Biology subjects

Tang, C. M.

Publications and source records attributed to Tang, C. M..

9 recordsLinked to original sources

bioRxiv2026

Emergence of short-lived meningococci causing focal epidemics can be associated with gene transfer from carriage-associated Neisseria

In March 2026, an unusually large outbreak of invasive meningococcal disease (IMD) in Kent, UK, was linked to attendance at one nightclub over a single weekend. The outbreak organism was a Neisseria meningitidis variant belonging to the longstanding hyperinvasive genotype, cc41/44. Using genome analysis of six isolates from patients, alongside >48,000 meningococcal genomes, we investigated whether the outbreak variant had acquired traits potentially contributing to the highly invasive phenotype. The six isolates were capsular group B, sequence type (ST-)485, and essentially indistinguishable, consistent with the focal nature of the outbreak. Compared with their closest available relatives, we found changes mediated by phase variation, nucleotide variation, and horizontal gene transfer (HGT) involving adhesins, iron-acquisition systems (including Transferrin and Lactoferrin binding proteins, and FetA), and Type IV pili (Tfp), factors which affect bacteria-bacteria and bacteria-host interactions. These changes occurred in a ST-485 sub-lineage that expressed capsule at high levels and a PorA porin with a truncated surface-exposed epitope, both of which are predicted to reduce immune recognition. Donors for the HGT events were predominantly carriage-associated N. meningitidis and Neisseria cinerea. We show that meningococcal variants responsible for previous focal outbreaks have not been seen subsequently. We propose that focal outbreaks of IMD are caused by meningococcal variants that may have acquired traits from non- or less invasive organisms, but subsequently these variants disappear, as their highly invasive phenotype is inconsistent with sustained transmission. Ongoing disease surveillance alongside carriage studies are therefore essential to inform public health risk and manage epidemic IMD.

genomics↗

bioRxiv2026

A murine model of Shigella sonnei intestinal colonization

Shigella sonnei is a leading cause of bacterial dysentery and a high priority WHO pathogen because of the spread of multidrug resistant strains. Understanding microbiome-Shigella-host interactions during colonization of the gastrointestinal tract, and the development of vaccines have been hampered by the lack of small animal models of shigellosis. Here, we developed a murine model of intestinal colonization with S. sonnei. Pre-treatment of mice with antibiotics disturbed the intestinal microbiome and rendered mice susceptible to high level, gastrointestinal colonization with S. sonnei for over one week. Infection with S. sonnei CS14 harbouring a stable virulence plasmid induced an initial inflammatory response in wild type mice, with weight loss and elevated levels of fecal lipocalin 2; the S. sonnei Type III Secretion System was responsible for this inflammatory response. Expression of O-antigen and Group IV capsule by S. sonnei promoted sustained intestinal colonization, with infected mice developing mucosal and systemic antibody responses predominantly directed at these glycans. Finally, infection with S. sonnei induced a degree of protection against subsequent re-challenge. Overall, this murine model successfully mimics aspects of S. sonnei colonization and should be helpful in understanding how S. sonnei successfully survives within the gastrointestinal tract and competes with the microbiota as well as the evaluation of vaccine candidates.

microbiology↗

bioRxiv2026

Genomic epidemiology of Neisseria gonorrhoeae isolates from the G-ToG clinical trial, 2014-2016

Neisseria gonorrhoeae remains a major public health threat due to rising incidence and increasing antimicrobial resistance (AMR). To characterise the landscape of gonococci circulating in England a decade ago, we analysed whole genome sequences and clinical metadata from 354 isolates collected during the G-ToG clinical trial between 2014 and 2016. Comparison with global datasets demonstrated that the G-ToG isolates captured the breadth of UK gonococcal diversity, mapping across multiple lineages without evidence of marked bias related to participant demographic characteristics. The phylogenetic structure of gonococcal isolates within the collection was strongly shaped by sexual network, with statistically significant clustering of isolates circulating within heterosexual individuals compared with the men who have sex with men (MSM) transmission group. MSM-associated lineages exhibited higher minimum inhibitory concentration (MICs) to azithromycin and ceftriaxone and were enriched for corresponding chromosomal AMR determinants and AMR-associated plasmids. These data provide a valuable baseline preceding the implementation of several major UK public health interventions, including HIV pre-exposure prophylaxis (HIV PrEP), doxycycline post-exposure prophylaxis (Doxy-PEP) and vaccination with Bexsero. Continued integration of genomic and epidemiological surveillance will be essential to monitor whether these interventions reshape gonococcal transmission dynamics and AMR trajectories, guiding future control strategies.

genomics↗

bioRxiv2026

Phase-variable restriction modification systems dynamically regulate plasmid transmission in Neisseria gonorrhoeae

Horizontal gene transfer (HGT) in bacteria is shaped by restriction-modification systems (RMSs) that define genetic barriers between species and lineages. Neisseria gonorrhoeae harbours numerous RMS, most of which are part of its core genome. Here, we show that phase variation in these RMSs can limit interspecies and intraspecies plasmid exchange. While NlaIV likely influenced the acquisition of pConj from the meningococcus, phase variation of the NgoAV RMS produces epigenetically heterogeneous populations that present variable bottlenecks to within-species plasmid transmission, influencing the spread of anti-microbial-resistance plasmids, pConj and pbla. A LEAT sequence extends or retracts a molecular ruler within the HsdS specificity subunit, altering spacing of recognition motifs, while truncation of the protein leads to a switch from non-palindromic to palindromic recognition motifs. Thus, while the repertoire of gonococcal RMSs is largely conserved, phase-variation dynamically modulates gene flow, shaping plasmid transmission, and the evolution and spread of antimicrobial resistance.

microbiology↗

bioRxiv2025

An antibody-drug conjugate exploiting a bacterial immune evasion mechanism is effective against multidrug resistant Neisseria gonorrhoeae

Neisseria gonorrhoeae is the causative agent of gonorrhoea, a sexually transmitted infection which is rising in incidence, with increasing drug-resistant strains posing a significant public health threat. To address the urgent need for novel therapies, we developed an antibody-drug conjugate (ADC) that targets this important human pathogen. We utilised Tridecaptin A1 a potent antimicrobial peptide against Gram-negative bacteria but exhibits significant toxicity against human cells, limiting its development for clinical use. By conjugating the Tridecaptin A1 analogue, Oct-TriA1 to a monoclonal antibody (mAb) that specifically targets gonococcal MtrE, the outer membrane component of a drug efflux pump that is upregulated in resistant strains, we aim to deliver selectively deliver the antimicrobial peptide to the gonococcus. However, Oct-TriA1 was not bactericidal when directly conjugated to mAb. To circumvent this, we exploited an immune evasion mechanism employed by the gonococcus by introducing a linker between Oct-TriA1 and the mAb which is specifically cleaved by the IgA protease (IgAP) secreted by the gonococcus; the IgAP inactivates human IgA. This ADC has no detectable toxicity for relevant human cells, kills the gonococcus in an MtrE- and IgAP-dependent manner, and is active against a strain which is resistant to first line agents. This modular ADC platform could be extended to other bacterial pathogens which employ proteases that use proteases to evade immune killing, offering a new strategy in the fight against antimicrobial resistance.

microbiology↗

bioRxiv2025

The origin and evolution of the gonococcal beta-lactamase plasmid, and implications for public health

Neisseria gonorrhoeae is a leading cause of sexually transmitted infection (STI) and a priority AMR pathogen. Two narrow host range plasmids, pbla and pConj, have contributed to ending penicillin and tetracycline therapy, respectively, and undermine current prevention strategies including Doxy-PEP. Here, we investigated the origin and evolution of the beta-lactamase plasmid, pbla. We show that the interplay between pbla and pConj influences their co-occurrence and the spread of pbla in the gonococcal population. We demonstrate that pbla was acquired by the gonococcus on at least two occasions from Haemophilus ducreyi, and describe the subsequent evolutionary pathways taken by the three major pbla variants. Changes that mitigate fitness costs of pbla and the emergence of TEM beta-lactamases which confer increased resistance have contributed to the success of pbla. In particular, TEM-135, which has arisen in certain pbla variants, increases resistance to beta-lactams and only requires one amino acid change to become an extended spectrum beta-lactamase (ESBL). The evolution of pbla underscores the threat of plasmid-mediated resistance to current therapeutic and preventive strategies against gonococcal infection. Given the close relationship between pbla and pConj, widespread use of Doxy-PEP is likely to promote spread of pConj and pbla, and emergence of plasmid-mediated ESBL in the gonococcus, with dire public health consequences.

microbiology↗

bioRxiv2020

Type VI secretion system killing by commensal Neisseria is influenced by the spatial dynamics of bacteria

Type VI Secretion Systems (T6SS) are widespread in bacteria and can dictate the development and organisation of polymicrobial ecosystems by mediating contact dependent killing. In Neisseria species, including Neisseria cinerea a commensal of the human respiratory tract, interbacterial contacts are mediated by Type four pili (Tfp) which promote formation of aggregates and govern the spatial dynamics of growing Neisseria microcolonies. Here we show that N. cinerea expresses a plasmid-encoded T6SS that is active and can limit growth of related pathogens. We explored the impact of Tfp expression on N. cinerea T6SS-dependent killing and show that expression of Tfp by prey strains enhances their susceptibility to T6SS, by keeping them in close proximity of T6SS-wielding attacker strains. Our findings have important implications for understanding how spatial constraints during contact-dependent antagonism can shape the evolution of microbial communities.

microbiology↗

bioRxiv2020

The role of toxin:antitoxin systems and insertion sequences in the loss of virulence in Shigella sonnei

The Shigella plasmid, pINV, contains a 30 kb pathogenicity island (PAI) encoding a Type III secretion system (T3SS) which is essential for virulence. During growth in the laboratory, avirulent colonies of Shigella (which do not express a T3SS) arise spontaneously. Avirulence in Shigella flexneri mostly follows loss of the PAI, following recombination between insertion sequences (ISs) on pINV; toxin:antitoxin (TA) systems on pINV promote its retention through post-segregational killing (PSK). We show that avirulence in Shigella sonnei mainly results from plasmid loss, consistent with previous findings; IS-mediated PAI deletions can occur in S. sonnei, but through different ISs than in S. flexneri. We investigated the molecular basis for frequent loss of the S. sonnei plasmid, pINVSsonn. Introduction into pINVSsonn of CcdAB and GmvAT, toxin:antitoxin TA systems in pINV from S. flexneri but not S. sonnei, reduced plasmid loss and the emergence of avirulent bacteria. However, plasmid loss remained the leading cause of avirulence. We show that a single amino acid difference in the VapC toxin of the VapBC TA system in pINV also contributes to high frequency plasmid loss in S. sonnei compared to S. flexneri. Our findings demonstrate that the repertoire of ISs, complement of TA systems, and polymorphisms in TA systems influence plasmid dynamics and virulence loss in S. sonnei. Understanding the impact of polymorphisms should be informative about how TA systems contribute to PSK, and could be exploited for generating strains with stable plasmids.

microbiology↗

bioRxiv2017

Structural Design of Chimeric Antigens for Multivalent Protein Vaccines

The development of prophylactic vaccines against pathogenic bacteria is a major objective of the World Health Organisation. However, vaccine development is often hindered by antigenic diversity and the difficulties encountered manufacturing immunogenic membrane proteins. Here, we employed structure-based design as a strategy to develop Chimeric Antigens (ChAs) for subunit vaccines. ChAs were generated against serogroup B Neisseria meningitidis (MenB), the predominant cause of meningococcal disease in the Western hemisphere. MenB ChAs exploit the lipoprotein factor H binding protein (fHbp) as a molecular scaffold to display the immunogenic VR2 epitope from the integral membrane protein PorA. Structural analyses demonstrate fHbp is correctly folded and that PorA VR2 epitope adopts an immunogenic conformation. In mice, ChAs elicit antibodies directed against fHbp and PorA, with antibody responses correlating to protection against meningococcal disease. ChAs offer a novel approach for generating multivalent subunit vaccines, containing of epitopes from integral membrane proteins, whose composition can be selected to circumvent pathogen diversity.

molecular biology↗