bioRxiv Science⌕ Search

Biology subjects

Slater, D.

Publications and source records attributed to Slater, D..

3 recordsLinked to original sources
bioRxiv2024

Antibody responses in Klebsiella pneumoniae bloodstream infection: a cohort study

BackgroundKlebsiella pneumonia (Kpn) is the fourth leading cause of infection-related deaths globally, yet little is known about human antibody responses to invasive Kpn. In this study, we sought to determine whether the O-specific polysaccharide (OPS) antigen, a vaccine candidate, is immunogenic in humans with Kpn bloodstream infection (BSI). We also sought to define the cross-reactivity of human antibody responses among structurally related Kpn OPS subtypes and to assess the impact of capsule production on OPS-targeted antibody binding and function. MethodsWe measured plasma antibody responses to OPS (and MrkA, a fimbrial protein) in a cohort of patients with Kpn BSI and compared these with controls, including a cohort of healthy individuals and a cohort of individuals with Enterococcus BSI. We performed flow cytometry to measure the impact of Kpn capsule production on whole cell antibody binding and complement deposition, utilizing patient isolates with variable levels of capsule production and isogenic capsule-deficient strains derived from these isolates. FindingsWe enrolled 69 patients with Kpn BSI. Common OPS serotypes accounted for 57/69 (83%) of infections. OPS was highly immunogenic in patients with Kpn BSI, and peak OPS-IgG antibody responses in patients were 10 to 30-fold higher than antibody levels detected in healthy controls, depending on the serotype. There was significant cross-reactivity among structurally similar OPS subtypes, including the O1v1/O1v2, O2v1/O2v2 and O3/O3b subtypes. Physiological amounts of capsule produced by both hyperencapsulated and non-hyperencapsulated Kpn significantly inhibited OPS-targeted antibody binding and function. InterpretationOPS was highly immunogenic in patients with Kpn BSI, supporting its potential as a candidate vaccine antigen. The strong cross-reactivity observed between similar OPS subtypes in humans with Kpn BSI suggests that it may not be necessary to include all subtypes in an OPS-based vaccine. However, these observations are tempered by the fact that capsule production, even in non-highly encapsulated strains, has the potential to interfere with OPS antibody binding. This may limit the effectiveness of vaccines that exclusively target OPS. FundingNational Institute of Allergy and Infectious Diseases at the National Institutes of Health. Research in ContextO_ST_ABSEvidence before this studyC_ST_ABSDespite the potential of O-specific polysaccharide (OPS) as a vaccine antigen against Klebsiella pneumoniae (Kpn), the immunogenicity of OPS in humans remains largely unstudied, creating a significant knowledge gap with regard to vaccine development. A search of PubMed for publications up to March 18, 2024, using the terms "Klebsiella pneumoniae" and "O-specific polysaccharide" or "O-antigen" or "lipopolysaccharide" revealed no prior studies addressing OPS antibody responses in humans with Kpn bloodstream infections (BSI). One prior study1 evaluated antibody response to a single lipopolysaccharide (which contains one subtype of OPS) in humans with invasive Kpn infection; however, in this study OPS typing of the infecting strains and target antigen were not described. Added value of this studyOur investigation into OPS immunogenicity in a human cohort marks a significant advance. Analyzing plasma antibody responses in 69 patients with Kpn BSI, we found OPS to be broadly immunogenic across all the types and subtypes examined, and there was significant cross-reactivity among structurally related OPS antigens. We also demonstrated that Kpn capsule production inhibit OPS antibody binding and the activation of complement on the bacterial surface, even in classical Kpn strains expressing lower levels of capsule. Implications of all the available evidenceWhile the immunogenicity and broad cross-reactivity of OPS in humans with Kpn BSI suggests it is a promising vaccine candidate, the obstruction of OPS antibody binding and engagement by physiologic levels of Kpn capsule underscores the potential limitations of an exclusively OPS-antigen based vaccine for Kpn. Our study provides insights for the strategic development of vaccines aimed at combating Kpn infections, an important antimicrobial resistant pathogen.

microbiology↗
bioRxiv2017

Simultaneous Estimation of Population Receptive Field and Hemodynamic Parameters from Single Point BOLD Responses using Metropolis-Hastings Sampling

We introduce a new approach to Bayesian pRF model estimation using Markov Chain Monte Carlo (MCMC) sampling for simultaneous estimation of pRF and hemodynamic parameters. To obtain high performance on commonly accessible hardware we present a novel heuristic consisting of interpolation between precomputed responses for predetermined stimuli and a large cross-section of receptive field parameters. We investigate the validity of the proposed approach with respect to MCMC convergence, tuning and biases. We compare different combinations of pRF - Compressive Spatial Summation (CSS), Dumoulin-Wandell (DW) and hemodynamic (5-parameter and 3-parameter Balloon-Windkessel) models within our framework with and without the usage of the new heuristic. We evaluate estimation consistency and log probability across models. We perform as well a comparison of one model with and without lookup table within the RStan framework using its No-U-Turn Sampler. We present accelerated computation of whole-ROI parameters for one subject. Finally, we discuss risks and limitations associated with the usage of the new heuristic as well as the means of resolving them. We found that the new algorithm is a valid sampling approach to joint pRF/hemodynamic parameter estimation and that it exhibits very high performance.

neuroscience↗
bioRxiv2017

Convex Optimized Population Receptive Field (CO-pRF) Mapping

Population receptive field (pRF) mapping represents an invaluable non-invasive tool for the study of sensory organization and plasticity within the human brain. Despite the very appealing result that fMRI derived pRF measures agree well with measurements made from other fields of neuroscience, current techniques often require very computationally expensive non-linear optimization procedures to fit the models to the data which are also vulnerable to bias due local minima issues. In this work we present a general framework for pRF model estimation termed Convex Optimized Population Receptive Field (CO-pRF) mapping and show how the pRF fitting problem can be linearized in order to be solved by extremely fast and efficient algorithms. The framework is general and can be readily applied to a variety of pRF models and measurement schemes. We provide an example of the CO-pRF methodology as applied to a computational neuroimaging approach used to map sensory processes in human visual cortex - the CSS-pRF model. Via simulation and in-vivo fMRI results we demonstrate that the CO-pRF approach achieves robust model fitting even in the presence of noise or reduced data, providing parameter estimates closer to the global optimum across 93% of in-vivo responses as compared to a typical nonlinear optimization procedure. Furthermore the example CO-pRF application substantially reduced model fitting times by a factor of 50. We hope that the availability of such highly accelerated and reliable pRF estimation algorithms will facilitate the spread of pRF techniques to larger imaging cohorts and the future study of neurological disorders and plasticity within the human brain.

neuroscience↗