PMC:4928686 / 3880-9397
Annnotations
{"target":"http://pubannotation.org/docs/sourcedb/PMC/sourceid/4928686","sourcedb":"PMC","sourceid":"4928686","source_url":"https://www.ncbi.nlm.nih.gov/pmc/4928686","text":"Sepsis and CMV\nBacterial sepsis is an associated trigger of CMV reactivation that was first recognized in the 1990s. Domart et al. [14] first showed that a significant number of non-immune-suppressed patients with mediastinitis following cardiac surgery had CMV reactivation. Subsequent work by Prosch and Volk and the Berlin group showed in a trio of manuscripts that CMV reactivation occurs at a high rate in septic patients and suggested that this reactivation might be a consequence of TNF and nuclear factor-κβ stimulation of the major immediate early promoter [28–30]. This clinical association was later experimentally confirmed by combining murine models of CMV latency and polymicrobial sepsis [31] and then subsequently with direct administration of inflammatory mediators in the murine latency model [32]. It has been recently proposed that reactivation events associated with sepsis are a consequence of inflammatory stimulation of the major immediate early promoter, transient immune compromise, and likely some component of epigenetic regulation of viral DNA (reviewed in [33]).\nOnce the connection between bacterial sepsis and viral reactivation was solidified, focus was next turned to the consequences of such reactivation events. It has been shown that pulmonary inflammatory responses induced by polymicrobial sepsis are exaggerated in mice with latent CMV [34]. This exaggerated inflammatory response, something that we have termed CMV-ALI (CMV-associated lung injury) [4], is associated with enhanced pulmonary fibrosis in latently infected mice after sepsis [34]. Virgin et al. [35] demonstrated subsequently that previous infection with CMV or the Epstein–Barr virus homolog γ-herpes virus 68 can confer protection against subsequent bacterial challenges. The mechanism for this resistance appeared to be macrophage activation [35], and more recent work suggests that for CMV infection, this may be a consequence of enhanced Toll-like receptor (TLR) expression and responsiveness on infected macrophages [36]. This enhanced TLR responsiveness is accompanied by enhanced CD14 expression, thereby increasing macrophage responsiveness to TLR-2, TLR-4, and TLR-5 ligands.\nInterestingly, this enhanced TLR responsiveness might actually provide a survival advantage for the virus, by ensuring that the major immediate early promoter is tickled repeatedly (if not continuously) by endogenous bacteria throughout an infected host’s lifetime, perhaps causing shedding of virus and thus transmission opportunities. If this hypothesis is true, then one would expect to see some differences in germ-free hosts after CMV infection. It is known that CMV infection can induce dramatic CMV-specific T cell responses, a phenomenon that is popularly referred to as “memory inflation.” Curiously germ-free mice do not develop memory inflation after CMV infection, but do develop memory inflation after bacterial reconstitution [37]. If CMV-specific T cells are inflating in response to viral transcriptional activity, then one could speculate that host bacteria facilitate such activity. This makes the enhanced TLR/CD14 expression after CMV infection even more interesting, leaving hosts even more susceptible to bacterial stimulation and inflammation. Such stimulation might explain the perpetual low-level viral transcriptional activity during “latency” shown by the Reddehase group [38, 39], and in moments of immune weakness during relative health allow intermittent shedding, giving survival advantage to the virus. Conversely, such enhancements in Toll-like receptors might also contribute to the exaggerated immune responses seen during sepsis, becoming detrimental when those same hosts encounter severe bacterial infections.\nWhether such viral preconditioning by CMV has a beneficial or detrimental impact on humans during bacterial septic challenges is unknown. On the one hand, it is logical that a viral infection that enhances immunity to bacterial infections should benefit the septic host. If this is true, then latently infected mice should show enhanced survival following bacterial sepsis, which is not consistent with our experience (unpublished data). Likewise, IgG-positive patients should also show improved outcomes during sepsis, but the single study to date evaluating this shows no such benefit [40]. In fact, this study shows no association with improved or worsened outcomes in CMV-IgG-positive patients [40]. One shortcoming of this trial, however, is that IgG titers were not studied, and all studies to date that have correlated CMV serostatus with detrimental outcomes have found such associations only in those with the highest IgG titers [41–43].\nOn the other hand, the septic response is considered by many to be a deranged host response, and it is equally logical that CMV preconditioning might contribute to such exaggerated inflammation. Hosts with coincident CMV reactivation and bacterial infections have more inflammation and immune system activation that is accompanied by an increased risk of septic shock, supporting the detrimental hypothesis [34, 35, 44]. By looking at the CMV-specific immune responses to infection in human hosts, it seems clear that not all naturally occurring infections are equal and show a broad mix of infectious titers [41–43, 45]. This mix of high- and low-titer infections may in part explain why the work by De Vlieger et al. did not show an advantage or disadvantage of previous CMV infection in outcome after sepsis or critical 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