Biology subjects

Hurst, J. R.

Publications and source records attributed to Hurst, J. R..

3 recordsLinked to original sources

bioRxiv2025

Resolution of the circulating pathogenic phenotype of alpha-1 antitrypsin deficiency following liver transplantation

Alpha-1 antitrypsin is a member of the serpin family of protease inhibitors and normally found in monomeric form at high concentration in the circulation. Certain pathogenic variants of this protein self-assemble into flexible chains (polymers) that undergo toxic accumulation in the liver, underlying the development of liver disease, and a corresponding functional deficiency in circulation results in a susceptibility to chronic damage to the lungs and thereby COPD. A proportion of these polymers are detectable in the circulation. This study aimed to provide data on the dynamics of AAT monomers and polymers in the circulation after correction of a deficiency state by liver transplantation. The evolution of the circulating AAT phenotype was characterised quantitatively over time by analysis of blood samples taken pre- and post-liver transplant from three PiZZ AAT deficiency patients, using a panel of conformer-specific monoclonal antibodies and a novel ELISA with enhanced sensitivity for AAT polymers. Circulating wild-type M AAT was found to increase with a half-time of 29-39 h, attaining a clinically-defined putative protective threshold level within 24-50 h post-transplant. Baseline circulating polymer levels ranged from 5-35 g/mL with a half-time clearance of 3-12 h following transplant, and levels were indistinguishable from reference wild-type plasma 22 months post-surgery. The glycosylation profile and disappearance of detectable circulating polymers of AAT were consistent with their origin in, and canonical secretion by, the liver. To our knowledge this is the first post-transplant evaluation of the hybrid conformational profile of endogenous and donor tissue-derived AAT.

pathology↗

bioRxiv2025

Characterising the microbial and antimicrobial resistance signatures of hospital-acquired pneumonia using nanopore metagenomic sequencing

Hospital-acquired pneumonia (HAP) is a significant burden in nosocomial settings, yet its microbial underpinnings remain poorly understood. Here, we leverage shotgun nanopore sequencing to characterise the respiratory microbiomes of 250 HAP patients in a UK multi-site cohort, validating these using paired PCR and culture assays. Sequencing identified the dominant microbes implicated in HAP, including detection of probable pathogens in 49 PCR- and culture-negative cases. We found a high prevalence of fungi in 81/239 (34%) in HAP patients, of whom 26/81 (32%) were PCR/culture-negative, suggesting that fungi may represent an under-investigated component of HAP, whether as colonists or pathogens. Although HAP is clinically sub-categorised based on the use and duration of ventilation before disease onset, we found that the microbial profiles of these sub-groups were indistinguishable. We also found a concerningly high proportion of multi-drug-resistant microbes in HAP patients, with 21% of assembled bacterial genomes harbouring acquired antimicrobial resistance (AMR) genes that confer resistance to at least three classes of antimicrobials. This included high AMR gene carriage associated to Staphylococcus epidermidis, which may be an important reservoir of AMR, though typically viewed as a commensal. Our work provides extensive metagenomic characterisation of HAP, underscores the value of metagenomics in describing its complex aetiology, and further prompts its potential role for pathogen detection, resistance profiling and treatment.

microbiology↗

bioRxiv2022

The Streptococcus pyogenes hyaluronic acid capsule promotes experimental nasal and skin infection by preventing neutrophil-mediated clearance

Streptococcus pyogenes is a globally prominent human-specific pathogen responsible for an enormous burden of human illnesses, including >600 million pharyngeal and >100 million skin infections each year. Despite intensive efforts that focus on invasive indications, much remains unknown about this bacterium in its natural state during colonization of the nasopharynx and skin. Using acute experimental infection models in HLA-transgenic mice, we evaluated how the hyaluronic acid (HA) capsule contributes to S. pyogenes MGAS8232 infection within these limited biological niches. Herein, we demonstrate that HA capsule expression promotes bacterial burden in murine nasal turbinates and skin lesions by resisting neutrophil-mediated killing. HA capsule production is encoded by the hasABC operon and compared to wildtype S. pyogenes infections, mice infected with a {Delta}hasA mutant exhibited over a 1000-fold CFU reduction at 48-hours post{-}nasal challenge, and a 10,000-fold CFU reduction from skin lesions 72-hours post-skin challenge. HA capsule expression contributed substantially to skin lesion size development following subdermal inoculations. In the absence of capsule expression, S. pyogenes revealed drastically impeded growth in whole human blood and increased susceptibility to killing by isolated neutrophils ex vivo, highlighting its important role in resisting phagocytosis. Furthermore, we establish that neutrophil depletion in mice, but not macrophage depletion, recovered the reduced burden by the {Delta}hasA mutant in both the nasopharynx and skin. Together, this work confirms that the HA capsule is a key virulence determinant during acute infections by S. pyogenes and demonstrates that its predominant function is to protect S. pyogenes against neutrophil-mediated killing. AUTHOR SUMMARYStreptococcus pyogenes is a globally disseminated and human-adapted bacterial pathogen that has evolved an arsenal of evasion strategies to overcome and escape host immune clearing mechanisms. Many strains of S. pyogenes are covered by a polysaccharide capsule composed of hyaluronic acid (HA) that is widely recognized to promote severe infections. In this study, we demonstrate using the encapsulated S. pyogenes MGAS8232 strain that the HA capsule is a key virulence factor that facilitates non-invasive infections of the nasopharynx and skin. Although bacterial adhesion and entry into host cells was impeded by HA capsule expression, we show that the key function for both nasal and skin infections is to protect S. pyogenes from neutrophil-mediated killing. Depletion of neutrophils, but not macrophages, recovered the low bacterial burden by unencapsulated S. pyogenes at both sites of infection. Our findings outline an important interaction between the HA capsule and neutrophils in the establishment of acute upper respiratory and skin infections by S. pyogenes.

microbiology↗