Biology subjects

Toh, J.

Publications and source records attributed to Toh, J..

5 recordsLinked to original sources

bioRxiv2025

A conserved immune dysregulation is associated with infection severity, risk factors prior to infection, and treatment response

Older age, being male, obesity, smoking, and comorbidities (e.g., diabetes, asthma) are associated with the increased risk for severe infections. We hypothesized that there is a conserved common immune dysregulation across these risk factors. We integrated single cell and bulk transcriptomic data and proteomic data from 12,026 blood samples across 68 cohorts to test this hypothesis. We found that our previously described 42-gene Severe-or-Mild (SoM) signature, is associated with each of these risk factors prior to infection. Furthermore, we found this conserved immune signature is modifiable using immunomodulatory drugs and lifestyle changes. The SoM score predicted patients with sepsis that would be harmed from hydrocortisone treatment, and patients with asthma that will not respond to monoclonal antibody treatment. Finally, the SoM score was associated with all-cause mortality. The SoM signature has the potential to redefine the immunologic framing of baseline immune state and response to chronic, subacute, and acute illnesses.

immunology↗

bioRxiv2025

Guidestar: a spike-in approach to improve RNA detection accuracy in imaging-based spatial transcriptomics

Imaging-based spatial transcriptomics technologies, such as MERFISH and seq-FISH, use combinatorial barcoding and imaging to simultaneously detect individual RNA molecules from 10s to 10,000s of genes. These technologies require the decoding of individual RNA molecules location and gene identity from stacks of images. However, beyond using blank code-words as negative controls, there is a lack of ground truth information embedded within the assay to experimentally measure the accuracy and sensitivity of the decoding algorithm. We introduce Guidestar, a system of spike-in controls integrated within a combinatorial FISH assay, that labels a subset of RNA transcripts with additional probes. These probes are imaged separately as guide bits, which serve as ground-truth data to assess decoding accuracy at the level of individual RNA molecules. Using Guidestar to evaluate accuracy of an existing decoding method suggested alternative parameter settings that increased sensitivity with minimal impact on accuracy. We also used the Guidestar dataset to train a machine-learning based classifier to distinguish true from false RNA calls, yielding 9% and 40% higher F1 scores across cell line and tissue samples, respectively.

genomics↗

bioRxiv2023

Systems immunology of transcriptional responses to viral infection identifies conserved antiviral pathways across macaques and humans

Viral pandemics and epidemics pose a significant global threat, with emerging and re-emerging viruses responsible for four pandemics in the 21st century alone. While macaques have been utilized as a model for understanding viral disease in a controlled setting, it remains unclear how conserved the antiviral responses to diverse viruses are between macaques and humans. To address this critical knowledge gap, we conducted a comprehensive cross-species analysis of transcriptomic data from over 6000 blood samples from macaques and humans infected with one of 31 viruses, including Lassa, Ebola, Marburg, Zika, and dengue. Our findings demonstrate that irrespective of primate or viral species, there are conserved antiviral responses which are consistent regardless of infection phase (acute, chronic, or latent) and viral genome type (DNA or RNA viruses). Moreover, by leveraging longitudinal data from experimental challenges, we identified virus-specific response dynamics such as host responses to Coronaviridae and Orthomyxoviridae infections peaking 1-3 days earlier than responses to Filoviridae and Arenaviridae viral infections. Additionally, through comparative analysis of immune responses across viruses, we identified a unique enrichment of lymphoid cellular response modules in macaque Flaviviridae infection that persists in human responses to dengue. Our results underscore macaque studies as a powerful tool for gaining new insights into viral pathogenesis and immune responses that translate to humans, which can inform viral therapeutic development and enable pandemic preparedness. One sentence summaryUsing longitudinal macaque viral challenge studies, we identified shared and virus-specific responses to infection that replicate in human viral disease - thereby demonstrating the utility of macaque models of viral infection to understand antiviral biology and for pandemic preparedness.

immunology↗

bioRxiv2022

An in situ quantitative map of initial human colorectal HIV transmission

The initial immune response to HIV is critical in determining transmission. However, due to technical limitations we still do not have a comparative map of early mucosal transmission events. We combined RNAscope, cyclic-immunofluorescence and novel image analysis tools to quantify HIV transmission dynamics in intact human colorectal tissue. We mapped HIV enrichment to mucosal dendritic cells (DC) and submucosal macrophages, but not CD4+ T-cells, the primary targets of downstream infection. DCs appeared to funnel virus to lymphoid aggregates which acted as early sanctuaries of high viral titres whilst facilitating HIV passage to the submucosa. Finally, HIV entry induced rapid recruitment and clustering of target cells, facilitating DC and macrophage mediated HIV transfer and enhanced infection of CD4+ T-cells. These data demonstrate a rapid response to HIV structured to maximise the likelihood of mucosal infection, and provide a framework for in situ studies of host pathogen interactions and immune mediated pathologies. Highlights- in situ quantification of host cellular microenvironment response to pathogen invasion in human colorectal tissue. - HIV first localises to mucosal DCs and submucosal macrophages, but not CD4+ T cells. - Viral enrichment first occurs in lymphoid aggregates which is associated with passage into the submucosa. - Early localisation of HIV to CD4+ T cells is associated with interactions with DCs and macrophages. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/490175v1_ufig1.gif" ALT="Figure 1"> View larger version (67K): org.highwire.dtl.DTLVardef@ef8000org.highwire.dtl.DTLVardef@1bc8ed7org.highwire.dtl.DTLVardef@45ddbdorg.highwire.dtl.DTLVardef@e0a57c_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2019

Parasite histones mediate leak and coagulopathy in cerebral malaria

Coagulopathy and leak, specific to the brain vasculature, are central pathogenetic components of cerebral malaria (CM). It is unclear how the parasite, Plasmodium falciparum, triggers these processes. Extracellular histones, released from damaged host cells, bind to cell membranes and cause coagulation activation, platelet aggregation and vascular leak in diverse critical illnesses. In CM patients with P. falciparum, serum histones correlate with fibrin formation, thrombocytopenia, and endothelial activation and predict brain swelling on magnetic resonance imaging and fatal outcome. Post-mortem, histones bind to the luminal vascular surface, co-localizing with P. falciparum-infected erythrocytes (IE), and with thrombosis and leak. Purified P. falciparum histones cause toxicity and barrier disruption in cultured human brain microvascular endothelial cells, as does serum from CM patients, reversed by anti-histone antibodies and non-anticoagulant heparin. These data implicate parasite histones as a key trigger of fatal brain swelling in CM. Neutralizing histones with agents such as non-anticoagulant heparin warrant exploration to prevent brain swelling and improve outcome.

microbiology↗