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1.
Cell Microbiol ; 23(7): e13349, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33930228

RESUMEN

To study the dynamics of infection processes, it is common to manually enumerate imaging-based infection assays. However, manual counting of events from imaging data is biased, error-prone and a laborious task. We recently presented HRMAn (Host Response to Microbe Analysis), an automated image analysis program using state-of-the-art machine learning and artificial intelligence algorithms to analyse pathogen growth and host defence behaviour. With HRMAn, we can quantify intracellular infection by pathogens such as Toxoplasma gondii and Salmonella in a variety of cell types in an unbiased and highly reproducible manner, measuring multiple parameters including pathogen growth, pathogen killing and activation of host cell defences. Since HRMAn is based on the KNIME Analytics platform, it can easily be adapted to work with other pathogens and produce more readouts from quantitative imaging data. Here we showcase improvements to HRMAn resulting in the release of HRMAn 2.0 and new applications of HRMAn 2.0 for the analysis of host-pathogen interactions using the established pathogen T. gondii and further extend it for use with the bacterial pathogen Chlamydia trachomatis and the fungal pathogen Cryptococcus neoformans.


Asunto(s)
Infecciones por Chlamydia/diagnóstico por imagen , Criptococosis/diagnóstico por imagen , Interacciones Huésped-Patógeno , Procesamiento de Imagen Asistido por Computador/métodos , Toxoplasmosis/diagnóstico por imagen , Inteligencia Artificial , Línea Celular Tumoral , Humanos
2.
Blood ; 133(6): 600-604, 2019 02 07.
Artículo en Inglés | MEDLINE | ID: mdl-30401709

RESUMEN

Thrombosis is a frequent, life-threatening complication of systemic infection associated with multiple organ damage. We have previously described a novel mechanism of inflammation-driven thrombosis induced by Salmonella Typhimurium infection of mice. Thrombosis in the liver develops 7 days after infection, persisting after the infection resolves, and is monocytic cell dependent. Unexpectedly, thrombosis was not prominent in the spleen at this time, despite carrying a similar bacterial burden as the liver. In this study, we show that thrombosis does occur in the spleen but with strikingly accelerated kinetics compared with the liver, being evident by 24 hours and resolving rapidly thereafter. The distinct kinetics of thrombosis and bacterial burden provides a test of the hypothesis that thrombi form in healthy vessels to trap or remove bacteria from the circulation, often termed immunothrombosis. Remarkably, despite bacteria being detected throughout infected spleens and livers in the early days of infection, immunohistological analysis of tissue sections show that thrombi contain very low numbers of bacteria. In contrast, bacteria are present throughout platelet aggregates induced by Salmonella in vitro. Therefore, we show that thrombosis develops with organ-specific kinetics and challenge the universality of immunothrombosis as a mechanism to capture bacteria in vivo.


Asunto(s)
Hígado/microbiología , Infecciones por Salmonella/complicaciones , Salmonella typhimurium/patogenicidad , Bazo/microbiología , Trombosis/microbiología , Animales , Hígado/inmunología , Hígado/patología , Ratones , Ratones Endogámicos C57BL , Infecciones por Salmonella/microbiología , Bazo/inmunología , Bazo/patología , Trombosis/inmunología , Trombosis/patología
3.
Front Immunol ; 14: 1139329, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37033932

RESUMEN

Introduction: Vaccination with Vi capsular polysaccharide (Vi-PS) or protein-Vi typhoid conjugate vaccine (TCV) can protect adults against Salmonella Typhi infections. TCVs offer better protection than Vi-PS in infants and may offer better protection in adults. Potential reasons for why TCV may be superior in adults are not fully understood. Methods and results: Here, we immunized wild-type (WT) mice and mice deficient in IgG or IgM with Vi-PS or TCVs (Vi conjugated to tetanus toxoid or CRM197) for up to seven months, with and without subsequent challenge with Vi-expressing Salmonella Typhimurium. Unexpectedly, IgM or IgG alone were similarly able to reduce bacterial burdens in tissues, and this was observed in response to conjugated or unconjugated Vi vaccines and was independent of antibody being of high affinity. Only in the longer-term after immunization (>5 months) were differences observed in tissue bacterial burdens of mice immunized with Vi-PS or TCV. These differences related to the maintenance of antibody responses at higher levels in mice boosted with TCV, with the rate of fall in IgG titres induced to Vi-PS being greater than for TCV. Discussion: Therefore, Vi-specific IgM or IgG are independently capable of protecting from infection and any superior protection from vaccination with TCV in adults may relate to responses being able to persist better rather than from differences in the antibody isotypes induced. These findings suggest that enhancing our understanding of how responses to vaccines are maintained may inform on how to maximize protection afforded by conjugate vaccines against encapsulated pathogens such as S. Typhi.


Asunto(s)
Fiebre Tifoidea , Vacunas Tifoides-Paratifoides , Animales , Ratones , Salmonella typhi , Vacunas Conjugadas , Fiebre Tifoidea/prevención & control , Polisacáridos Bacterianos , Inmunoglobulina G , Formación de Anticuerpos , Inmunoglobulina M
4.
Nat Commun ; 11(1): 851, 2020 02 12.
Artículo en Inglés | MEDLINE | ID: mdl-32051408

RESUMEN

Lipopolysaccharide (LPS) O-antigen (O-Ag) is known to limit antibody binding to surface antigens, although the relationship between antibody, O-Ag and other outer-membrane antigens is poorly understood. Here we report, immunization with the trimeric porin OmpD from Salmonella Typhimurium (STmOmpD) protects against infection. Atomistic molecular dynamics simulations indicate this is because OmpD trimers generate footprints within the O-Ag layer sufficiently sized for a single IgG Fab to access. While STmOmpD differs from its orthologue in S. Enteritidis (SEn) by a single amino-acid residue, immunization with STmOmpD confers minimal protection to SEn. This is due to the OmpD-O-Ag interplay restricting IgG binding, with the pairing of OmpD with its native O-Ag being essential for optimal protection after immunization. Thus, both the chemical and physical structure of O-Ag are key for the presentation of specific epitopes within proteinaceous surface-antigens. This enhances combinatorial antigenic diversity in Gram-negative bacteria, while reducing associated fitness costs.


Asunto(s)
Anticuerpos Antibacterianos/inmunología , Proteínas de la Membrana Bacteriana Externa/química , Proteínas de la Membrana Bacteriana Externa/inmunología , Inmunización , Antígenos O/inmunología , Salmonella typhimurium/inmunología , Animales , Anticuerpos Antibacterianos/sangre , Formación de Anticuerpos , Especificidad de Anticuerpos , Antígenos Bacterianos/inmunología , Proteínas de la Membrana Bacteriana Externa/genética , Protección Cruzada , Modelos Animales de Enfermedad , Epítopos/química , Epítopos/inmunología , Inmunoglobulina G/sangre , Ratones , Modelos Moleculares , Antígenos O/química , Antígenos O/genética , Porinas/química , Porinas/genética , Porinas/inmunología , Conformación Proteica , Salmonelosis Animal/inmunología , Salmonelosis Animal/prevención & control , Análisis de Secuencia de Proteína
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