Syphilis Reactivates Latent Epstein-Barr Virus Reservoir via Toll-Like Receptor 2 and B-Cell Receptor Activation

Hirsiger, Julia R; Fuchs, P.S.; Häusermann, Peter; Müller-Durovic, Bojana; Daikeler, Thomas; Recher, Mike; Hirsch, Hans H.; Terracciano, Luigi; Berger, Christoph T.

doi:10.1093/ofid/ofz317

Cited by 12 publications

(13 citation statements)

References 16 publications

(10 reference statements)

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“…Similarly, previous studies suggest that HIV-1, HPV, HHV-6, Plasmodium falciparum, Leptospirosis, and Group A Streptococci stimulate EBV reactivation [183][184][185][186][187][188]. In the case of EBV, it was also highlighted that the lytic cycle can be induced by Treponema pallidum through TLR2 and B-cell receptor (BCR) activation [189]. The increased number of antigens or decreased level of circulating antibodies are also likely to trigger EBV reactivation in memory B-cells through BCR [190].…”

Section: Virus Reactivationmentioning

confidence: 70%

Herpesviral Latency—Common Themes

2020

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Latency establishment is the hallmark feature of herpesviruses, a group of viruses, of which nine are known to infect humans. They have co-evolved alongside their hosts, and mastered manipulation of cellular pathways and tweaking various processes to their advantage. As a result, they are very well adapted to persistence. The members of the three subfamilies belonging to the family Herpesviridae differ with regard to cell tropism, target cells for the latent reservoir, and characteristics of the infection. The mechanisms governing the latent state also seem quite different. Our knowledge about latency is most complete for the gammaherpesviruses due to previously missing adequate latency models for the alpha and beta-herpesviruses. Nevertheless, with advances in cell biology and the availability of appropriate cell-culture and animal models, the common features of the latency in the different subfamilies began to emerge. Three criteria have been set forth to define latency and differentiate it from persistent or abortive infection: 1) persistence of the viral genome, 2) limited viral gene expression with no viral particle production, and 3) the ability to reactivate to a lytic cycle. This review discusses these criteria for each of the subfamilies and highlights the common strategies adopted by herpesviruses to establish latency.

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Section: Virus Reactivationmentioning

confidence: 70%

Herpesviral Latency—Common Themes

2020

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“… Artificial stimulation triggers reactivation? 1/2 Cell surface; Diacyl lipopeptides (Pam3CSK4) Activated – EBV [ 21 , 26 ] No – KSHV[ 35 ] Yes – EBV [ 44 , 45 ] Yes – KSHV [ 62 ] Yes – MHV68 in vivo [ 15 ] No – EBV [ 31 ] No – EBV [ 39 ] Yes – EBV [ 67 , 68 ] Minor effect – MHV68 in cells [ 34 ] Yes – MHV68 in cells [ 42 ] 2/6 Cell surface; Triacyl lipopeptides(FSL-1) Activated – EBV [ 21 , 26 ] No – KSHV[ 35 ] Yes – EBV [ 44 , 45 ] Yes – KSHV [ 62 ] Yes – MHV68 in vivo [ 15 ] Minor effect – MHV68 in cells [ 34 ] No – EBV [ 39 ] Yes – EBV [ 67 , 68 ] Yes – MHV68 in cells [ 42 ] No – higher—MHV68 in vivo [ 15 ] 3 Endosome; dsRNA (polyI:C) …”

Section: Discussionmentioning

confidence: 99%

“…Nonetheless, another group found that TLR3 activation directly increases RTA expression in a transfection setting [ 66 ], suggesting other TLRs may induce KSHV lytic reactivation in other conditions. In the case of EBV, virus reactivation and EBV-linked hepatitis were reported in a patient with infection with the syphilis pathogen Treponema pallidum, a known inducer of TLR2 [ 67 ]. In addition, stimulation of multiple TLRs can induce expression of the lytic regulator ZEBRA in EBV latently infected cell lines [ 68 ].…”

Section: Tlr Signaling As a Trigger For Lytic Reactivation Of γ-Herpesvirusesmentioning

confidence: 99%

Anti-viral and pro-inflammatory functions of Toll-like receptors during gamma-herpesvirus infections

Gaglia

2021

Virol J

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Toll-like receptors (TLRs) control anti-viral responses both directly in infected cells and in responding cells of the immune systems. Therefore, they are crucial for responses against the oncogenic γ-herpesviruses Epstein-Barr virus and Kaposi’s sarcoma-associated herpesvirus and the related murine virus MHV68, which directly infect immune system cells. However, since these viruses also cause lifelong persistent infections, TLRs may also be involved in modulation of inflammation during latent infection and contribute to virus-driven tumorigenesis. This review summarizes work on both of these aspects of TLR/γ-herpesvirus interactions, as well as results showing that TLR activity can drive these viruses’ re-entry into the replicative lytic cycle.

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“…It has recently been described that T pallidum infection can cause EBV reactivation with hepatitis in an immunocompetent patient 14 . The authors proved using in vitro EBV reactivation assay that T pallidum reactivated EBV in a Toll‐like receptor 2/B‐cell receptor signaling dependent manner, suggesting that EBV‐associated reactivation or lymphoproliferation should be considered in infections with pathogens that activate TLR2, like T pallidum 14 . In our case, we excluded this possibility with a negative EBV‐IgM serology and the negativity of in situ hybridization for EBV in the liver biopsy.…”

Section: Discussionmentioning

confidence: 99%

Secondary syphilis with liver involvement in a liver transplant recipient

Ferrándiz-Pulido

Ferrer

Salcedo

et al. 2020

Transplant Infectious Dis

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Syphilis is capable of compromising almost any organ; however, syphilitic hepatitis is a rare manifestation that has been described most often in HIV‐infected patients. Herein, we present a 33‐year‐old male liver transplant recipient who presented with progressive liver dysfunction characterized by mild ALT elevation and rising cholestasis, malaise, skin rash, and alopecia. Skin biopsy was characteristic of secondary syphilis, confirmed by both skin and liver biopsy‐positive immunohistochemical staining for Treponema pallidum. The patient was treated with benzathine penicillin G 2.4 million units IM q week × 3 weeks. Three months later, the patient was asymptomatic and recovered from his general malaise. He showed no skin lesions and demonstrated complete regrowth of the hair on his scalp, beard, and eyebrows. The presence of liver dysfunction with cholestasis in a transplant recipient should alert transplant providers to the possibility of syphilitic hepatitis, particularly in men who have sex with men. Though not an early manifestation, cutaneous signs of secondary syphilis may be a helpful diagnostic indicator in most cases.

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Syphilis Reactivates Latent Epstein-Barr Virus Reservoir via Toll-Like Receptor 2 and B-Cell Receptor Activation

Cited by 12 publications

References 16 publications

Herpesviral Latency—Common Themes

Herpesviral Latency—Common Themes

Anti-viral and pro-inflammatory functions of Toll-like receptors during gamma-herpesvirus infections

Secondary syphilis with liver involvement in a liver transplant recipient

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