RESUMEN

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.

RESUMEN

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.

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IgA nephropathy (IgAN) is a leading cause of kidney failure, yet little is known about the immunopathogenesis of this disease. IgAN is characterized by deposition of IgA in the kidney glomeruli, but the source and stimulus for IgA production are not known. Clinical and experimental data suggest a role for aberrant immune responses to mucosal microbiota in IgAN, and in some countries with high disease prevalence, tonsillectomy is regarded as standard-of-care therapy. To evaluate the relationship between microbiota and mucosal immune responses, we characterized the tonsil microbiota in patients with IgAN versus nonrelated household-matched control group participants and identified increased carriage of the genus Neisseria and elevated Neisseria-targeted serum IgA in IgAN patients. We reverse-translated these findings in experimental IgAN driven by BAFF overexpression in BAFF-transgenic mice rendered susceptible to Neisseria infection by introduction of a humanized CEACAM-1 transgene (B × hC-Tg). Colonization of B × hC-Tg mice with Neisseria yielded augmented levels of systemic Neisseria-specific IgA. Using a custom ELISPOT assay, we discovered anti-Neisseria-specific IgA-secreting cells within the kidneys of these mice. These findings suggest a role for cytokine-driven aberrant mucosal immune responses to oropharyngeal pathobionts, such as Neisseria, in the immunopathogenesis of IgAN. Furthermore, in the presence of excess BAFF, pathobiont-specific IgA can be produced in situ within the kidney.

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RESUMEN

Neisseria meningitidis causes a devastating invasive disease but is also a normal colonizer of the human nasopharynx. Due to the rapid progression of disease, the best tool to protect individuals against meningococcal infections is immunization. Clinical experience with polysaccharide conjugate vaccines has revealed that an ideal meningococcal vaccine must prevent both invasive disease and nasal colonization, which confers herd immunity. However, not all meningococcal vaccines are equal in their ability to prevent nasal colonization, for unknown reasons. Herein, we describe recent efforts to utilize humanized mouse models to understand the impact of different meningococcal vaccines on nasal colonization. These mice are susceptible to nasal colonization, and they become immune following live nasal infection or immunization with matched capsule-conjugate or protein-based vaccines, replicating findings from human work. We bring together insights regarding meningococcal colonization and immunity from clinical work with findings using humanized mouse models, providing new perspective into the different determinants of mucosal versus systemic immunity. Then, we use this as a framework to help focus future studies toward understanding key mechanistic aspects left unresolved, including the bacterial factors required for colonization and immune evasion, determinants of nasal mucosal protection, and characteristics of an ideal meningococcal vaccine.

RESUMEN

Background: The multicomponent meningococcal serogroup B vaccine (4CMenB) is an outer membrane vesicle and recombinant protein-based vaccine licensed to protect against serogroup B meningococcal disease. It remains unknown whether this vaccine will prevent carriage or transmission, key aspects in long-term vaccine success and disease eradication. Methods: Using a "humanized" transgenic mouse model of nasal colonization, we took a systematic approach to estimate the potential for carriage prevention against antigenically diverse Neisseria meningitidis strains and to compare this protection to an invasive meningococcal disease challenge model. Results: The 4CMenB vaccine prevented morbidity and mortality after lethal invasive doses of all meningococcal strains tested. Immunization effectively prevented carriage with only 1 of 4 single antigen-matched strains but reduced or prevented nasal colonization by all 4 isolates with multiple cross-reacting antigens. Each immunized mouse had substantial immunoglobulin G targeting the challenge strains, indicating that antibody correlates with protection against sepsis but not nasal carriage. Conclusions: Immunization with the 4CMenB vaccine elicits a robust humoral response that correlates with protection against invasive challenge but not with prevention of asymptomatic colonization. This suggests that widespread use of this vaccine will reduce morbidity and mortality rates in immunized individuals, with the potential to contribute to herd protection against a subset of strains.

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