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Whether mice are an appropriate model for S. aureus infection and vaccination studies is a matter of debate, because they are not considered as natural hosts of S. aureus. We previously identified a mouse-adapted S. aureus strain, which caused infections in laboratory mice. This raised the question whether laboratory mice are commonly colonized with S. aureus and whether this might impact on infection experiments. Publicly available health reports from commercial vendors revealed that S. aureus colonization is rather frequent, with rates as high as 21% among specific-pathogen-free mice. In animal facilities, S. aureus was readily transmitted from parents to offspring, which became persistently colonized. Among 99 murine S. aureus isolates from Charles River Laboratories half belonged to the lineage CC88 (54.5%), followed by CC15, CC5, CC188, and CC8. A comparison of human and murine S. aureus isolates revealed features of host adaptation. In detail, murine strains lacked hlb-converting phages and superantigen-encoding mobile genetic elements, and were frequently ampicillin-sensitive. Moreover, murine CC88 isolates coagulated mouse plasma faster than human CC88 isolates. Importantly, S. aureus colonization clearly primed the murine immune system, inducing a systemic IgG response specific for numerous S. aureus proteins, including several vaccine candidates. Phospholipase C emerged as a promising test antigen for monitoring S. aureus colonization in laboratory mice. In conclusion, laboratory mice are natural hosts of S. aureus and therefore, could provide better infection models than previously assumed. Pre-exposure to the bacteria is a possible confounder in S. aureus infection and vaccination studies and should be monitored.
Purpose
Postapproval reports of intraocular inflammation (IOI) and occlusive retinal vasculitis following intravitreal brolucizumab are accumulating. A role of anti-drug antibodies (ADAs) to brolucizumab is under current scientific discussion. The purpose of the present study was to measure brolucizumab ADAs in a cross-sectional ophthalmic patient population and to compare the occurrence of brolucizumab ADAs with that of ranibizumab ADAs.
Methods
One hundred and ninety-two serum samples and 54 vitreous samples were collected from patients with a range of eye diseases including neovascular age-related macular degeneration (AMD), diabetic retinopathy, retinal vein occlusion, cataract, glaucoma, dry eye disease, macular hole, epiretinal membranes and intraocular lens (IOL) dislocation. Serum and vitreous samples were analysed for immune globuline (Ig) G ADAs to brolucizumab and ranibizumab using indirect enzyme-linked immunosorbent assay (ELISA). Optical Density (OD) was read at 450 nm (wavelength correction at 550 nm) for ADA level measurements.
Results
Presence of brolucizumab ADAs was observed in patients with and without prior brolucizumab exposure. Both the frequency of notable ADA signals (OD > 0.1) and the mean ADA signal in serum samples were higher for brolucizumab than for ranibizumab. Two patients who experienced severe IOI and occlusive retinal vasculitis following intravitreal brolucizumab had high brolucizumab ADA serum levels. In one of these two patients, high brolucizumab ADA levels were also found in vitreous. Another patient developed moderate IOI without retinal vasculitis in the presence of low brolucizumab ADA serum levels. Overall, notable brolucizumab ADA levels were less frequent in vitreous than in the corresponding serum samples but with a tendency for higher prevalence in vitreous from patients with diabetic retinopathy.
Conclusion
Brolucizumab ADAs occur with significant prevalence in a typical ophthalmic patient population and may represent a risk factor for IOI and occlusive retinal vasculitis following brolucizumab.
Introduction: Vessel-associated retinal diseases are a major cause of blindness and severe visual impairment. The identification of appropriate biomarkers is of great importance to better anticipate disease progression and establish more targeted treatment options. MicroRNAs (miRNAs) are short, single-stranded, noncoding ribonucleic acids that are involved in the posttranscriptional regulation of gene expression through hybridization with messenger RNA. The expression of certain miRNAs can be different in patients with pathological processes and can be used for the detection and differentiation of various diseases. In this study, we investigate to what extent previously in vitro identified miRNAs are present as cell-free circulating miRNAs in the serum and vitreous of human patients with and without vessel-associated retinal diseases. Methods: Relative quantification by quantitative real-time polymerase chain reaction was used to analyze miRNA expression in patients with vessel-associated retinal diseases such as age-related macular degeneration (AMD), diabetic retinopathy (DR), and retinal vein occlusion compared with control patients. Results: In serum samples, miR-29a-3p and miR-192-5p showed increased expression in patients with neovascular AMD relative to control patients. Similarly, miR-335-5p, miR-192-5p, and miR-194-5p showed increased expression in serum from patients with proliferative DR. In vitreous samples, miR-100-5p was decreased in patients with proliferative DR. Differentially expressed miRNAs showed good diagnostic accuracy in receiver operating characteristic (ROC) and area under the ROC curve analysis. Conclusion: The miRNAs investigated in this study may have the potential to serve as biomarkers for vessel-associated retinal diseases. Combining multiple miRNAs may enhance the predictive power of the analysis.