Early-life immunity and susceptibility to Mycobacteria

dc.contributor.advisorHorsnell, William
dc.contributor.advisorHatherill, Mark
dc.contributor.advisorCunningham, Adam F
dc.contributor.authorLogan, Erin
dc.date.accessioned2019-02-01T10:45:55Z
dc.date.available2019-02-01T10:45:55Z
dc.date.issued2018
dc.date.updated2019-02-01T10:41:56Z
dc.description.abstractThe naïve and not-yet developed infant immune system exhibits heightened susceptibility to external factors (e.g pathogens), and is shaped by these and others, such as maternal immunity. However, we do not yet fully understand their impact on development of infant immunity. A better understanding of these effects would benefit children world-wide, but especially those in low-middle income countries (LMIC), where increased exposure to pathogens due to poorer living conditions highlights the necessity of robust early-life immunity. Mycobacterium tuberculosis (Mtb) and helminths are pathogens co-endemic in many LMIC and cause significant morbidity and mortality in children. Infant immune responses to these pathogens, whether during standalone infection, co-infection or resulting from maternal infection are not fully understood. To contribute to this knowledge gap, we investigated early-life immune responses, how they relate to childhood Mtb/helminth infection and how they are affected by maternal infectious history and immunity. Analysis of clinical humoral responses revealed total IgG that increased significantly between baseline and tuberculosis (TB) investigation in infants who did not acquire Mtb infection; these infants also exhibited raised levels of measles-specific IgG and BCG-specific IgG2. No active helminth infections were detected, but the presence of Ascaris lumbricoides- and Trichuris trichiura-specific class-switched antibodies indicated prior exposure. No association was found between helminth-specific humoral responses and risk of Mtb infection, nor with maternal helminth-specific humoral responses. Conversely, data from murine experiments revealed a protective effect of maternal helminth infection (Nippostrongylus brasiliensis) on BCG infection in offspring, with reduced lung bacterial burden and increased numbers of activated CD4+ T cells and B cells. Maternal Nb infection may have a synergistic effect on BCG vaccination, as BCGvaccinated/infected pups from Nb-infected mothers had reduced lung bacterial burdens, increased CD4+ T cell and B cell responses and increased IFNγ-producing CD4+ T cells. Findings from this study suggest that childhood vaccines could provide heterologous protection against unrelated pathogens such as Mtb. The murine data suggest a protective effect of maternal helminth infection against BCG infection in offspring, but no similar finding was observed with the clinical data. The clear protective effect of maternal Nb infection during offspring BCG infection warrants a more in-depth clinical study addressing the functional effects of maternal helminth infection on Mtb infection outcome in infants.
dc.identifier.apacitationLogan, E. (2018). <i>Early-life immunity and susceptibility to Mycobacteria</i>. (). University of Cape Town ,Faculty of Health Sciences ,Department of Pathology. Retrieved from http://hdl.handle.net/11427/29195en_ZA
dc.identifier.chicagocitationLogan, Erin. <i>"Early-life immunity and susceptibility to Mycobacteria."</i> ., University of Cape Town ,Faculty of Health Sciences ,Department of Pathology, 2018. http://hdl.handle.net/11427/29195en_ZA
dc.identifier.citationLogan, E. 2018. Early-life immunity and susceptibility to Mycobacteria. University of Cape Town.en_ZA
dc.identifier.ris TY - Thesis / Dissertation AU - Logan, Erin AB - The naïve and not-yet developed infant immune system exhibits heightened susceptibility to external factors (e.g pathogens), and is shaped by these and others, such as maternal immunity. However, we do not yet fully understand their impact on development of infant immunity. A better understanding of these effects would benefit children world-wide, but especially those in low-middle income countries (LMIC), where increased exposure to pathogens due to poorer living conditions highlights the necessity of robust early-life immunity. Mycobacterium tuberculosis (Mtb) and helminths are pathogens co-endemic in many LMIC and cause significant morbidity and mortality in children. Infant immune responses to these pathogens, whether during standalone infection, co-infection or resulting from maternal infection are not fully understood. To contribute to this knowledge gap, we investigated early-life immune responses, how they relate to childhood Mtb/helminth infection and how they are affected by maternal infectious history and immunity. Analysis of clinical humoral responses revealed total IgG that increased significantly between baseline and tuberculosis (TB) investigation in infants who did not acquire Mtb infection; these infants also exhibited raised levels of measles-specific IgG and BCG-specific IgG2. No active helminth infections were detected, but the presence of Ascaris lumbricoides- and Trichuris trichiura-specific class-switched antibodies indicated prior exposure. No association was found between helminth-specific humoral responses and risk of Mtb infection, nor with maternal helminth-specific humoral responses. Conversely, data from murine experiments revealed a protective effect of maternal helminth infection (Nippostrongylus brasiliensis) on BCG infection in offspring, with reduced lung bacterial burden and increased numbers of activated CD4+ T cells and B cells. Maternal Nb infection may have a synergistic effect on BCG vaccination, as BCGvaccinated/infected pups from Nb-infected mothers had reduced lung bacterial burdens, increased CD4+ T cell and B cell responses and increased IFNγ-producing CD4+ T cells. Findings from this study suggest that childhood vaccines could provide heterologous protection against unrelated pathogens such as Mtb. The murine data suggest a protective effect of maternal helminth infection against BCG infection in offspring, but no similar finding was observed with the clinical data. The clear protective effect of maternal Nb infection during offspring BCG infection warrants a more in-depth clinical study addressing the functional effects of maternal helminth infection on Mtb infection outcome in infants. DA - 2018 DB - OpenUCT DP - University of Cape Town LK - https://open.uct.ac.za PB - University of Cape Town PY - 2018 T1 - Early-life immunity and susceptibility to Mycobacteria TI - Early-life immunity and susceptibility to Mycobacteria UR - http://hdl.handle.net/11427/29195 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/29195
dc.identifier.vancouvercitationLogan E. Early-life immunity and susceptibility to Mycobacteria. []. University of Cape Town ,Faculty of Health Sciences ,Department of Pathology, 2018 [cited yyyy month dd]. Available from: http://hdl.handle.net/11427/29195en_ZA
dc.language.isoeng
dc.publisher.departmentDepartment of Pathology
dc.publisher.facultyFaculty of Health Sciences
dc.publisher.institutionUniversity of Cape Town
dc.subject.otherpathology
dc.titleEarly-life immunity and susceptibility to Mycobacteria
dc.typeDoctoral Thesis
dc.type.qualificationlevelDoctoral
dc.type.qualificationnamePhD
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