CMV Late Phase-Induced mTOR Activation Is Essential for Efficient Virus Replication in Polarized Human Macrophages

Poglitsch, Marko; Weichhart, Thomas; Hecking, Manfred; Werzowa, Johannes; Karl, Katharina; Antlanger, Marlies; Krmpotić, Astrid; Jonjić, Stipan; Hörl, Walter H.; Zlabinger, Gerhard J.; Puchhammer, E; Säemann, Marcus D.

doi:10.1111/j.1600-6143.2012.04002.x

Cited by 65 publications

(53 citation statements)

References 49 publications

(71 reference statements)

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“…In line with previous studies, we found that M2 M are more susceptible to HCMV infection than M1 M (17,18). Additionally, we observed a more efficient expression of all three classes of viral proteins as well as a 10-times-higher release of viral progenies in M2 compared to M1 M. The ultrastructural analysis of the course of infection revealed that the viral morphogenetic events occurring in primary M were comparable to those previously observed in fibroblasts (44,45).…”

Section: Discussionsupporting

confidence: 91%

“…The M2 designation refers to alternatively activated M, namely, a very heterogeneous group of cells contributing to resolution of inflammation, tissue repair, extracellular matrix remodeling, and pathogen scavenging. Recent evidence indicates different susceptibilities of M1 and M2 M to HCMV infection (17,18). Nevertheless, the course of HCMV infection in these two types of M as well as the M-specific contribution to the adaptive immune response against HCMV still remains elusive.…”

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confidence: 99%

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Human Cytomegalovirus Infection of M1 and M2 Macrophages Triggers Inflammation and Autologous T-Cell Proliferation

Bayer

Varani

Wang

et al. 2013

J Virol

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H uman cytomegalovirus (HCMV) (1) is a herpesvirus that persistently infects the majority of the human population. After primary infection, HCMV remains lifelong in its host, being able to avoid clearance from the immune system. Whether HCMV persists in a truly latent state (defined as persistence in the absence of detectable infectious virus particles) or in a continuous lowlevel replication state is not clear (2, 3). However, the observation that around 10% of CD8 ϩ and CD4 ϩ T cells in the peripheral blood of healthy seropositive persons are committed to anti-HCMV responses (4) argues for continuous restimulation of T cells with antigens produced during phases of viral reactivation or low-grade active replication. Antigen recognition and T-cell activation are defined by the tightly regulated interaction between the T-cell receptor (TCR) and antigenic peptides that are presented in the context of class I or class II major histocompatibility complex (MHC) molecules on the surface of antigen-presenting cells (APC). A number of studies have shown that the most potent APC, i.e., dendritic cells (DC), are severely impaired by HCMV in their antigen presentation, migration, and T-cell activation capabilities (reviewed in reference 5). How APC that are altered in their function can trigger and maintain a massive HCMVspecific T-cell repertoire is difficult to explain. Due to their dual nature of being permissive to HCMV infection (6-9) and being professional APC (10), macrophages (M) would represent the ideal site for antigen production, processing, and presentation to the adaptive branch of the immune system during HCMV infection.We and others have shown that M are highly susceptible to HCMV infection in vitro and that these cells produce viral progeny (11)(12)(13)(14)(15). Nevertheless, the majority of previous studies did not take into account that, in the context of immunity and inflammation, M acquire different activation states. For the sake of simplicity, M have been classified along what could be viewed as a linear scale, in which M1 M represent one extreme and M2 M the other (16). In this classification, the M1 designation refers to classically activated M, namely, cells that are capable of sustaining the immune response to pathogens through release of proinflammatory factors as well as efficient antigen presentation and T-cell stimulation. The M2 designation refers to alternatively activated M, namely, a very heterogeneous group of cells contributing to resolution of inflammation, tissue repair, extracellular matrix remodeling, and pathogen scavenging. Recent evidence indicates different susceptibilities of M1 and M2 M to HCMV infection (17,18). Nevertheless, the course of HCMV infection in these two types of M as well as the M-specific contribution to the adaptive immune response against HCMV still remains elusive.In this study, we addressed how M polarization defines HCMV susceptibility and how HCMV infection modifies M activation. We also determined the capability of HCMV-infected M to present antigen to ...

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Section: Discussionsupporting

confidence: 91%

mentioning

confidence: 99%

Human Cytomegalovirus Infection of M1 and M2 Macrophages Triggers Inflammation and Autologous T-Cell Proliferation

Bayer

Varani

Wang

et al. 2013

J Virol

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“…For example, M2 alternatively activated macrophages productively infected with HCMV are ineffective in stimulation of natural killer (NK) cells, while M1 macrophages are able to efficiently promote NK cell-mediated IFN-␥ secretion (49). Furthermore, this and other studies reported more efficient HCMV replication in M2 alternatively activated macrophages than in M1 classically activated macrophages (49)(50)(51). Taken together with the findings we present here, the increased permissiveness of M2 macrophages to HCMV productive infection raises the intriguing possibility that viral IL-10-mediated polarization of monocytes to an M2c phenotype not only results in deactivation of the CD4 ϩ T cell function but also may enhance the efficiency of subsequent HCMV infection when viral IL-10-polarized monocytes differentiate into M2c macrophages at sites of infection.…”

Section: Discussionmentioning

confidence: 67%

Human Cytomegalovirus Interleukin-10 Polarizes Monocytes toward a Deactivated M2c Phenotype To Repress Host Immune Responses

Avdic

Cao

McSharry

et al. 2013

J Virol

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“…The importance of mTORC1 activation in the life cycle of HCMV has been demonstrated by in vitro studies (14,20,21,(39)(40)(41)(42)(43). The therapeutic immune suppression in transplant recipients with mTORC1 inhibitors has significantly reduced the incidence of HCMV reactivation (44,45), implying an antiviral role of targeting mTORC1 in clinical settings.…”

Section: Discussionmentioning

confidence: 99%

Tuberous Sclerosis Complex Protein 2-Independent Activation of mTORC1 by Human Cytomegalovirus pUL38

Bai

Xuan

Liu

et al. 2015

J Virol

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The mammalian target of rapamycin complex 1 (mTORC1) controls cell growth and anabolic metabolism and is a critical host factor activated by human cytomegalovirus (HCMV) for successful infection. The multifunctional HCMV protein pUL38 previously has been reported to activate mTORC1 by binding to and antagonizing tuberous sclerosis complex protein 2 (TSC2) . pUL38 also plays a role in blocking endoplasmic reticulum stress-induced cell death during HCMV infection. In this study, we showed that a mutant pUL38 lacking the N-terminal 24 amino acids (pHA-UL38 25-331 ) was fully functional in suppressing cell death during infection. Interestingly, pHA-UL38 25-331 lost the ability to interact with TSC2 but retained the ability to activate mTORC1, although to a lesser extent than full-length pHA-UL38. Recombinant virus expressing pHA-UL38 25-331 replicated with ϳ10-fold less efficiency than the wild-type virus at a low multiplicity of infection (MOI), but it grew similarly well at a high MOI, suggesting an MOIdependent importance of pUL38-TSC2 interaction in supporting virus propagation. Site-directed mutational analysis identified a TQ motif at amino acid residues 23 and 24 as critical for pUL38 interaction with TSC2. Importantly, when expressed in isolation, the TQ/AA substitution mutant pHA-UL38 TQ/AA was capable of activating mTORC1 just like pHA-UL38 25-331 . We also created TSC2-null U373-MG cell lines by CRISPR genome editing and showed that pUL38 was capable of further increasing mTORC1 activity in TSC2-null cells. Therefore, this study identified the residues important for pUL38-TSC2 interaction and demonstrated that pUL38 can activate mTORC1 in both TSC2-dependent and -independent manners. IMPORTANCE HCMV, like other viruses, depends exclusively on its host cell to propagate. Therefore, it has developed methods to protect against host stress responses and to usurp cellular processes to complete its life cycle. mTORC1 is believed to be important for virus replication, and HCMV maintains high mTORC1 activity despite the stressful cellular environment associated with infection. mTORC1 inhibitors suppressed HCMV replication in vitro and reduced the incidence of HCMV reactivation in transplant recipients. We demonstrated that mTORC1 was activated by HCMV protein pUL38 in both TSC2-dependent and TSC2-independent manners. The pUL38-independent mode of mTORC1 activation also has been reported. These novel findings suggest the evolution of sophisticated approaches whereby HCMV activates mTORC1, indicating its importance in the biology and pathogenesis of HCMV.( Human cytomegalovirus (HCMV) is a member of the betaherpesvirus family with broad cell tropism. It is capable of escaping the immune surveillance and persists as a lifelong latent and recurrent infection in the host (1, 2). HCMV infection in adults and healthy people normally is asymptomatic or causes mild illness, but it can cause severe and life-threatening diseases in immunocompromised individuals, and importantly, HCMV congenital infection is a leadin...

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CMV Late Phase-Induced mTOR Activation Is Essential for Efficient Virus Replication in Polarized Human Macrophages

Cited by 65 publications

References 49 publications

Human Cytomegalovirus Infection of M1 and M2 Macrophages Triggers Inflammation and Autologous T-Cell Proliferation

Human Cytomegalovirus Infection of M1 and M2 Macrophages Triggers Inflammation and Autologous T-Cell Proliferation

Human Cytomegalovirus Interleukin-10 Polarizes Monocytes toward a Deactivated M2c Phenotype To Repress Host Immune Responses

Tuberous Sclerosis Complex Protein 2-Independent Activation of mTORC1 by Human Cytomegalovirus pUL38

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