Control of immune ligands by members of a cytomegalovirus gene expansion suppresses natural killer cell activation

Fielding, Ceri Alan; Weekes, Michael P.; Nobre, Luis; Růčková, Eva; Wilkie, Gavin S.; Paulo, João A.; Chang, Chiwen; Suárez, Nicolás M.; Davies, James A.; Antrobus, Robin; Stanton, Richard J.; Aicheler, Rebecca; Nichols, Hester; Vojtesek, Borek; Trowsdale, John; Davison, Andrew J.; Gygi, Steven P.; Tomašec, Peter; Lehner, Paul J.; Wilkinson, Gavin W. G.

doi:10.7554/elife.22206

Cited by 72 publications

(91 citation statements)

References 58 publications

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“…Together with UL148A (described here), we now know of five HCMV mechanisms that operate to target MICA, including UL142, which also targets ULBP3, US18, US20, and US9 (15,16,18). MICB is also known to be downregulated by five HCMV factors: microRNA (miRNA) HCMV-miR-UL112, US12, US13, US20, and UL16 (29)(30)(31). Besides MICB, US12, US13, and US20 target ULBP2, and UL16 additionally targets ULBP1, ULBP2, and ULBP6.…”

Section: Discussionmentioning

confidence: 93%

The Human Cytomegalovirus Protein UL148A Downregulates the NK Cell-Activating Ligand MICA To Avoid NK Cell Attack

Dassa

Seidel

Oiknine‐Djian

et al. 2018

J Virol

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Natural killer (NK) cells are lymphocytes of the innate immune system capable of killing hazardous cells, including virally infected cells. NK cell-mediated killing is triggered by activating receptors. Prominent among these is the activating receptor NKG2D, which binds several stress-induced ligands, among them major histocompatibility complex (MHC) class I-related chain A (MICA). Most of the human population is persistently infected with human cytomegalovirus (HCMV), a virus which employs multiple immune evasion mechanisms, many of which target NK cell responses. HCMV infection is mostly asymptomatic, but in congenitally infected neonates and in immunosuppressed patients it can lead to serious complications and mortality. Here we discovered that an HCMV protein named UL148A whose role was hitherto unknown is required for evasion of NK cells. We demonstrate that UL148A-deficient HCMV strains are impaired in their ability to downregulate MICA expression. We further show that when expressed by itself, UL148A is not sufficient for MICA targeting, but rather acts in concert with an unknown viral factor. Using inhibitors of different cellular degradation pathways, we show that UL148A targets MICA for lysosomal degradation. Finally, we show that UL148A-mediated MICA downregulation hampers NK cell-mediated killing of HCMV-infected cells. Discovering the full repertoire of HCMV immune evasion mechanisms will lead to a better understanding of the ability of HCMV to persist in the host and may also promote the development of new vaccines and drugs against HCMV. Human cytomegalovirus (HCMV) is a ubiquitous pathogen which is usually asymptomatic but that can cause serious complications and mortality in congenital infections and in immunosuppressed patients. One of the difficulties in developing novel vaccines and treatments for HCMV is its remarkable ability to evade our immune system. In particular, HCMV directs significant efforts to thwarting cells of the innate immune system known as natural killer (NK) cells. These cells are crucial for successful control of HCMV infection, and yet our understanding of the mechanisms which HCMV utilizes to elude NK cells is partial at best. In the present study, we discovered that a protein encoded by HCMV which had no known function is important for preventing NK cells from killing HCMV-infected cells. This knowledge can be used in the future for designing more-efficient HCMV vaccines and for formulating novel therapies targeting this virus.

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Section: Discussionmentioning

confidence: 93%

The Human Cytomegalovirus Protein UL148A Downregulates the NK Cell-Activating Ligand MICA To Avoid NK Cell Attack

Dassa

Seidel

Oiknine‐Djian

et al. 2018

J Virol

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“…Inhibition of MICB mRNA translation [165] UL142 Downregulation of full-length MICA and ULBP3 from the cell surface [166,167] m138 (M) US2 and US12 family members have been shown to target multiple membrane proteins [140,175] whose relevance to NK cell immune evasion is not yet clear. In addition, deletion of individual US12 family members resulted in changes in NK cell reactivity toward infected cells [175] however the receptors mediating this recognition not yet known.…”

Section: Us9 Nkg2dmentioning

confidence: 99%

CMV and natural killer cells: shaping the response to vaccination

et al. 2017

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Cytomegaloviruses (CMVs) are highly prevalent, persistent human pathogens that not only evade but also shape our immune responses. Natural killer (NK) cells play an important role in the control of CMV and CMVs have in turn developed a plethora of immunoevasion mechanisms targeting NK cells. This complex interplay can leave a long-lasting imprint on the immune system in general and affect responses toward other pathogens and vaccines. This review aims to provide an overview of NK cell biology and development, the manipulation of NK cells by CMVs and the potential impact of these evasion strategies on responses to vaccination.Keywords: CMV r HCMV r Immune evasion r NK cells r Vaccination IntroductionCytomegaloviruses (CMVs) are beta-herpesviruses that establish life-long persistent infection of their hosts. After resolution of acute infection, the virus enters a state of latency during which very few genes are transcribed and no new viral progeny are being generated. Latency is interrupted by occasional reactivations of the virus and expression of genes associated with the lytic virus lifecycle [1]. The success of CMVs as pathogens is a consequence of multiple immunoevasion mechanisms such as downregulation of immunoreceptor ligands or expression of decoy molecules that they employ against every arm of the immune system, including NK cells, which play an important role in the early control of virally infected and malignant cells [2]. Individuals lacking NK cells may suffer from recurrent virus infections, most commonly caused by herpes viruses and papilloma viruses, as well as increased susceptibility to malignant tumors [3][4][5]. However, in other cases, there is no obvious clinical immunodeficiency associated with the Correspondence: Dr. Vanda Juranić Lisnić e-mail: vanda.juranic@medri.uniri.hr absence of NK cells, indicating redundancy with other immune compartments for distinct genetic deficiencies [6,7]. As NK cells also regulate other arms of the immune response, their modulation by CMV can have broader consequences for immunity [8]. For instance, the strength of the primary NK cell response against the virus can have a significant impact on the adaptive immune response, although the underlying mechanisms for this are not yet clear and vary according to host and virus genotypes [9,10]. CMV infection is associated with expansion of effector memory CD8 T cell clones that are sustained for the lifetime of the host and can comprise a significant percentage of the total CD8 T cell population in aging individuals [11]. Multiple lines of evidence in experimental animals and in humans which will be discussed in this review, now indicate that CMV infection leaves a similar long-lasting imprint on NK cell phenotype and function, affecting NK cell responses to other pathogens and to vaccination.Vaccines facilitate control and eradication of infectious diseases that have plagued humanity for centuries but new infections, * Current address: Eleanor M. Riley NK cell activity depends on a balance of signals from inhibit...

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“…ULBP3 is instead targeted by UL142, also blocking MICA expression (Ashiru et al, 2009;Bennett et al, 2010). The ability to simultaneously evade multiple cellular pathways has also been reported for US18 and US20, capable of inhibiting both MICA and the NKp30 ligand B7-H6 (Charpak-Amikam et al, 2017;Fielding et al, 2017).…”

Section: Nk Cells and Hcmv: A Balance Of Opposing Forcesmentioning

confidence: 93%

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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Control of immune ligands by members of a cytomegalovirus gene expansion suppresses natural killer cell activation

Cited by 72 publications

References 58 publications

The Human Cytomegalovirus Protein UL148A Downregulates the NK Cell-Activating Ligand MICA To Avoid NK Cell Attack

The Human Cytomegalovirus Protein UL148A Downregulates the NK Cell-Activating Ligand MICA To Avoid NK Cell Attack

CMV and natural killer cells: shaping the response to vaccination

Tuning the Orchestra: HCMV vs. Innate Immunity

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