Biology subjects

Currie, E. G.

Publications and source records attributed to Currie, E. G..

4 recordsLinked to original sources

bioRxiv2024

Adjuvant-dependent impacts on vaccine-induced humoral responses and protection in preclinical models of nasal and genital colonization by pathogenic Neisseria

Neisseria gonorrhoeae, which causes the sexually transmitted infection gonorrhea and N. meningitidis, a leading cause of bacterial meningitis and septicemia, are closely related human-restricted pathogens that inhabit distinct primary mucosal niches. While successful vaccines against invasive meningococcal disease have been available for decades, the rapid rise in antibiotic resistance has led to an urgent need to develop an effective gonococcal vaccine. Several surface antigens are shared among these two pathogens, making cross-species protection an exciting prospect. However, the type of vaccine-mediated immune response required to achieve protection against respiratory versus genital infection remains ill defined. In this study, we utilize well established mouse models of female lower genital tract colonization by N. gonorrhoeae and upper respiratory tract colonization by N. meningitidis to examine the performance of transferrin binding protein B (TbpB) vaccines formulated with immunologically distinct vaccine adjuvants. We demonstrate that vaccine-mediated protection is influenced by the choice of adjuvant, with Th1/2-balanced adjuvants performing optimally against N. gonorrhoeae, and both Th1/2-balanced and Th2-skewing adjuvants leading to a significant reduction in N. meningitidis burden. We further establish a lack of correlation between protection status and the humoral response or bactericidal titre. Combined, this work provides supports the feasibility for a single vaccine formulation to achieve pan-neisserial coverage.

immunology↗

bioRxiv2024

Protection against Neisseria meningitidis nasopharyngeal colonization relies on antibody opsonization and phagocytosis by neutrophils

Neisseria meningitidis is a human-restricted pathogen that can cause a rapidly progressing invasive meningococcal disease, yet it is also a regular inhabitant of the human nasopharynx. Vaccines that target N. meningitidis aim to prevent invasive disease, but their ability to interfere with nasal colonization could effectively eradicate this bacteria in a population, and so is an important target for meningococcal vaccine design. While protection against invasive meningococcal disease is classically attributed to IgG-dependent complement activation and bacterial killing, there remains no indication of what confers protection against nasopharyngeal colonization, making it impossible to deliberately target this stage during vaccine development. Moreover, without understanding what confers protection in this tissue site, it is impossible to understand the level of susceptibility within a population. To address this, we have taken advantage of the CEACAM1-humanized mouse model to characterize immune effectors that protect against nasal carriage of N. meningitidis. Protection against nasal colonization could be induced by live mucosal infection or by parenteral immunization with heat-killed bacteria. Mice possessing genetic deficiencies in B cells were used to evaluate the role of B cells and a specific antibody response, while neutrophil and complement depletion were used to evaluate their respective contributions to immunization-induced protection against meningococcal nasal carriage. Despite the essential role for complement killing in preventing invasive meningococcal disease, complement was not required for protection against nasal colonization. Instead, N. meningitidis-specific antibodies and neutrophils were both required to protect mice against the nasal infection. Combined, these data suggest that phagocytic bacterial killing is necessary for protection against mucosal colonization by N. meningitidis, indicating that nasal immunoglobulin with the ability to promote opsonophagocytosis must be considered as a correlate of protection against meningococcal carriage. AUTHORS SUMMARYNeisseria meningitidis can cause devastating and often fatal systemic infections including sepsis and meningitis, yet it frequently lives in the throat of healthy individuals. Vaccines developed against some meningococcal strains allow the individual to resist becoming colonized by the bacteria, an effect that protects them from disease and prevents them from spreading the bacteria to others, while other vaccines effectively protect against disease but still allow the individual to carry the bacteria in their throat. The reason for this difference has remained difficult to explain. Here, we use a humanized mouse model that allows N. meningitidis infection in the nasal passages to establish that effective protection against nasal colonization requires that antibodies present within the infected mucosal tissues can coat the bacteria so that they are engulfed by neutrophils, a potent bacteria-killing white blood cell that is recruited to the site of infection. These findings suggest that antibodies with the ability to promote neutrophil recognition and killing of N. meningitidis should be the goal of future vaccines, and the presence of these can be used to consider an individuals resistance against this terrible pathogen.

microbiology↗

bioRxiv2024

Rational selection of TbpB variants elucidates a bivalent vaccine formulation with broad spectrum coverage against Neisseria gonorrhoeae

Neisseria gonorrhoeae is the causative agent of gonorrhea, an on-going public health problem due in part to the lack of success with efforts to develop an efficacious vaccine to prevent this sexually transmitted infection. An attractive candidate vaccine antigen because of its essential function and surface exposure, the gonococcal transferrin binding protein B (TbpB) exhibits high levels of antigenic variability which poses a significant obstacle in evoking a broadly protective vaccine composition. Here, we utilize phylogenetic information to rationally select TbpB variants for inclusion into a potential gonococcal vaccine and identify two TbpB variants that when formulated together elicit a highly cross-reactive antibody response in both rabbits and mice against a diverse panel of TbpB variants and clinically relevant gonococcal strains. Further, this formulation performed well in experimental proxies of real-world usage, including eliciting bactericidal activity against 8 diverse gonococcal strains and decreasing the median duration of colonization after vaginal infection in female mice by two heterologous strains of N. gonorrhoeae. Together, these data support the use of a combination of TbpB variants for a broadly protective gonococcal vaccine.

microbiology↗

bioRxiv2024

Human transferrin and lactoferrin cooperatively support Neisseria meningitidis colonization in the murine nasopharynx

Neisseria meningitidis is a human-restricted bacteria that is a normal nasopharyngeal resident, yet it can also disseminate, causing invasive meningococcal disease. Meningococci are highly adapted to life in humans, with human-specific virulence factors contributing to bacterial adhesion, nutrient acquisition and immune evasion. While these factors have been explored in isolation, their relative contribution during infection has not been considered due to their absence in small animal models and their expression by different human cell types not readily combined in either in vitro or ex vivo systems. Herein, we show that transgenic expression of the iron-binding glycoproteins human transferrin and lactoferrin can each facilitate N. meningitidis replication in mouse serum but that transferrin was required to support infection-induced sepsis. While these host proteins are insufficient to allow nasopharyngeal colonization alone, mice co-expressing these and human CEACAM1 support robust colonization. In this case, meningococcal colonization elicits an acute elevation in both transferrin and lactoferrin levels within the upper respiratory mucosa, with transferrin levels remaining elevated while lactoferrin returns to basal levels after establishment of infection. Competitive infection of triple transgenic animals with transferrin- and lactoferrin- binding protein mutants selects for bacteria expressing the transferrin receptor, implicating the critical contribution of transferrin-based iron acquisition to support colonization. These transgenic animals have thus allowed us to disentangle the relative contribution of three virulence factors during colonization and invasive disease, and provides a novel in vivo model that can support extended meningococcal colonization, opening a new avenue to explore the meningococcal lifestyle within its primary niche.

microbiology↗