Early-life immunity and susceptibility to Mycobacteria

Doctoral Thesis


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University of Cape Town

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.