Abstract

Understanding how the innate immune system keeps human cytomegalovirus (HCMV) in check has recently become a critical issue in light of the global clinical burden of HCMV infection in newborns and immunodeficient patients. Innate immunity constitutes the first line of host defense against HCMV as it involves a complex array of cooperating effectors – e.g., inflammatory cytokines, type I interferon (IFN-I), natural killer (NK) cells, professional antigen-presenting cells (APCs) and phagocytes – all capable of disrupting HCMV replication. These factors are known to trigger a highly efficient adaptive immune response, where cellular restriction factors (RFs) play a major gatekeeping role. Unlike other innate immunity components, RFs are constitutively expressed in many cell types, ready to act before pathogen exposure. Nonetheless, the existence of a positive regulatory feedback loop between RFs and IFNs is clear evidence of an intimate cooperation between intrinsic and innate immunity. In the course of virus-host coevolution, HCMV has, however, learned how to manipulate the functions of multiple cellular players of the host innate immune response to achieve latency and persistence. Thus, HCMV acts like an orchestra conductor able to piece together and rearrange parts of a musical score (i.e., innate immunity) to obtain the best live performance (i.e., viral fitness). It is therefore unquestionable that innovative therapeutic solutions able to prevent HCMV immune evasion in congenitally infected infants and immunocompromised individuals are urgently needed. Here, we provide an up-to-date review of the mechanisms regulating the interplay between HCMV and innate immunity, focusing on the various strategies of immune escape evolved by this virus to gain a fitness advantage.

Highlights

  • The innate immune response is a fundamental defense mechanism, shielding the host from constant attacks of invading pathogens of different origin, whether they are bacterial, fungal, transposon or viral (Akira et al, 2006; Yan and Chen, 2012)

  • This review provides an in-depth description of the complex interplay between the host innate immune responses and human cytomegalovirus (HCMV), highlighting multiple viral feedback mechanisms that modulate and counteract the various arms of innate immunity

  • We have provided a comprehensive overview of the main characteristics of HCMV that have allowed this virus to evolve multiple immune evasion strategies and achieve latency and seroprevalence

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Summary

Introduction

The innate immune response is a fundamental defense mechanism, shielding the host from constant attacks of invading pathogens of different origin, whether they are bacterial, fungal, transposon or viral (Akira et al, 2006; Yan and Chen, 2012). Intrinsic cellular restriction factors (RFs) are constitutively expressed and play physiological roles in uninfected cells by cooperating with innate immune effectors, as some of them appear to be IFN-inducible, contributing to early host defense (Bieniasz, 2004; Duggal and Emerman, 2012).

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