Coevolution pays off: Herpesviruses have the license to escape the DNA sensing pathway

Stempel, Markus; Chan, Baca; Brinkmann, Melanie M.

doi:10.1007/s00430-019-00582-0

Cited by 58 publications

(52 citation statements)

References 121 publications

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“…Herpesviruses are known for the impressive toolbox they have evolved to circumvent the host's immune response. Throughout the lifelong coexistence with their hosts, herpesviruses antagonise the immune response at every level: the signalling pathways downstream of pattern recognition receptors (PRR) (reviewed in Liu et al, 2019;Stempel et al, 2019) and the IFNα/β receptor (IFNAR) (Zimmermann et al, 2005), Natural Killer cell responses (reviewed in De Pelsmaeker et al, 2018), the complement system (reviewed in Stoermer and Morrison, 2011) and the adaptive immune response (reviewed in Smith and Khanna, 2013). However, our understanding of the interplay between herpesviruses and the interferon-stimulated gene (ISG) network is only in its infancy.…”

Section: Introductionmentioning

confidence: 99%

One Step Ahead: Herpesviruses Light the Way to Understanding Interferon-Stimulated Genes (ISGs)

et al. 2020

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Section: Introductionmentioning

confidence: 99%

One Step Ahead: Herpesviruses Light the Way to Understanding Interferon-Stimulated Genes (ISGs)

et al. 2020

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“…In particular, the DNA sensor cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS)/STING axis is crucial for activating the IFN-I signaling (Diner et al, 2016;Paijo et al, 2016;Jønsson et al, 2017;Biolatti et al, 2018b). On the other hand, HCMV has evolved a wide range of proteins with which to manipulate and counteract the host IFN response (Biolatti et al, 2018c;Goodwin et al, 2018;Marques et al, 2018;Stempel et al, 2019). This complex and intertwined relationship between HCMV and IFN has been addressed by a number of studies discussed below and schematically represented in Figure 1.…”

Section: The Ifn System and Hcmv: A Stormy Relationshipmentioning

confidence: 99%

“…Some viruses, such as herpesviruses, have succeeded in establishing lifelong persistence in humans by evading immune surveillance (Stempel et al, 2019). For example, human cytomegalovirus (HCMV), a notorious opportunistic pantropic betaherpesvirus with a worldwide seroprevalence of 50 to > 90% in adults (Cannon et al, 2010), has the remarkable ability to manipulate and evade immune detection, literally transforming the host cellular environment into an ideal niche in which to thrive (Griffiths et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Tuning the Orchestra: HCMV vs. Innate Immunity

et al. 2020

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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 virushost 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.

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“…It is critical to understand how the early interaction between a CMV vector and its host may influence the induction of protective immune response, as it will be required for the vector to escape initial control and at the same time avoid pathogenicity. In the first phase of MCMV infection, type I IFN and Natural Killer (NK) cells have the most important role in containing propagation [85,86]. Initial IFN production takes place within the first 8 h in a cGAS/STING dependent manner in liver Kupffer cells [87] and in splenic stromal cells [88].…”

Section: Innate Immune Response To CMV Is Relevant For Its Vector Promentioning

confidence: 99%

Vaccine Vectors Harnessing the Power of Cytomegaloviruses

2019

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Cytomegalovirus (CMV) species have been gaining attention as experimental vaccine vectors inducing cellular immune responses of unparalleled strength and protection. This review outline the strengths and the restrictions of CMV-based vectors, in light of the known aspects of CMV infection, pathogenicity and immunity. We discuss aspects to be considered when optimizing CMV based vaccines, including the innate immune response, the adaptive humoral immunity and the T-cell responses. We also discuss the antigenic epitopes presented by unconventional major histocompatibility complex (MHC) molecules in some CMV delivery systems and considerations about routes for delivery for the induction of systemic or mucosal immune responses. With the first clinical trials initiating, CMV-based vaccine vectors are entering a mature phase of development. This impetus needs to be maintained by scientific advances that feed the progress of this technological platform.Vaccines 2019, 7, 152 2 of 28 CMV-based vaccines, the large pool of functional antigen-specific T cells in the periphery and the possibility to modify CMV genomes due to improvements in viral genetics [11] draw a strong interest to CMV as a vaccine vector [12,13] (Table 1). The inflationary response appears linked to immune protection [14,15] and has been proposed as a target for immunization induction [16]. Vaccines 2019, 7, 152 3 of 28 Full-length HPV16 E6 and E7 Antigen fused to the C-terminus of ie2 Transient limitation of tumour cell growth MCMV IE2E7 [14] MHC-I restricted HPV16 E7 49-57 epitope Epitope fused to the C-terminus of ie2 No tumour cell growth upon challenge MCMV-M79-FKBP-E7 [36] MCMV Smith Strain with FKBP-mediated destabilization of the essential M79 gene Vaccines 2019, 7, 152 5 of 28Besides the exceptional induction of adaptive immune response in humans [2,37], CMV possesses assets that conveniently address weaknesses common to other vector candidates. The cloning of CMV genomes as bacterial artificial chromosomes in Escherichia coli [38] has allowed genetic engineering approaches to effectively express multiple exogenous immunogens or modify large genome portions [39,40]. Furthermore, CMV is known to superinfect hosts with a history of prior exposure to the virus [41] due to its immune evasive properties that protect the virus from recognition by primed T-cells [42] and CMV vectors induce protective immunity in experimentally vaccinated animals with documented prior exposure to 36]. Therefore, CMV vector candidates would avoid immune interference as described for AdV. CMV is a pathogenic organism in immunodeficient populations [43] or in congenitally infected children. Therefore, it is imperative for any HCMV vaccine vector to be attenuated. The generation of replication deficient CMVs that maintain their immunogenicity [36,44] and the modification of genome portions that contain evasions genes [45], as well as the insertion of activating ligands to increase immune control of CMV [46][47][48] are strategies that will be described in this review. Inter...

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Coevolution pays off: Herpesviruses have the license to escape the DNA sensing pathway

Cited by 58 publications

References 121 publications

One Step Ahead: Herpesviruses Light the Way to Understanding Interferon-Stimulated Genes (ISGs)

One Step Ahead: Herpesviruses Light the Way to Understanding Interferon-Stimulated Genes (ISGs)

Tuning the Orchestra: HCMV vs. Innate Immunity

Vaccine Vectors Harnessing the Power of Cytomegaloviruses

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