINT), a total of six neurointerventional fellows in five countries observed live cases performed by experienced neurointerventionalists (mentors) in six different high-volume neurovascular centers across Europe equipped with live-streaming technology (Tegus Medical, Hamburg, Germany). Cases were prospectively evaluated during a 12-month period, followed by a final questionnaire after completion of the course. Results A total of 102/161 (63%) cases with a 1:1 allocation of fellow and mentor were evaluated during a 12-month period. Most frequent conditions were ischemic stroke (27.5%), followed by embolization of unruptured aneurysms (25.5%) and arteriovenous malformations (AVMs) (15.7%). A high level of situational awareness was reported by fellows in 75.5% of all cases. After finishing the program, the general improvement of neurointerventional knowledge was evaluated to be extensive (1/6 fellows), substantial (3/6), and moderate (2/6). The specific fields of improvement were procedural knowledge (6/6 fellows), technical knowledge (3/6) and complication management (2/6). Conclusion Online streaming technology facilitates location-independent training of complex neurointerventional procedures through high levels of situational awareness and can therefore supplement live hands-on-training. In addition, it leads to a training effect for fellows with a perceived improvement of their neurointerventional knowledge.Open Access funding enabled and organized by Projekt DEAL

Transmission of Bartonella henselae by Ixodes ricinus

The causative agent of cat-scratch disease in humans can be transmitted by this tick through saliva

Neuroimaging of Acute Intracerebral Hemorrhage

Intracerebral hemorrhage (ICH) accounts for 10% to 20% of all strokes worldwide and is associated with high morbidity and mortality. Neuroimaging is clinically important for the rapid diagnosis of ICH and underlying etiologies, but also for identification of ICH expansion, often as-sociated with an increased risk for poor outcome. In this context, rapid assessment of early hema-toma expansion risk is both an opportunity for therapeutic intervention and a potential hazard for hematoma evacuation surgery. In this review, we provide an overview of the current literature surrounding the use of multimodal neuroimaging of ICH for etiological diagnosis, prediction of early hematoma expansion, and prognostication of neurological outcome. Specifically, we discuss standard imaging using computed tomography, the value of different vascular imaging modalities to identify underlying causes and present recent advances in magnetic resonance imaging and computed tomography perfusion

Bartonella spp. DNA Associated with Biting Flies from California

Bartonella DNA was investigated in 104 horn flies (Haematobia spp.), 60 stable flies (Stomoxys spp.), 11 deer flies (Chrysops spp.), and 11 horse flies (Tabanus spp.) collected on cattle in California. Partial sequencing indicated B. bovis DNA in the horn fly pool and B. henselae type M DNA in one stable fly

Ecological fitness and strategies of adaptation of Bartonella species to their hosts and vectors

Bartonella spp. are facultative intracellular bacteria that cause characteristic hostrestricted hemotropic infections in mammals and are typically transmitted by blood-sucking arthropods. In the mammalian reservoir, these bacteria initially infect a yet unrecognized primary niche, which seeds organisms into the blood stream leading to the establishment of a long-lasting intra-erythrocytic bacteremia as the hall-mark of infection. Bacterial type IV secretion systems, which are supra-molecular transporters ancestrally related to bacterial conjugation systems, represent crucial pathogenicity factors that have contributed to a radial expansion of the Bartonella lineage in nature by facilitating adaptation to unique mammalian hosts. On the molecular level, the type IV secretion system VirB/VirD4 is known to translocate a cocktail of different effector proteins into host cells, which subvert multiple cellular functions to the benefit of the infecting pathogen. Furthermore, bacterial adhesins mediate a critical, early step in the pathogenesis of the bartonellae by binding to extracellular matrix components of host cells, which leads to firm bacterial adhesion to the cell surface as a prerequisite for the efficient translocation of type IV secretion effector proteins. The best-studied adhesins in bartonellae are the orthologous trimeric autotransporter adhesins, BadA in Bartonella henselae and the Vomp family in Bartonella quintana. Genetic diversity and strain variability also appear to enhance the ability of bartonellae to invade not only specific reservoir hosts, but also accidental hosts, as shown for B. henselae. Bartonellae have been identified in many different blood-sucking arthropods, in which they are typically found to cause extracellular infections of the mid-gut epithelium. Adaptation to specific vectors and reservoirs seems to be a common strategy of bartonellae for transmission and host diversity. However, knowledge regarding arthropod specificity/res