Sara van den Berg

215 8 General discussion of the immune system, would include a moderate, modulatory role of CMV [40]. CMV may only marginally influence the immune system by inducing bystander effects, which may be negligible or even beneficial during young adulthood and which may become detrimental only at older age [40]. However, it goes without saying that correlations and associations between CMV and hallmarks of immunological ageing or health outcomes cannot distinguish between cause and consequence. Therefore, an alternative model that we would like to propose is that a high immune response to CMV may not be the cause, but the result of an aged immune system. Model 1: CMV is only detrimental in individuals with impaired control of the virus Several studies identified individuals with high CMV-specific antibody levels as at higher risk for impaired immune responses to heterologous viruses [8, 57] or poor general health status [12, 13, 54, 58, 59]. However, we suggest that the link between experienced viral reactivation and the CMV-specific antibody level is probably more complicated than simply reflecting experienced viral reactivation ( chapter 7 ). We expect that the size of the established latent reservoir after primary infection is essential in the level of the CMV-specific immune response. We speculate that after a delayed or diminished primary immune response to CMV, a high level of CMV-specific immunity is necessary to maintain control of latent infection. Therefore, we think it is crucial to measure the viral reservoir and reactivation itself, instead of the immune response as a surrogate marker. Some groups have managed to measure the, relatively low, latent reservoir of CMV in monocytes using digital droplet PCR [60] or even nested PCR [61]. We were not able to reproduce such measurements of CMV DNA by nested PCR in the healthy older adults in our studies ( chapters 4 and 6 ), even though 1-10 virus copies could be detected in control samples (data not shown). Whether the latent reservoir of CMV in monocytes is representative of the total CMV reservoir, being aware of the broad tropism of CMV, and whether the size of the latent reservoir indeed reflects the chance for the virus to reactivate, remains to be investigated. Nevertheless, there are some first indications for a positive correlation between the height of the CMV-specific immune response and the size of the latent reservoir[60], highlighting the importance of the host-virus balance. Next to genetics, environmental experiences determine our immune status to a great extent, which could obscure relatively small modulatory effects of CMV. In humans, CMV infection might be just one of many important environmental influences defining the immune status. In the last decade, studies have uncovered a major role for the microbiome in general health, including regulation of the immune system. In mice [62] and monkeys [63], CMV was shown to affect the microbiome composition of the gut, and thereby increase inflammatory bowel disease [62] and decrease the influenza antibody immune response [63]. Almost all the animal models of CMV until now have been performed in clean, specific-pathogen-free mice. New mouse models, in which clean inbred mice are cohoused with pet shop mice [64] or born from wild mice [65], and thereby exposed to large numbers of different antigens, have received a lot of attention in the last couple of years. The immune systems of these so-called ‘dirty mice’