| It has been hypothesised that the regulation of human life histories is explained by the disposable soma theory, which postulates that investments in survival are traded against investments in reproduction. We consider the innate immune system as one of the main regulatory mechanisms that can explain for this trade-off. After all, a strong immune response offers protection against, amongst other things dangers, mortality from infection, whereas it increases the risk of a prematurely interrupted pregnancy. Here, we argue that this immunogenetic trade-off is best being studied in a population living under adverse conditions where infection is the main cause of death. In the present work we propose to perform a combined cross-sectional and longitudinal study in Bawku-East, an underdeveloped area in the Upper East Region of Ghana. We have previously shown for women living in this area that fecundity is inversely related with the proportional survival of their offspring. This confirms, at least at the phenotypic level, that investments in reproduction trades off with early survival. The first aim of the present proposal is to characterise the innate immune responses of hyper- versus hypofertile women. Hereto, we will perform ex vivo whole blood stimulations with bacterial lipopolysaccharide (LPS) in a series of 500 women and study these cytokine profiles (including Tumour Necrosis Factor-alpha and Interleukin-10) in association with the variation in reproductive success and proportional child survival. Second, the contribution of candidate genes will be studied by identifying polymorphisms that associate with the responsiveness of the innate immune system, and those of the Toll-like receptor system and Interleukin-10 in particular. Genetic variation in these receptors and interleukins has already been associated with variation in cytokine profiles and fertility histories of women under affluent conditions. Third, in a longitudinal study we aim to confirm that these genetic markers, as identified in the women, predict early survival of children. Hereto, we will include four cohorts of newborns (in total approximately 3000 children) that will be followed for survival dependent on their genetic background. We expect to provide evidence that under adverse conditions there is selection for a pro-inflammatory response pattern. This knowledge adds to our basic understanding of host defence mechanisms and may offer new strategies to combat infectious diseases. Moreover, knowledge on the regulation of human life histories under adverse conditions is key to comprehend and anticipate on the expression of chronic diseases under new, affluent conditions. |
