Sara van den Berg

216 Chapter 8 are more representative of the human immune system, which also encounters numerous pathogens and antigens during life. Whether CMV also plays a dominant role in dirty mice would be interesting to investigate. Another important difference between studies in mice and humans might be the order in which different infections occur. Humans are thought to be exposed to influenza virus approximately every 5 years. In the first five years of life, most children have already encountered their first influenza infection, while only about 25% of them are CMV-seropositive [66]. Thus, in humans it is more likely that influenza exposure precedes CMV exposure. It has been suggested that, at least for antibody responses, the first encountered influenza strain in childhood confers lifelong protection against severe disease for this group of influenza strains (the HA antigen group) – also referred to as ‘first flu forever’ [67, 68]. Thus, the first influenza virus infection might affect sequential influenza infections for life, thereby possibly reducing the effect of CMV on the immune response to this type of influenza. In mice, CMV infection always given before the immune response to a heterologous infection is investigated. Also the number of influenza infections might be crucial. In mice, most studies look into the effect of CMV on one heterologous infection. However, humans are likely to encounter multiple influenza infections after CMV infection, inducing a recall response instead of a de novo immune response. Mice experiments looking into the impact of the number and sequence of infections, and different environmental influences, could help to understand the difference between mouse and human in the CMV-induced effects on the function of the immune system. Model 2: High CMV-specific immune responses may be a hallmark rather than a cause of immunological ageing Prolonged exposure to CMV infection has been suggested to be harmful because in older adults the CMV-specific immune response was found to be higher than in younger adults. However, as ageing is inevitable, it is impossible to pull apart the factors age and time in CMV+ individuals. In order to distinguish between age and time of CMV infection comparative studies, separately assessing ageing in CMV- individuals and CMV+ individuals, are required [69]. We found that higher age at the moment of CMV seroconversion was associated with more profound changes in the T-cell pool and with higher CMV-immune responses ( chapter 7 ), highlighting that multiple reactivation events are not necessary to establish a high CMV-specific immune response. As CMV leads to full viral reactivation in severely immunocompromised individuals, such as transplantation patients on immunosuppressive drugs and HIV-infected individuals, it is not surprising that CMV partially reactivates in moderately immune-affected situations, such as in aged individuals or immune immature children. Indeed, detection of viral load in urine and saliva occur to a greater extent in older adults than in younger adults. In conclusion, high CMV-specific immune responses may identify individuals in which the immune system is impaired by ageing. Even more, receiving primary infection with CMV at older age was associated with a worse overall health status as assessed by a multiple deficit frailty index ( chapter 7 ). This indicates that receiving a primary CMV infection may in fact be a consequence of immunological ageing and poor health. Sensitivity for CMV infection indeed seems to play a role in general, as only 2/3 rd of