Biology subjects

Grunwald, T.

Publications and source records attributed to Grunwald, T..

4 recordsLinked to original sources

bioRxiv2021

Protective mucosal immunity against SARS-CoV-2 after heterologous systemic RNA-mucosal adenoviral vector immunization

Several effective SARS-CoV-2 vaccines are currently in use, but in the light of waning immunity and the emergence of novel variants, effective boost modalities are needed in order to maintain or even increase immunity. Here we report that intranasal vaccinations with adenovirus 5 and 19a vectored vaccines following a systemic DNA or mRNA priming result in strong systemic and mucosal immunity in mice. In contrast to two intramuscular injections with an mRNA vaccine, the mucosal boost with adenoviral vectors induced high levels of IgA and tissue-resident memory T cells in the respiratory tract. Mucosal neutralization of virus variants of concern was also enhanced by the intranasal boosts. Importantly, priming with mRNA provoked a more comprehensive T cell response consisting of circulating and tissue-resident memory T cells after the boost, while a DNA priming induced mostly mucosal T cells. Concomitantly, the intranasal boost strategies provided protection against symptomatic disease. Therefore, a mucosal booster immunization after mRNA priming is a promising approach to establish mucosal immunity in addition to systemic responses.

immunology↗

bioRxiv2021

A pair of non-competing neutralizing human monoclonal antibodies protecting from disease in a SARS-CoV-2 infection model

TRIANNI mice carry an entire set of human immunoglobulin V region gene segments and are a powerful tool to rapidly generate human monoclonal antibodies. After immunizing these mice against the spike protein of SARS-CoV-2, we identified 29 hybridoma antibodies that reacted with the SARS-CoV-2 spike protein. Nine antibodies neutralized SARS-CoV-2 infection at IC50 values in the subnanomolar range. ELISA-binding studies and DNA sequence analyses revealed one cluster of clonally related neutralizing antibodies that target the receptor-binding domain and compete with the cellular receptor hACE2. A second cluster of neutralizing antibodies binds to the N-terminal domain of the spike protein without competing with the binding of hACE2 or cluster 1 antibodies. SARS-CoV-2 mutants selected for resistance to an antibody from one cluster are still neutralized by an antibody from the other cluster. Antibodies from both clusters markedly reduced viral spread in mice transgenic for human ACE2 and protected the animals from SARS-CoV-2 induced weight loss. Thus, we report two clusters of potent non-competing SARS-CoV-2 neutralizing antibodies providing potential candidates for therapy and prophylaxis of COVID-19. The study further supports the use of transgenic animals with human immunoglobulin gene repertoires in pandemic preparedness initiatives.

immunology↗

bioRxiv2020

Neuronal firing in the medial temporal lobe reflects human working memory workload, performance and capacity.

2The involvement of the medial temporal lobe (MTL) in working memory is controversially discussed. Critically, it is unclear whether and how the MTL supports performance of working memory. We recorded single neuron firing in 13 epilepsy patients while they performed a visual working memory task. The number of colored squares in the stimulus set determined the workload of the trial. We used the subjects memory capacity (Cowans K) to split them into a low and high capacity group. We found MTL neurons that showed persistent firing during the maintenance period. Firing was higher in the hippocampus for trials with correct compared to incorrect performance. Population firing predicted workload particularly during the maintenance period. Prediction accuracy of single trial activity was strongest for neurons in the entorhinal cortex of low capacity subjects. We provide evidence that low capacity subjects recruit their MTL to cope with an overload of working memory task demands. 1 SignificanceHumans are highly limited in processing multiple objects over a short period of time. The capacity to retain multiple objects in working memory is typically associated with frontal and parietal lobe functioning, even though medial temporal lobe (MTL) neural architecture seems capable to process such information. However, there are conflicting findings from patient, electrophysiological and neuroimaging studies. Here we show for the first time that correct performance, workload and individual performance differences are reflected in separate mechanisms of neural activity within the MTL during maintenance of visual information in working memory. The data suggest that low capacity subjects use the MTL to process the overload of information.

neuroscience↗

bioRxiv2020

Functional synchronization between hippocampal sEEG, parietal ECoG and scalp EEG during a verbal working memory task.

BackgroundThe maintenance of items in working memory (WM) relies on a widespread network of brain areas where synchronization between electrophysiological recordings may reflect functional coupling. While the coupling from hippocampus to scalp EEG is well established, we provide here direct cortical recordings for a fine-grained analysis. MethodsA patient performed a WM task where a string of letters was presented all at once, thus separating the encoding period from the maintenance period. We recorded sEEG from the hippocampus, temporo-parietal ECoG from a 64-contact grid electrode, and scalp EEG. ResultsPower spectral density (PSD) showed a clear task dependence: PSD in the posterior parietal lobe (10 Hz) and in the hippocampus (20 Hz) peaked towards the end of the maintenance period. Inter-area synchronization was characterized by the phase locking value (PLV). WM maintenance enhanced PLV between hippocampal sEEG and scalp EEG specifically in the theta range [6 7] Hz. PLV from hippocampus to parietal cortex increased during maintenance in the [9 10] Hz alpha and the 20 Hz range. When analyzing the information flow to and from auditory cortex by Granger causality, the flow was from auditory cortex to hippocampus with a peak in the [8 18] Hz range while letters were presented, and this flow was subsequently reversed during maintenance, while letters were maintained in memory. ConclusionsThe increased functional interaction between hippocampus and cortex through synchronized oscillatory activity and the directed information flow provide physiological basis for reverberation of memory items during maintenance. This points to a network for working memory that is bound by coherent oscillations involving cortical areas and hippocampus. SIGNIFICANCE STATEMENTHippocampal activity is known for its role in cognitive tasks involving episodic memory or spatial navigation, but its role in working memory and its sensitivity to workload is still under debate. Here, we investigated hippocampal and cortical activity while a subject maintained sets of letters in verbal working memory for a few seconds to guide action. After confirming the coupling between hippocampal oscillations and oscillations on the scalp, we found during maintenance that hippocampal oscillations increased coupling differentially to several areas of cortex by recording directly from the cortex.. During encoding of the letters, information flow was from auditory cortex to hippocampus and subsequently reversed during maintenance, thus providing a physiological basis for memory encoding and maintenance. This demonstrates a network for working memory that is bound by coherent oscillations that underlie the functional connectivity between cortical areas and hippocampus.

neuroscience↗