Biology subjects

Drayson, M. T.

Publications and source records attributed to Drayson, M. T..

3 recordsLinked to original sources

bioRxiv2023

Inhibition of Neisseria gonorrhoeae complement-mediated killing during acute gonorrhoea is dependent upon the IgG2:IgG3 antibody ratio

Excessive binding of antibodies to the bacterial cell surface can paradoxically increase resistance of some Gram-negative pathogens to complement-mediated killing (CMK). We examined CMK of 336 Neisseria gonorrhoeae clinical isolates sampled from participants recruited to a clinical trial. Serum bactericidal assays revealed 3% (9/336) of the autologous participant sera that were tested inhibited CMK. Gonococci isolated from these participants were resistant to the autologous host serum, sensitive to a pool of healthy control sera (HCS) and protected by the host serum in a 1:1 mixture with HCS. Analysis of the clinical metadata showed that there were a significantly higher proportion of inhibitory sera found in participants with urethral infections and from men within the transmission network of men who have sex with women (MSW), when compared to the whole cohort. Following antibody purification from selected participants with inhibitory sera (5/9), IgG and IgM protected the autologous isolates from HCS-mediated killing. Only three of these isolates were protected by purified IgA. A closer examination of IgG subclasses using whole gonococcal cell ELISAs revealed a strong correlation between increased IgG2 binding and decreased IgG3 binding to the bacterial cell surface of isolates that were resistant to CMK. This suggests that IgG2 prevents bactericidal IgG3 from initiating CMK and that the IgG2:IgG3 ratio is important for determining either inhibition or killing of isolates. We therefore reveal a previously unreported mechanism by which inhibitory antibodies prevent CMK of N. gonorrhoeae.

microbiology↗

bioRxiv2023

Pathogen and human NDPK-proteins promote AML cell survival via monocyte NLRP3-inflammasome activation.

A history of infection has been linked with increased risk of acute myeloid leukaemia (AML) and related myelodysplastic syndromes (MDS). Furthermore, AML and MDS patients suffer frequent infections because of disease-related impaired immunity. However, the role of infections in the development and progression of AML and MDS remains poorly understood. We and others previously demonstrated that the human nucleoside diphosphate kinase (NDPK) NM23-H1 protein promotes AML blast cell survival by inducing secretion of IL-1{beta} from accessory cells. NDPKs are an evolutionary highly conserved protein family and pathogenic bacteria secrete NDPKs that regulate virulence and host-pathogen interactions. Here, we demonstrate the presence of IgM antibodies against a broad range of pathogen NDPKs and more selective IgG antibody activity against pathogen NDPKs in the blood of AML patients and normal donors, demonstrating that in vivo exposure to NDPKs likely occurs. We also show that pathogen derived NDPK-proteins faithfully mimic the catalytically independent pro-survival activity of NM23-H1 against primary AML cells. Flow cytometry identified that pathogen and human NDPKs selectively bind to monocytes in peripheral blood. We therefore used vitamin D3 differentiated monocytes from wild type and genetically modified THP1 cells as a model to demonstrate that NDPK-mediated IL-1{beta} secretion by monocytes is NLRP3-inflammasome and caspase 1 dependent, but independent of TLR4 signaling. Monocyte stimulation by NDPKs also resulted in activation of NF-{kappa}B and IRF pathways but did not include the formation of pyroptosomes or result in pyroptotic cell death which are pivotal features of canonical NLRP3 inflammasome activation. In the context of the growing importance of the NLRP3 inflammasome and IL-1{beta} in AML and MDS, our findings now implicate pathogen NDPKs in the pathogenesis of these diseases. Author SummaryAcute myeloid leukaemia (AML) and myelodysplastic syndromes MDS) are related blood cancers that are associated with frequent infections because the cancers suppress normal immunity. These infections are therefore generally considered as medical complications arising as a result of but separate to the cancer. However, we provide evidence here that infections may promote or drive cancer progression. We and others previously demonstrated that a human protein called NM23-H1 promotes the survival of AML cells by eliciting survival signals from other cells. NM23-H1 belongs to a highly conserved family of proteins that also occur in bacteria and fungi that cause infections in AML and MDS patients. Here we demonstrate that these bacterial and fungal proteins recapitulate the pro-survival effect of NM23-H1 on AML cells. We also determine that these effects are mediated via mechanisms already known to be important in the development and progression of AML and MDS. This study is the first to identify NM23-H1 like proteins from pathogenic microorganisms as novel activators of these pathways. These findings have important implications for how we understand infections in AML and MDS patients and suggest that in addition to being the consequence of these diseases, infections may also drive the cancer process.

microbiology↗

bioRxiv2019

Unique Neurophysiological Vulnerability of Visual Attention Networks to Acute Inflammation

Illness is often accompanied by perceived cognitive sluggishness, a symptom that may stem from immune system activation. The current study used electroencephalography (EEG) to assess how inflammation affected three different distinct attentional processes: alerting, orienting and executive control. In a double-blinded placebo-controlled within-subjects design (20 healthy males, mean age = 24.5, SD = 3.4), Salmonella typhoid vaccination (0.025 mg; Typhim Vi, SanofiPasteur) was used to induce transient mild inflammation, while a saline injection served as a placebo-control. Participants completed the Attention Network Test with concurrent EEG recorded six hours post-injection. Analyses focused on behavioral task performance and on modulation of oscillatory EEG activity in the alpha band (9-12 Hz) for alerting as well as orienting attention and frontal theta band (4-8 Hz) for executive control. Vaccination induced mild systemic inflammation, as assessed by interleukin-6 (IL-6) levels. While no behavioral task performance differences between the inflammation and placebo condition were evident, inflammation caused significant alterations to task-related brain activity. Specifically, inflammation produced greater cue-induced suppression of alpha power in the alerting aspect of attention while individual variation in the inflammatory response was significantly correlated with the degree of alpha power suppression. Notably, inflammation did not affect orienting (i.e., alpha lateralization) or executive control (i.e., frontal theta activity). These results reveal a unique neurophysiological vulnerability to acute mild inflammation of the neural network that underpins attentional alerting functions. Observed in the absence of performance decrements, these novel findings suggest that acute inflammation requires individuals to exert greater cognitive effort when preparing for a task in order to maintain adequate behavioral performance.\n\nHighlights O_LITyphoid vaccination induced a transient mild inflammatory state\nC_LIO_LIMild inflammation alters neurophysiological process associated with attention\nC_LIO_LIMild inflammation selectively increased alerting-related alpha suppression while behavior was unaffected\nC_LIO_LIA greater inflammatory response was correlated with more alpha suppression\nC_LI

neuroscience↗