Biology subjects

Svensson, L.

Publications and source records attributed to Svensson, L..

5 recordsLinked to original sources

bioRxiv2026

Human enterochromaffin cells and apical-out intestinal organoids as models for human sapovirus infection

Human sapovirus is increasingly recognized as a significant cause of acute viral gastroenteritis, but in vitro studies have been limited due to the previous lack of cell models. In this study, we optimized two novel in vitro models for sapovirus infection: the human enteroendocrine cell (EEC) line GOT1 and apical-out 3D human enteroids. Using 31 sapovirus-positive fecal samples, we compared these models with the EEC-derived HuTu80, and human enteroid monolayers, both previously used for sapovirus infection. Among the analyzed samples, genotypes GI.1 (36%), GII.1 (32%), and GII.3 (26%) were identified, with GI.1 exhibiting the highest fecal viral load. We demonstrated that GOT1 cells supported replication of more of the samples containing GI.1 sapovirus (9 of 11) compared to HuTu80 (8 of 11) and with a generally higher replication fold change. Moreover, GOT1 cells were able to support the replication of several GII.1 (3 of 10) and GII.3 (5 of 8) samples, unlike HuTu80 cells that only supported replication of one sample with GII.3 and none of the GII.1 sapoviruses. Given that organoids are considered a more physiologically relevant model than transformed cell lines, we established a sapovirus infection model using human apical-out 3D enteroids. Compared to previously used enteroid monolayers, the apical-out model supported replication of a higher number of samples with GI.1 and with higher replication fold change. In conclusion, these findings provide valuable insights for future in vitro studies of sapovirus infection and replication, which may contribute to a better understanding of sapovirus cell tropism and pathogenesis. ImportanceUnderstanding sapovirus biology requires efficient, reliable, and physiologically relevant in vitro models. By systematically comparing four infection models using clinical samples from three common sapovirus genotypes, this study contributes to important information about differences in cellular susceptibility between these in vitro models. We identified the GOT1 cell line as an efficient model for sapovirus replication and introduced apical-out enteroids as a sensitive organoid-based system for studying sapovirus GI.1. Together, the introduced models provide complementary platforms that can contribute to knowledge about sapovirus pathogenesis and cell tropism as well as provide guidance in selecting suitable in vitro models for future sapovirus research.

microbiology↗

bioRxiv2023

Dysregulated Platelet Function and Thrombosis in Patients with Post-Acute Sequelae of COVID-19

BackgroundPost-acute sequelae of COVID-19 (PASC), also referred as Long-COVID, sometimes follows COVID-19, a disease caused by SARS-CoV-2. While SARS-CoV-2 is well-known to promote a prothrombotic state, less is known about the thrombosis risk in PASC. AimOur objective was to evaluate the platelet function and thrombotic potential in patients following recovery from SARS-CoV-2 with clear symptoms of PASC. MethodsPASC patients and matched healthy controls were enrolled in the study on average 15 months after documented SARS-CoV-2 infection. Platelet activation was evaluated by Light Transmission Aggregometry (LTA) and flow cytometry in response to platelet surface receptor agonists. Thrombosis in platelet-deplete plasma was evaluated by Factor Xa activity. A microfluidics system assessed thrombosis in whole blood under shear stress conditions. ResultsA mild increase in platelet aggregation in PASC patients through the thromboxane receptor was observed and platelet activation through the glycoprotein VI (GPVI) receptor was decreased in PASC patients compared to age- and sex-matched healthy controls. Thrombosis under shear conditions as well as Factor Xa activity were reduced in PASC patients. Plasma from PASC patients was an extremely potent activator of washed, healthy platelets - a phenomenon not observed when stimulating healthy platelets after incubation with plasma from healthy individuals. ConclusionsPASC patients show dysregulated responses in platelets and coagulation in plasma, likely caused by a circulating molecule that promotes thrombosis. A hitherto undescribed protective response appears to exists in PASC patients to counterbalance ongoing thrombosis that is common to SARS-CoV-2 infection.

pharmacology and toxicology↗

bioRxiv2023

Confidence-based Prediction of Antibiotic Resistance at the Patient-level Using Transformers

Rapid and accurate diagnostics of bacterial infections are necessary for efficient treatment of antibiotic-resistant pathogens. Cultivation-based methods, such as antibiotic susceptibility testing (AST), are limited by bacterial growth rates and seldom yield results before treatment needs to start, increasing patient risk and contributing to antibiotic overprescription. Here, we present a deep-learning method that leverages patient data and available AST results to predict antibiotic susceptibilities that have not yet been measured. After training on three million AST results from 30 European countries, the method achieved an average accuracy of 93% across bacterial species and antibiotics. It predicted susceptibility with an average major error rate below 5% for quinolones, cephalosporins, and carbapenems, and below 8% and 14% for aminoglycosides and penicillins, respectively. Furthermore, the model predicted resistance with an average very major rate below 10% for cephalosporins, carbapenems, and aminoglycosides, but with higher very major error rates for penicillins and quinolones. We combined the method with conformal prediction and demonstrated accurate estimation of the predictive uncertainty at the patient level. Our results suggest that AI-based decision support may offer new means to meet the growing burden of antibiotic resistance. IMPORTANCEImproved diagnostic tools are vital for maintaining efficient treatment of antibiotic-resistant bacteria and for reducing antibiotic overconsumption. In our research, we introduce a new deep learning-based method capable of predicting untested antibiotic resistance phenotypes. The method uses transformers, a powerful AI technique that efficiently leverages both antibiotic susceptibility tests (AST) and patient data simultaneously. The model produces predictions that can be used as time- and cost-efficient alternatives to results from cultivation-based diagnostic assays. Significantly, our study highlights the potential of AI technologies to address the increasing prevalence of antibiotic-resistant bacterial infections.

microbiology↗

bioRxiv2023

Conversion of monoclonal IgG to dimeric and secretory IgA restores neutralizing ability and prevents infection of Omicron lineages

The emergence of Omicron lineages and descendent subvariants continues to present a severe threat to the effectiveness of vaccines and therapeutic antibodies. We have previously suggested that an insufficient mucosal IgA response induced by the mRNA vaccines is associated with a surge in breakthrough infections. Here, we further show that the intramuscular mRNA and/or inactivated vaccines cannot sufficiently boost the mucosal sIgA response in uninfected individuals, particularly against the Omicron variant. We thus engineered and characterized recombinant monomeric, dimeric and secretory IgA1 antibodies derived from four neutralizing IgG monoclonal antibodies targeting the receptor-binding domain of the spike protein (01A05, rmAb23, DXP-604 and XG014). Compared to their parental IgG antibodies, dimeric and secretory IgA1 antibodies showed a higher neutralizing activity against different variants of concern (VOCs), in part due to an increased avidity. Importantly, the dimeric or secretory IgA1 form of the DXP-604 antibody significantly outperformed its parental IgG antibody, and neutralized the Omicron lineages BA.1, BA.2 and BA.4/5 with a 50-150-fold increase in potency, reaching the level of the most potent monoclonal antibodies described till date. In hACE2 transgenic mice, a single intranasal dose of the dimeric IgA DXP-604 conferred prophylactic and therapeutic protection against Omicron BA.5. Conversion of IgA and dimerization further enhanced or restored the neutralizing ability against the emerging Omicron sub-variants (DXP-604 for BQ.1, BQ.1.1 and BA2.75; 01A05 for BA2.75, BA.2.75.2 and XBB.1). Thus, dimeric or secretory IgA delivered by nasal administration may potentially be exploited for the treatment and prevention of Omicron infection, thereby providing an alternative tool for combating immune evasion by subvariants and, potentially, future VOCs. One Sentence SummaryEngineered dimeric and secretory IgA1 neutralized Omicron variant with higher potency than parental IgG.

microbiology↗

bioRxiv2021

Rotavirus pre-symptomatically downregulates ileum-innervating sympathetic nerves concomitant with increased intestinal transit and altered brain activity

While diarrhea, the hallmark symptom of rotavirus infection, has been considered to occur only due to intrinsic intestinal effects, we show evidence for central control underlying the symptomology. With large-scale 3D volumetric tissue imaging a mouse model, we show that rotavirus infection disrupts the autonomic balance by downregulating the noradrenergic sympathetic nervous system in ileum, concomitant with increased intestinal transit. A most interesting observation was that nervous response from CNS occurs pre-symptomatically, an observation that bring new understanding to how virus give raise to clinical symptoms. In the CNS of infected animals, we found increased pS6 immunoreactivity in the area postrema and decreased phosphorylated STAT5-immunoreactive neurons in the bed nucleus of the stria terminalis, which are associated with autonomic control including stress response. Our observations bring new and important knowledge of how rotavirus virus infection induce gut-nerve-brain crosstalk giving raise to sickness symptoms.

microbiology↗