The Natural History of BK Polyomavirus and the Host Immune Response After Stem Cell Transplantation

Laskin, Benjamin L.; Denburg, Michelle R.; Furth, Susan L.; Moatz, Taylor; Altrich, Michelle; Kleiboeker, Steve; Lutzko, Carolyn; Zhu, Xin‐Guang; Blackard, Jason T.; Jodele, Sonata; Lane, Adam; Wallace, Gregory; Dandoy, Christopher E.; Lake, Kelly E; Duell, Alexandra; Litts, Bridget; Seif, Alix E.; Olson, Timothy S.; Bunin, Nancy; Davies, Stella M.

doi:10.1093/cid/ciz1194

Cited by 45 publications

(46 citation statements)

References 30 publications

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“…[43][44][45][46][47] BK virus has been shown to trigger high interferon-g production in renal transplant recipients and also to be associated with an increased risk of complement mediated TA-TMA in HSCT recipients. 48 In addition, BK virus can directly injure endothelial cells and promote release of interferon-g. 49 Inflammatory cytokines like IL-6, IL-8, and interferong are also released from circulating activated T cells, NK cells, monocytes, and tissue macrophages as a result of BK virus infection, GVHD and in disorders like hemophagocytic lymphohistiocytosis, with high interferon production resulting in thrombotic microangiopathy. 49,50 Our study has strengths and limitations.…”

Section: Discussionmentioning

confidence: 99%

Interferon-complement loop in transplant-associated thrombotic microangiopathy

et al. 2020

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Transplant-associated thrombotic microangiopathy (TA-TMA) is an important cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). The complement inhibitor eculizumab improves TA-TMA, but not all patients respond to therapy, prompting a search for additional targetable pathways of endothelial injury. TA-TMA is relatively common after HSCT and can serve as a model to study mechanisms of tissue injury in other thrombotic microangiopathies. In this work, we performed transcriptome analyses of peripheral blood mononuclear cells collected before HSCT, at onset of TA-TMA, and after resolution of TA-TMA in children with and without TA-TMA after HSCT. We observed significant upregulation of the classical, alternative, and lectin complement pathways during active TA-TMA. Essentially all upregulated genes and pathways returned to baseline expression levels at resolution of TA-TMA after eculizumab therapy, supporting the clinical practice of discontinuing complement blockade after resolution of TA-TMA. Further analysis of the global transcriptional regulatory network showed a notable interferon signature associated with TA-TMA with increased STAT1 and STAT2 signaling that resolved after complement blockade. In summary, we observed activation of multiple complement pathways in TA-TMA, in contrast to atypical hemolytic uremic syndrome (aHUS), where complement activation occurs largely via the alternative pathway. Our data also suggest a key relationship between increased interferon signaling, complement activation, and TA-TMA. We propose a model of an “interferon-complement loop” that can perpetuate endothelial injury and thrombotic microangiopathy. These findings open opportunities to study novel complement blockers and combined anti-complement and anti-interferon therapies in patients with TA-TMA and other microangiopathies like aHUS and lupus-associated TMAs.

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Section: Discussionmentioning

confidence: 99%

Interferon-complement loop in transplant-associated thrombotic microangiopathy

et al. 2020

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“…It can present with pain, urinary obstruction, and hematuria and is associated with prolonged hospitalization and significant morbidity. A recent prospective study 93 of 193 hematopoietic stem cell transplant recipients from 2 centers noted hemorrhagic cystitis in 22.3% of participants. Among the 147 asymptomatic patients, 40% had BKV viremia ≥ 10,000 copies/mL.…”

Section: Clinical Featuresmentioning

confidence: 99%

Advances in BK Virus Complications in Organ Transplantation and Beyond

et al. 2020

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Reactivation of BK virus (BKV) remains a dreaded complication in immunosuppressed states. Conventionally, BKV is known as a cause for BKV-associated nephropathy and allograft dysfunction in kidney transplant recipients. However, emerging studies have shown its negative impact on native kidney function and patient survival in other transplants and its potential role in diseases such as cancer. Because BKV-associated nephropathy is driven by immunosuppression, reduction in the latter is a convenient standard of care. However, this strategy is risk prone due to the development of donor-specific antibodies affecting long-term allograft survival. Despite its pathogenic role, there is a distinct lack of effective anti-BKV therapeutics. This limitation combined with increased morbidity and health care cost of BKV-associated diseases add to the complexity of BKV management. While summarizing recent advances in the pathogenesis of BKV-associated nephropathy and its reactivation in other organ transplants, this review illustrates the limitations of current and emerging therapeutic options and provides a compelling argument for an effective targeted anti-BKV drug.

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“…That certain viruses can trigger complement-mediated TMA leading to multiorgan injury and death is well described, and such cases may require concomitant therapy with complement inhibition and VSTs to control both viral illness and complement overactivation. 10,21 Animal models demonstrate that complement system overactivation is implicated in acute respiratory distress syndrome 22 (one of the immune-driven pathologies observed in severe cases of coronavirus such as severe acute respiratory syndrome coronavirus) and suggests that inhibition of complement signaling might be an effective treatment option. 23 A subgroup of patients with severe COVID-19 is shown to have a hyperinflammatory syndrome with multiorgan failure, for which treatment with immune-modulating therapy, including complement-blocking agents, may be of benefit.…”

Section: Resultsmentioning

confidence: 99%

“…7,8 Thrombotic microangiopathy (TMA), a severe complication in susceptible individuals that can lead to organ failure or death, can be often triggered by viruses that can lead to complement-mediated systemic endothelial injury. [9][10][11][12][13][14] The use of complement blockers has been reported to mitigate TMA, 15 but the impact of complement blockade on the efficacy of VST activity has not yet been described. We assessed the impact of terminal complement blocker eculizumab on VST activity in patients receiving concurrent therapies for TMA and viral infection.…”

Section: Introductionmentioning

confidence: 99%