Biology subjects

Moss, P.

Publications and source records attributed to Moss, P..

5 recordsLinked to original sources

bioRxiv2024

Global variation in prior exposure shapes antibody neutralization profiles of SARS-CoV-2 variants up to BA.2.86

The highly mutated SARS-CoV-2 variant, BA.2.86, and its descendants are now the most frequently sequenced variants of SARS-CoV-2. We analyze antibody neutralization data from eight laboratories from the UK, USA, Denmark, and China, including two datasets assessing the effect of XBB.1.5 vaccines, to determine the effect of infection and vaccination history on neutralization of variants up to and including BA.2.86, and produce antibody landscapes to describe these neutralization profiles. We find evidence for lower levels of immune imprinting on pre-Omicron variants in sera collected from Denmark and China, which may be explained by lower levels of circulation of the ancestral variant in these countries, and the use of an inactivated virus vaccine in China.

immunology↗

bioRxiv2023

Spatial determination and prognostic impact of the fibroblast transcriptome in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma has a poor clinical outcome and responses to immunotherapy are suboptimal. Stromal fibroblasts are a dominant but heterogenous population within the tumor microenvironment and therapeutic targeting of stromal subsets may have therapeutic utility. Here we combined spatial transcriptomics and scRNA-Seq to define the transcriptome of tumor-proximal and tumor-distal cancer-associated fibroblasts (CAFs) and linked this to clinical outcome. Tumor-proximal fibroblasts comprised large populations of myofibroblasts, strongly expressed podoplanin, and were enriched for Wnt ligand signaling. In contrast, inflammatory CAFs were dominant within tumor-distal subsets and expressed complement components and the Wnt-inhibitor SFRP2. Poor clinical outcome was correlated with elevated HIF-1 and podoplanin whilst high level expression of inflammatory and complement genes was predictive of extended survival. These findings demonstrate the extreme transcriptional heterogeneity of CAFs and its determination by apposition to tumor. Selective targeting of tumor-proximal subsets, potentially combined with HIF-1 inhibition and immune stimulation, may offer a multimodal therapeutic approach for this disease. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=170 SRC="FIGDIR/small/524883v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@b34606org.highwire.dtl.DTLVardef@1ba47c3org.highwire.dtl.DTLVardef@bd75f1org.highwire.dtl.DTLVardef@8a602b_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2022

Primary Omicron infection elicits weak antibody response but robust cellularimmunity in children

Omicron variants of SARS-CoV-2 are globally dominant and infection rates are very high in children. We determined immune responses following Omicron BA.1/2 infection in children aged 6-14 years and related this to prior and subsequent SARS-CoV-2 infection or vaccination. Primary Omicron infection elicited a weak antibody response with poor functional neutralizing antibodies. Subsequent Omicron reinfection or COVID-19 vaccination elicited increased antibody titres with broad neutralisation of Omicron subvariants. Prior pre-Omicron SARS-CoV-2 virus infection or vaccination primed for robust antibody responses following Omicron infection but these remained primarily focussed against ancestral variants. Primary Omicron infection thus elicits a weak antibody response in children which is boosted after reinfection or vaccination. Cellular responses were robust and broadly equivalent in all groups, providing protection against severe disease irrespective of SARS-CoV-2 variant. Immunological imprinting is likely to act as an important determinant of long-term humoral immunity, the future clinical importance of which is unknown.

immunology↗

bioRxiv2022

A single episode of CMV reactivation initiates long-term expansion and differentiation of the NK cell repertoire

NK cells play an important role in suppression of viral replication and are critical for effective control of persistent infections such as herpesviruses. Cytomegalovirus infection is associated with expansion of adaptive-memory NK cells with a characteristic CD16brightCD56dim NKG2C+ phenotype but the mechanisms by which this population is maintained remain uncertain. We studied NK cell reconstitution in patients undergoing haemopoietic stem cell transplantation and related this to CMV reactivation. NK cells expanded in the early post-transplant period but then remained stable in the absence of viral reactivation. However, a single episode of CMV reactivation led to a rapid and sustained 10-fold increase in NK cell number. NKG2C expression was increased on all NK subsets although the kinetics of expansion peaked at 6 months on immature CD56bright cells whilst continuing to rise on the mature CD56dim pool. Phenotypic maturation was observed by acquisition of CD57 and KIR expression. Transplantation from CMV-seropositive donors was associated with more rapid NK expansion and superior control of viral reactivation. Effective control of viral reactivation was seen when the peripheral NK cell count reached 20,000/ml. These data show that a single episode of CMV reactivation acts to reprogramme hemopoiesis to drive a sustained modulation and expansion of the NK cell pool and reveal further insight into long term regulation of the innate immune repertoire by infectious challenge. Author Summaryim to highlight where your work fits within a broader context; present the significance or possible implications of your work simply and objectively; and avoid the use of acronyms and complex terminology wherever possible. The goal is to make your findings accessible to a wide audience that includes both scientists and non-scientists Innate immune cells respond rapidly to infectious challenge and it has previously been thought that they were unable to learn from specific infecitons but provided only short term control. However, in recent years it has become apparent that some subsets of innate cells, termed adaptive natural killer (NK) cells, are permanently increased in people who have become infected with cytomegalovirus. The mechanism by which this is maintained is not known. We studied the kinetics of adaptive NK cell expansion in patients who had recently undergone stem cell (bone marrow) transplantation as CMV very often reactivates in this setting and allows study of how this affects the immune system. We find that one short term episode of viral replication led to a large and prolonged expansion of adaptive NK cells. Indeed, their levls increasd 11-fold over 10 months.

immunology↗

bioRxiv2020

Robust SARS-CoV-2-specific T-cell immunity is maintained at 6 months following primary infection

The immune response to SARS-CoV-2 is critical in both controlling primary infection and preventing re-infection. However, there is concern that immune responses following natural infection may not be sustained and that this may predispose to recurrent infection. We analysed the magnitude and phenotype of the SARS-CoV-2 cellular immune response in 100 donors at six months following primary infection and related this to the profile of antibody level against spike, nucleoprotein and RBD over the previous six months. T-cell immune responses to SARS-CoV-2 were present by ELISPOT and/or ICS analysis in all donors and are characterised by predominant CD4+ T cell responses with strong IL-2 cytokine expression. Median T-cell responses were 50% higher in donors who had experienced an initial symptomatic infection indicating that the severity of primary infection establishes a setpoint for cellular immunity that lasts for at least 6 months. The T-cell responses to both spike and nucleoprotein/membrane proteins were strongly correlated with the peak antibody level against each protein. The rate of decline in antibody level varied between individuals and higher levels of nucleoprotein-specific T cells were associated with preservation of NP-specific antibody level although no such correlation was observed in relation to spike-specific responses. In conclusion, our data are reassuring that functional SARS-CoV-2-specific T-cell responses are retained at six months following infection although the magnitude of this response is related to the clinical features of primary infection.

immunology↗