Biology subjects

Lee, I. S.

Publications and source records attributed to Lee, I. S..

4 recordsLinked to original sources

bioRxiv2024

Meningococcal vaccine Bexsero elicits a robust cellular immune response that targets but is not consistently protective against Neisseria gonorrhoeae during murine vaginal infection

Retrospective epidemiological studies suggest that the licensed serogroup B meningococcal vaccine 4CMenB (Bexsero) provides some protection against the closely related pathogen Neisseria gonorrhoeae in humans. This result has been replicated in murine models of gonococcal colonization, with a gonococci-reactive humoral response and more rapid clearance of vaginal infection. However, immunization with Bexsero consistently elicits a robust humoral response but does not protect all individuals, so the correlates of protection remain undefined. Herein, we exploit the fact that Bexsero promotes clearance in only a subset of immunized mice to perform a broad analysis of the adaptive response in animals that are or are not protected. We observe that Bexsero vaccination induces high levels of anti-neisserial antibodies in both serum and the vaginal lumen, and a robust cellular response highlighted by an increase in both conventional naive and memory populations as well as unconventional lymphocyte subsets. Multiplex and flow cytometry results show that Bexsero vaccination generates a robust, multi-faceted cytokine response that spans numerous T cell subsets (TH1, TH2, Treg and TH17 responses) and that non-T non-B lymphocytes play an important role in this response, as indicated by an unbiased principal component analysis. Together, this work provides the first comprehensive analysis of the robust humoral and complex cellular response to Bexsero so as to reveal the effector mechanisms that may contribute to immunity against vaginal gonococcal infection.

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

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↗

bioRxiv2017

Histone Deacetylase 7 Mediates Tissue-Specific Autoimmunity via Control of Innate Effector Function in Invariant Natural Killer T-Cells

We report that Histone Deacetylase 7 (HDAC7) controls the thymic effector programming of Natural Killer T (NKT) cells, and that interference with this function contributes to tissue-specific autoimmunity. Gain of HDAC7 function in thymocytes blocks both negative selection and NKT development, diverting these cells into a Tconv-like lineage. Conversely, HDAC7 deletion promotes thymocyte apoptosis and causes aberrant expansion of innate-effector cells. Investigating the mechanisms involved, we found that HDAC7 binds PLZF and modulates PLZF-dependent transcription. Moreover, HDAC7 and many of its transcriptional targets are human risk loci for IBD and PSC, autoimmune diseases that strikingly resemble the disease we observe in HDAC7 gain-of-function in mice. Importantly, reconstitution of iNKT cells in these mice abrogated their disease, suggesting that interaction between the defects in negative selection and iNKT cells caused by altered HDAC7 function can cause tissue-restricted autoimmunity, a finding that may explain the association between HDAC7 and hepatobiliary autoimmunity.

immunology↗