Multi-step regulation of innate immune signaling by Kaposi's sarcoma-associated herpesvirus

Lee, Hye‐Ra; Amatya, Rina; Jung, Jae U.

doi:10.1016/j.virusres.2015.03.004

Cited by 19 publications

(22 citation statements)

References 71 publications

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“…KSHV encodes several proteins and microRNAs that have been shown to subvert the antiviral innate immune response. In many instances, the host proteins targeted by particular viral factors have been identified, and this is particularly true in the context of innate immune evasion mechanisms adopted by KSHV to evade or manipulate the IFN response (Sathish and Yuan, 2011; Brulois and Jung, 2014; Lee et al, 2015). While the specific viral factor(s) that transiently upregulates HO-1 to facilitate CO-mediated suppression of the TLR4 pathway remains to be identified, our data predict that a virion component is responsible, thereby allowing the inhibition of innate host defenses immediately upon infection.…”

Section: Discussionmentioning

confidence: 99%

The Heme Metabolite Carbon Monoxide Facilitates KSHV Infection by Inhibiting TLR4 Signaling in Endothelial Cells

2017

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Kaposi sarcoma herpesvirus (KSHV) is the etiologic agent of Kaposi sarcoma (KS) and certain rare B cell lymphoproliferative disorders. KSHV infection of endothelial cells (EC) in vitro increases expression of the inducible host-encoded enzyme heme oxygenase-1 (HO-1), which is also strongly expressed in KS tumors. HO-1 catalyzes the rate-limiting step in the conversion of heme into iron, biliverdin and the gasotransmitter carbon monoxide (CO), all of which share anti-apoptotic, anti-inflammatory, pro-survival, and tumorigenic activities. Our previous work has shown that HO-1 expression in KSHV-infected EC is characterized by a rapid yet transient induction at early times post-infection, followed by a sustained upregulation co-incident with establishment of viral latency. These two phases of expression are independently regulated, suggesting distinct roles for HO-1 in the virus life cycle. Here, we investigated the role of HO-1 during acute infection, prior to the onset of viral gene expression. The early infection phase involves a series of events that culminate in delivery of the viral genome to the nucleus. Primary infection also leads to activation of host innate immune effectors, including the pattern recognition receptor TLR4, to induce an antiviral response. It has been shown that TLR4-deficient EC are more susceptible to KSHV infection than wild-type controls, suggesting an important inhibitory role for TLR4 in the KSHV life cycle. TLR4 signaling is in turn subject to regulation by several virus-encoded immune evasion factors. In this report we identify HO-1 as a host protein co-opted by KSHV as part of a rapid immune evasion strategy. Specifically, we show that early HO-1 induction by KSHV results in increased levels of endogenous CO, which functions as a TLR4 signaling inhibitor. In addition, we show that CO-mediated inhibition of TLR4 signaling leads to reduced expression of TLR4-induced antiviral genes, thus dampening the host antiviral response and facilitating KSHV infection. Conversely, inhibition of HO-1 activity decreases intracellular CO, enhances the host antiviral response and inhibits KSHV infection. In conclusion, this study identifies HO-1 as a novel innate immune evasion factor in the context of KSHV infection and supports HO-1 inhibition as a viable therapeutic strategy for KS.

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Section: Discussionmentioning

confidence: 99%

The Heme Metabolite Carbon Monoxide Facilitates KSHV Infection by Inhibiting TLR4 Signaling in Endothelial Cells

2017

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“…Consequently, transcription of inflammatory cytokines and type I IFNs are initiated through the activation of NF-κB and IRFs by either MyD88-dependent or TRIF-dependent pathways (Akira et al, 2006; De Nardo, 2015; Lee et al, 2015). The association of all TLRs, except TLR3, with MyD88 sequentially stimulates the recruitment IRAK, activates TRAF6 and TAK1, and ultimately activates NF-κB and AP-1 activity through the respective IKK complex and MAP kinases.…”

Section: Tlr Signaling Pathwaymentioning

confidence: 99%

“…KSHV stimulates TLR3 gene expression that ultimately induces several cytokines and chemokines, including IFN-β, CCL-2, and CXCL10, during de novo infection (Lee et al, 2015; West and Damania, 2008). However, at later time points of infection, TLR3 expression is reduced, due to inhibition of the TLR3-mediated induction of IFN-responsive promoters by KSHV encoded vIRF (viral interferon regulatory factor)-1, -2, and -3 (Jacobs et al, 2013; West and Damania, 2008).…”

Section: Tlr Signaling Pathwaymentioning

confidence: 99%

“…MyD88 is another key adaptor that initiates signal transduction pathways for all human TLRs except TLR3 to produce pro-inflammatory cytokines and type I IFNs (Brubaker et al, 2015; De Nardo, 2015; Lee et al, 2015). Consistent with the destabilizing role of RTA on TRIF, Zhao et al recently found that RTA directly interacts with MyD88, leading to the proteasomal degradation of MyD88 and suppression of TLR4-mediated NF-κB activity as well as IFN production (Zhao et al, 2015).…”

Section: Tlr Signaling Pathwaymentioning

confidence: 99%

“…Remarkably, accumulated data indicates that regulation of host immune response is critical for maintaining these viral life cycles (Lee et al, 2012). Thus, a large portion of the KSHV genome is devoted to immunomodulatory proteins that subvert the host immune system to ensure viral persistence (Lee et al, 2015). …”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Viral Inhibition of PRR-Mediated Innate Immune Response: Learning from KSHV Evasion Strategies

Lee

Choi

Hwang

et al. 2016

Molecules and Cells

Self Cite

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The innate immune system has evolved to detect and destroy invading pathogens before they can establish systemic infection. To successfully eradicate pathogens, including viruses, host innate immunity is activated through diverse pattern recognition receptors (PRRs) which detect conserved viral signatures and trigger the production of type I interferon (IFN) and pro-inflammatory cytokines to mediate viral clearance. Viral persistence requires that viruses co-opt cellular pathways and activities for their benefit. In particular, due to the potent antiviral activities of IFN and cytokines, viruses have developed various strategies to meticulously modulate intracellular innate immune sensing mechanisms to facilitate efficient viral replication and persistence. In this review, we highlight recent advances in the study of viral immune evasion strategies with a specific focus on how Kaposi’s sarcoma-associated herpesvirus (KSHV) effectively targets host PRR signaling pathways.

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The potential impacts of early secreted antigenic target of 6 kDa of Mycobacterium tuberculosis on KSHV‐infected cells

Dai

Jung

Chen

et al. 2020

Journal of Medical Virology

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Kaposi's sarcoma‐associated herpesvirus (KSHV) causes several human cancers, including Kaposi's sarcoma (KS) and primary effusion lymphoma, which are mostly seen in immunocompromised patients, such as human immunodefeciency virus (HIV)+ individuals. Tuberculosis (TB), caused by the bacterial pathogen Mycobacterium tuberculosis (Mtb), remains one of the deadliest infectious diseases in the world. The risk of developing TB is dramatically higher in people living with HIV than among those without HIV infection. Case reports link cutaneous or pulmonary KS in HIV+ patients with mycobacterial co‐infections, however, impacts of Mtb infection or its products on KSHV‐infected cells are not known. We report here that ESAT‐6, a secreted Mtb virulence factor, induces viral reactivation from KSHV‐infected cells. KSHV‐infected pulmonary endothelial cells were resistant to ESAT‐6 induced inhibition of cell growth. Our data demonstrate that Mtb virulence factors influence the biology of KSHV‐infected cells, highlighting the need to study the interactions between these two pathogens commonly found in people living with HIV.

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Multi-step regulation of innate immune signaling by Kaposi's sarcoma-associated herpesvirus

Cited by 19 publications

References 71 publications

The Heme Metabolite Carbon Monoxide Facilitates KSHV Infection by Inhibiting TLR4 Signaling in Endothelial Cells

The Heme Metabolite Carbon Monoxide Facilitates KSHV Infection by Inhibiting TLR4 Signaling in Endothelial Cells

Viral Inhibition of PRR-Mediated Innate Immune Response: Learning from KSHV Evasion Strategies

The potential impacts of early secreted antigenic target of 6 kDa of Mycobacterium tuberculosis on KSHV‐infected cells

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