Die Another Day: Inhibition of Cell Death Pathways by Cytomegalovirus

Brune, Wolfram; Andoniou, Christopher E.

doi:10.3390/v9090249

Cited by 63 publications

(55 citation statements)

References 131 publications

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“…Non productive infection and apoptosis of the peripheral blood monocytes has been observed in infection with other betaherpesviruses, such as human cytomegalovirus (HCMV) [43,44]. Infection of peripheral blood monocytes with HCMV leads to induction of anti-apoptotic proteins, such as myeloid cell leukemia-1 (Mcl-1) and B cell lymphoma-1 (Bcl-1), as causes delay of apoptosis in the infected cells [12,45,46]. The delay apoptosis of HCMV-infected monocytes allow these cells to bridge the 48-72 hours viability gate, so then they can differentiate into mature phenotypes required for HCMV persistence, such as macrophages or dendritic cells [12,47].…”

Section: Discussionmentioning

confidence: 99%

Possible roles of monocytes/macrophages in response to elephant endotheliotropic herpesvirus (EEHV) infections in Asian elephants (Elephas maximus)

et al. 2019

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Elephant endotheliotropic herpesvirus-hemorrhagic disease (EEHV-HD) is the primary cause of acute, highly fatal, hemorrhagic diseases in young Asian elephants. Although monocytopenia is frequently observed in EEHV-HD cases, the role monocytes play in EEHV-disease pathogenesis is unknown. This study seeks to explain the responses of monocytes/macrophages in the pathogenesis of EEHV-HD. Samples of blood, frozen tissues, and formalin-fixed, paraffin-embedded (FFPE) tissues from EEHV1A-HD, EEHV4-HD, co-infected EEHV1A and 4-HD, and EEHV-negative calves were analyzed. Peripheral blood mononuclear cells (PBMCs) from the persistent EEHV4-infected and EEHV-negative calves were also studied. The results showed increased infiltration of Iba-1-positive macrophages in the inflamed tissues of the internal organs of elephant calves with EEHV-HD. In addition, cellular apoptosis also increased in the tissues of elephants with EEHV-HD, especially in the PBMCs, compared to the EEHV-negative control. In the PBMCs of persistent EEHV4-infected elephants, cytokine mRNA expression was high, particularly up-regulation of TNF-α and IFN-γ. Moreover, viral particles were observed in the cytoplasm of the persistent EEHV4-infected elephant monocytes. Our study demonstrated for the first time that apoptosis of the PBMCs increased in cases of EEHV-HD. Furthermore, this study showed that monocytes may serve as a vehicle for viral dissemination during EEHV infection in Asian elephants.

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Section: Discussionmentioning

confidence: 99%

Possible roles of monocytes/macrophages in response to elephant endotheliotropic herpesvirus (EEHV) infections in Asian elephants (Elephas maximus)

et al. 2019

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“…For example, poxviruses express serine protease inhibitors serpins, which inhibit the activity of cellular caspases (Nichols et al, 2017). Cytomegaloviruses utilize virally-encoded inhibitors of Bax and Bak, which trigger the intrinsic apoptotic pathway, for preventing cell death (Brune and Andoniou, 2017). Additionally, MCMV-encoded M45 protein diminishes RIPK3-dependent necroptosis of infected cells (Upton et al, 2010).…”

Section: Rna Viruses and Pleiotropic Transcription Factorsmentioning

confidence: 99%

Chandipura virus requires pro-survival RelA NF-κB function for its propagation

Bais

Ratra

Kushawaha

et al. 2019

Preprint

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In response to infection by RNA viruses, mammalian cells typically activate RelAcontaining NF-kB heterodimers, which induce genes encoding interferon-b and other antiviral mediators. Therefore, RelA is commonly thought to function as an anti-viral transcription factor. Notably, virus-specific mechanisms often modify mainstay immune pathways. Despite its human health relevance, how Chandipura virus (CHPV) per se interacts with the cellular signaling machinery has not been investigated. Here, we report that RelA deficiency abrogated antiviral gene expressions and yet surprisingly caused diminished growth of CHPV in mouse embryonic fibroblasts. Our experimental studies clarified that RelA-dependent synthesis of pro-survival factors restrained infection-inflicted cell death, and that exacerbated cell death processes prevented multiplication of CHPV in RelA-deficient cells. In sum, we identify a pro-viral function of the immune-activating transcription factorRelA NF-kB linked to its pro-survival properties. Highlights• Lack of RelA NF-kB leads to reduced growth of CHPV ex vivo• RelA deficiency exacerbates cell-death processes upon CHPV infection• Inhibition of cell-death processes restores CHPV multiplication in RelA-deficient MEFs

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“…Finally, triggered cell suicide processes (i.e., apoptosis and pyroptosis), resulting in death and removal of HCMV-infected cells, can also have a major impact on viral infection progression (Brune and Andoniou, 2017).…”

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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Die Another Day: Inhibition of Cell Death Pathways by Cytomegalovirus

Cited by 63 publications

References 131 publications

Possible roles of monocytes/macrophages in response to elephant endotheliotropic herpesvirus (EEHV) infections in Asian elephants (Elephas maximus)

Possible roles of monocytes/macrophages in response to elephant endotheliotropic herpesvirus (EEHV) infections in Asian elephants (Elephas maximus)

Chandipura virus requires pro-survival RelA NF-κB function for its propagation

Tuning the Orchestra: HCMV vs. Innate Immunity

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