The gammaherpesviruses Kaposi's sarcoma-associated herpesvirus and murine gammaherpesvirus 68 modulate the Toll-like receptor-induced proinflammatory cytokine response.

[primary effusion lymphoma]

The human pathogen Kaposi 's sarcoma -associated herpesvirus (KSHV ), the etiological agent of Kaposi 's sarcoma , primary effusion lymphoma , and multicentric Castleman 's disease , establishes lifelong latency upon infection . Murine gammaherpesvirus 68 (MHV 68 ) is a well-established model for KSHV . Toll-like receptors (TLRs ) play a crucial role for the innate immune response to pathogens . Although KSHV and MHV 68 are detected by TLRs , studies suggest they modulate TLR 4 and TLR 9 signaling , respectively . In this study , we show that in bone marrow-derived macrophages (BMDMs ), MHV 68 did not induce a detectable proinflammatory cytokine response . Furthermore , MHV 68 abrogated the response to TLR 2 , -4 , -7 , and -9 agonists in BMDMs . Similarly to observations with MHV 68 , infection with KSHV efficiently inhibited TLR 2 signaling in THP-1 monocytes . Using a KSHV open reading frame (ORF ) library , we found that K 4 .2 , ORF 21 , ORF 31 , and the replication and transcription activator protein (RTA )/ORF 50 inhibited TLR 2 -dependent nuclear factor kappa B (NF-ÎºB ) activation in HEK 293 TLR 2 -yellow fluorescent protein (YFP )- and Flag-TLR 2 -transfected HEK 293 T cells . Of the identified ORFs , RTA /ORF 50 strongly downregulated TLR 2 and TLR 4 signaling by reducing TLR 2 and TLR 4 protein expression . Confocal microscopy revealed that TLR 2 and TLR 4 were no longer localized to the plasma membrane in cells expressing RTA /ORF 50 . In this study , we have shown that the gammaherpesviruses MHV 68 and KSHV efficiently downmodulate TLR signaling in macrophages and have identified a novel function of RTA /ORF 50 in modulation of the innate immune response .The Toll-like receptors (TLRs ) are an important class of pattern recognition receptors of the innate immune system . They induce a potent proinflammatory cytokine response upon detection of a variety of pathogens . In this study , we found that the gammaherpesviruses murine gammaherpesvirus 68 (MHV 68 ) and Kaposi 's sarcoma -associated herpesvirus (KSHV ) efficiently inhibit the TLR-mediated innate immune response . We further identified the KSHV-encoded replication and transcription activator protein (RTA ) as a novel modulator of TLR signaling . Our data suggest that the gammaherpesviruses MHV 68 and KSHV prevent activation of the innate immune response by targeting TLR signaling .

Diseases
Validation

Diseases presenting "innate immune system" symptom

adrenomyeloneuropathy

allergic bronchopulmonary aspergillosis

familial mediterranean fever

inclusion body myositis

legionellosis

primary effusion lymphoma

typhoid

x-linked adrenoleukodystrophy

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