Cytomegalovirus infection enhances the immune response to influenza

Abstract

Cytomegalovirus (CMV) is a beta-herpes virus present in a latent form in most people worldwide. In immunosuppressed individuals, CMV can reactivate and cause serious clinical complications, but the effect of the latent state on healthy people remains elusive. We undertook a systems approach to understand the differences between seropositive and negative subjects and measured hundreds of immune system components from blood samples including cytokines and chemokines, immune cell phenotyping, gene expression, ex vivo cell responses to cytokine stimuli and the antibody response to seasonal influenza vaccination. As expected, we found decreased responses to vaccination and an overall down-regulation of immune components in aged individuals regardless of CMV serostatus. In contrast, CMV-infected young adults exhibited an overall up-regulation of immune components including enhanced antibody responses to influenza vaccination, increased CD8+ T cell sensitivity, and elevated levels of circulating IFN-γ compared to uninfected individuals. Experiments with young mice infected with murine CMV also showed significant protection from an influenza virus challenge compared with uninfected animals, although this effect declined with time. These data show that CMV and its murine equivalent can have a beneficial effect on the immune response of young, healthy individuals, which may explain the continued coexistence of CMV and mammals throughout their evolution.

Phylogenetic analysis of the human antibody repertoire reveals quantitative signatures of immune senescence and aging

“…This finding suggests that CMV infection may enhance the activation process of memory B cells in both young and elderly participants. Age-related deficiencies of other immune components or a lessened ability to diversify the existing memory pool into high-affinity antibodies in aging may explain why an enhanced serum antibody response to influenza vaccine has been detected only in young, but not in elderly, CMV + individuals (36).…”

How does cytomegalovirus factor into diseases of aging and vaccine responses, and by what mechanisms?

“…Results on the effect of CMV seropositivity on influenza vaccine responses are controversial with most of the studies showing a negative effect of CMV (Derhovanessian et al 2013b(Derhovanessian et al , 2014Frasca et al 2015;Trzonkowski et al 2003) and others showing no effect (den Elzen et al 2011;Furman et al 2015). The negative effects of CMV seropositivity have been associated in both elderly (Derhovanessian et al 2013b;Frasca et al 2015) and young (Frasca et al 2015) individuals with the presence of late differentiated/exhausted T cells (CD27 −CD28−CCR7−CD45RA+ or with CD28−CD57+), which produce pro-inflammatory cytokines and have therefore a significant role in age-related immune pathologies, suggesting that this virus may underlie rudimentary aspects of immunosenescence even in chronologically young individuals (Turner et al 2014).…”

“…Results from a recently published study have demonstrated that CMV seropositivity negatively affects antibody response to the influenza vaccine to a greater extent than inflammatory markers, such as β2-microglobulin and IL-6, in older adults (Reed et al 2017). Conversely, the positive effects of CMV seropositivity on the response to the influenza vaccine have been shown only in young individuals (Furman et al 2015). In particular, it has been shown that CMV-seropositive young individuals exhibited enhanced in vivo antibody responses, Th1 and Th2 responses, and cytotoxic T cell responses, as compared with CMV-seronegative individuals, suggesting that CMV can boost the immune response of young individuals and therefore shows features of a mutualistic agent conferring benefits to the host.…”

Identification of human cytomegalovirus in tumour tissues of colorectal cancer and its association with the outcome of non-elderly patients

“…In the elderly, chronic latent HCMV infection increases the mortality rate, which could be attributed to HCMV-induced immunosenescence with decreased immunity to microbes and cancers (Pawelec et al, 2010;Sansoni et al, 2014;Savva et al, 2013). In the non-elderly, on the other hand, chronic HCMV infection may actually be beneficial in that it augments the T-cell immunity and has been associated with a reduced cancer risk in transplant patients (Couzi et al, 2010;Furman et al, 2015;Pera et al, 2014). In this study, significant intra-tumoural inflammatory responses were more frequently observed in HCMVpositive tumours, suggesting that viral replication may activate the immune response in the tumour microenvironment and contribute to a favourable prognosis (Naito et al, 1998).…”