Biology subjects

Ingram, R.

Publications and source records attributed to Ingram, R..

4 recordsLinked to original sources

bioRxiv2026

Spacing theta-burst stimulation enhances synaptic potentiation in the vulnerable prefrontal cortex

Neuromodulation with intermittent theta-burst stimulation (iTBS) is a clinical treatment for major depression. One postulated mechanism of iTBS is to strengthen the synaptic connections which activate the prefrontal cortex to regulate mood. With ex vivo electrical stimulation and neuronal calcium imaging, we demonstrate that a common, clinical iTBS pattern (600-stimuli, ~3-minutes) reliably strengthens the synaptic recruitment of the adult mouse prefrontal cortex. This synaptic potentiation, however, becomes less reliable in the depressive-like mouse model of prolonged social isolation. To better understand this change, we examine the impact of social isolation on the complex pattern of calcium elevation during clinical iTBS. In social isolation, the calcium peaks rise more prominently, but the induction peak no longer predicts the synaptic potentiation outcome. To better regulate calcium dynamics during induction, we test a paradigm with fewer iTBS episodes, separated by longer intervals. This spaced iTBS (90-stimuli, ~10-minutes) in the adult prefrontal cortex limits calcium elevation during induction and yields reliable long-term potentiation (LTP) following either juvenile- or adult-onset social isolation. This research illustrates new strategies to interrogate and to enhance synaptic plasticity in the vulnerable prefrontal cortex.

neuroscience↗

bioRxiv2021

Klebsiella pneumoniae hijacks the Toll-IL-1R protein SARM1 in a type I IFN-dependent manner to antagonize host immunity.

Many bacterial pathogens antagonize host defence responses by translocating effector proteins into cells. It remains an open question how those pathogens not encoding effectors counteract anti-bacterial immunity. Here, we show that Klebsiella pneumoniae hijacks the evolutionary conserved innate immune protein SARM1 to control cell intrinsic immunity. Klebsiella exploits SARM1 to regulate negatively MyD88 and TRIF-governed inflammation, and the activation of the MAP kinases ERK and JNK. SARM1 is required for Klebsiella induction of IL10 by fine-tuning the p38-type I IFN axis. SARM1 inhibits the activation of Klebsiella-induced absent in melanoma 2 inflammasome to limit IL1{beta} production, suppressing further inflammation. Klebsiella exploits type I IFNs to induce SARM1 in a capsule and LPS O-polysaccharide-dependent manner via TLR4-TRAM-TRIF-IRF3-IFNAR1 pathway. Absence of SARM1 reduces the intracellular survival of K. pneumonaie in macrophages whereas sarm1 deficient mice control the infection. Altogether, our results illustrate a hitherto unknown anti-immunology strategy deployed by a human pathogen.

microbiology↗

bioRxiv2019

HLA class II polymorphism influences the immune response to protective antigen and susceptibility to Bacillus anthracis

The causative agent of anthrax, Bacillus anthracis, evades the host immune response and establishes infection through the production of binary exotoxins composed of Protective Antigen (PA) and one of two subunits, lethal factor (LF) or edema factor (EF). The majority of vaccination strategies have focused upon the antibody response to the PA subunit. We have used a panel of humanised HLA class II transgenic mouse strains to define HLA-DR-restricted and HLA-DQ-restricted CD4+ T cell responses to the immunodominant epitopes of PA. This was correlated with the binding affinities of epitopes to HLA class II molecules, as well as the responses of two human cohorts: individuals vaccinated with the Anthrax Vaccine Precipitated (AVP) vaccine (which contains PA and trace amounts of LF), and patients recovering from cutaneous anthrax infections. The infected and vaccinated cohorts expressing different HLA types were found to make CD4+ T cell responses to multiple and diverse epitopes of PA. The effects of HLA polymorphism were explored using transgenic mouse lines, which demonstrated differential susceptibility, indicating that HLA-DR1 and HLA-DQ8 alleles conferred protective immunity relative to HLA-DR15, HLA-DR4 and HLA-DQ6. The HLA transgenics enabled a reductionist approach, allowing us to better define CD4+ T cell epitopes. Appreciating the effects of HLA polymorphism on the variability of responses to natural infection and vaccination will be vital in planning protective strategies against anthrax. Author SummaryThe bacterium responsible for causing the disease anthrax, Bacillus anthracis, produces a binary toxin composed of Protective Antigen (PA) and either Lethal Factor (LF) or Edema Factor (EF). Previous vaccination strategies have focused upon the antibody response to the PA subunit. However, within the field of bacterial immunity, there is a growing appreciation of the importance of the adaptive immune response, specifically led by CD4+ T cells. We identified long-term CD4+ T cell responses to PA epitopes following cutaneous human anthrax infection and vaccination, indicating that this toxin component is a principle B. anthracis antigen. To characterise the impact of polymorphism in HLA class II alleles at DR and DQ loci, we used transgenic mice to map the immunodominant epitopes from PA. This was correlated with survival in the transgenic lines following live anthrax challenge. We were able to demonstrate the differential impact of HLA class II alleles upon the CD4+ T cell immunodominant epitopes which shaped the immune hierarchy and therefore susceptibility to anthrax infection.

immunology↗

bioRxiv2018

Modulation of antibiotic sensitivity and biofilm formation in Pseudomonas aeruginosa by interspecies diffusible signal factor analogues

The opportunistic pathogen Pseudomonas aeruginosa can participate in inter-species communication through signaling by cis-2-unsaturated fatty acids of the diffusible signal factor (DSF) family. Sensing these signals involves the histidine kinase PA1396 and leads to altered biofilm formation and increased tolerance to various antibiotics. Here, we show that the membrane-associated sensory input domain of PA1396 has five trans-membrane helices, two of which are required for DSF sensing. DSF binding is associated with enhanced auto-phosphorylation of PA1396 incorporated into liposomes. Further, we examined the ability of synthetic DSF analogues to modulate or inhibit PA1396 activity. Several of these analogues block the ability of DSF to trigger auto-phosphorylation and gene expression, whereas others act as inverse agonists reducing biofilm formation and antibiotic tolerance, both in vitro and in murine infection models. These analogues may thus represent lead compounds for novel adjuvants to improve the efficacy of existing antibiotics.

microbiology↗