Biology subjects

Hagbom, M.

Publications and source records attributed to Hagbom, M..

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↗

bioRxiv2024

Altered DNA methylation pattern contributes to differential epigenetic immune signaling in the upper respiratory airway of COVID-19 patients

The emergence of SARS-CoV-2 has had a profound adverse impact on global health and continues to remain a threat worldwide. The disease spectrum of COVID-19 ranges from asymptomatic to fatal clinical outcomes especially in the elderly population and in individuals with underlying medical conditions. The impact of COVID-19 on host immune responses and immune cells at the protein and DNA levels remains largely ambiguous. In a case-control study, here we explored the impact of COVID-19 on DNA methylation patterns in the upper respiratory airway to determine how SARS-CoV-2 infection altered the immune status of individuals requiring hospitalization for COVID-19. We performed DNA methylation arrays on nasopharyngeal swabs at inclusion/hospitalization as well as 6 weeks post-inclusion. Our study reveals a distinct DNA methylation pattern in COVID-19 patients compared to healthy controls, characterized by 317 779 differentially methylated CpGs. Notably, within the transcription start sites and gene body, COVID-19 patients exhibited a higher number of genes/CpGs with elevated methylation levels. Enrichment analysis of methylated genes at transcription start sites highlighted the impact on genes associated with inflammatory responses and immune functions. Some SARS-CoV-2 -induced CpG methylations were transient, returning to normal levels by 6 weeks post-inclusion. Enriched genes of interest included IL-17A, a pivotal cytokine implicated with inflammation and healing, and NUP93, associated with antiviral innate immunity. Further, six genes in our data set, OAS1, CXCR5, APP, CCL20, CNR2, and C3AR1, were found in enrichment analysis with previous COVID-19 studies. Additionally, RNAse1 and RNAse2 emerged as key regulators, while IL-18 played a role in various biological processes in COVID-19 patients. Overall, our results demonstrates that COVID-19 has a major impact on the upper airway by modifying the methylation pattern of many genes and this could have implications for the conditioning of the airways and how the individual response to future airway 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↗

bioRxiv2022

Lasting alterations in monocyte and dendritic cell subsets in individuals after hospitalization for COVID-19

After more than two years the COVID-19 pandemic continues to burden healthcare systems and economies worldwide, and it is evident that long-term effects of the disease can persist for months post-recovery in some individuals. The activity of myeloid cells such as monocytes and dendritic cells (DC) is essential for correct mobilization of the innate and adaptive responses to a pathogen. Impaired levels and responses of monocytes and DC to SARS-CoV-2 is likely to be a driving force behind the immune dysregulation that characterizes severe COVID-19. Here, we followed, for 6-7 months, a cohort of COVID-19 patients hospitalized during the early waves of the pandemic. The levels and phenotypes of circulating monocyte and DC subsets were assessed to determine both the early and long-term effects of the SARS-CoV-2 infection. We found increased monocyte levels that persisted for 6-7 months, mostly attributed to elevated levels of classical monocytes. While most DC subsets recovered from an initial decrease, we found elevated levels of cDC2/cDC3 at the 6-7 month timepoint. Analysis of functional markers on monocytes and DC revealed sustained reduction in PD-L1 expression but increased CD86 expression across almost all cell types examined. Finally, viral load and CRP correlated to the appearance of circulating antibodies and levels of circulating DC and monocyte subsets, respectively. By elucidating some of the long-term effects that SARS-CoV-2 infection has on these key innate myeloid cells, we have shed more light on how the immune landscape remains affected in the months following severe COVID-19.

immunology↗

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↗