Fulminant hepatitis due to human adenovirus

Ronan, B. A.; Agrwal, Neera; Carey, Elizabeth J.; Petris, Giovanni De; Kusne, Shimon; Seville, Maria Teresa; Blair, Janis E.; Vikram, Holenarasipur R.

doi:10.1007/s15010-013-0527-7

Cited by 81 publications

(85 citation statements)

References 58 publications

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“…1E). Although Ads do not normally encounter the liver during a natural infection, the liver is a major site of infection in Ad-based gene therapy recipients and immunocompromised patients (47,48). Wildtype Ad2 but not the RID␣-null virus was associated with LD accumulation in acutely infected shNPC1 cells (Fig.…”

Section: Resultsmentioning

confidence: 97%

Adenovirus Modulates Toll-Like Receptor 4 Signaling by Reprogramming ORP1L-VAP Protein Contacts for Cholesterol Transport from Endosomes to the Endoplasmic Reticulum

Cianciola

Chung

Manor

et al. 2017

J Virol

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Human adenoviruses (Ads) generally cause mild self-limiting infections but can lead to serious disease and even be fatal in high-risk individuals, underscoring the importance of understanding how the virus counteracts host defense mechanisms. This study had two goals. First, we wished to determine the molecular basis of cholesterol homeostatic responses induced by the early region 3 membrane protein RID␣ via its direct interaction with the sterol-binding protein ORP1L, a member of the evolutionarily conserved family of oxysterol-binding protein (OSBP)-related proteins (ORPs). Second, we wished to determine how this interaction regulates innate immunity to adenovirus. ORP1L is known to form highly dynamic contacts with endoplasmic reticulum-resident VAP proteins that regulate late endosome function under regulation of Rab7-GTP. Our studies have demonstrated that ORP1L-VAP complexes also support transport of LDL-derived cholesterol from endosomes to the endoplasmic reticulum, where it was converted to cholesteryl esters stored in lipid droplets when ORP1L was bound to RID␣. The virally induced mechanism counteracted defects in the predominant cholesterol transport pathway regulated by the late endosomal membrane protein Niemann-Pick disease type C protein 1 (NPC1) arising during early stages of viral infection. However, unlike NPC1, RID␣ did not reconstitute transport to endoplasmic reticulum pools that regulate SREBP transcription factors. RID␣-induced lipid trafficking also attenuated proinflammatory signaling by Toll-like receptor 4, which has a central role in Ad pathogenesis and is known to be tightly regulated by cholesterol-rich "lipid rafts." Collectively, these data show that RID␣ utilizes ORP1L in a way that is distinct from its normal function in uninfected cells to fine-tune lipid raft cholesterol that regulates innate immunity to adenovirus in endosomes.IMPORTANCE Early region 3 proteins encoded by human adenoviruses that attenuate immune-mediated pathology have been a particularly rich source of information regarding intracellular protein trafficking. Our studies with the early region 3-encoded RID␣ protein also provided fundamental new information regarding mechanisms of nonvesicular lipid transport and the flow of molecular information at membrane contacts between different organelles. We describe a new pathway that delivers cholesterol from endosomes to the endoplasmic reticulum, where it is esterified and stored in lipid droplets. Although lipid droplets are attracting renewed interest from the standpoint of normal physiology and human diseases, including those resulting from viral infections, experimental model systems for evaluating how and why they accumulate are still limited. Our studies also revealed an intriguing relationship between lipid droplets and innate immunity that may represent a new paradigm for viruses utilizing these organelles.KEYWORDS adenoviruses, cholesterol, endocytic pathway, endoplasmic reticulum, lipid droplet

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Section: Resultsmentioning

confidence: 97%

Adenovirus Modulates Toll-Like Receptor 4 Signaling by Reprogramming ORP1L-VAP Protein Contacts for Cholesterol Transport from Endosomes to the Endoplasmic Reticulum

Cianciola

Chung

Manor

et al. 2017

J Virol

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“…[25][26][27] or adenovirus [15][16][17] fulminant hepatitis. Confluent necrosis of affected hepatocytes is present, without a specific lobular predilection.…”

Section: Nonzonal Necrosismentioning

confidence: 99%

The Pathology of Acute Liver Failure

Lefkowitch

2016

Advances in Anatomic Pathology

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Acute liver failure (ALF) is a rare and severe liver disease that usually develops in 8 weeks or less in individuals without preexisting liver disease. Its chief causes worldwide are hepatitis virus infections (hepatitis A, B, and E) and drug hepatotoxicity (particularly intentional or unintentional acetaminophen toxicity). Massive hepatic necrosis is often seen in liver specimens in ALF and features marked loss of hepatocytes, variable degrees of inflammation, and a stereotypic proliferation of bile ductular structures (neocholangioles) derived from activated periportal hepatic progenitor cells. This paper reviews the liver pathology in ALF, including forms of zonal necrosis and their etiologies.

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“…Hepatitis is a well-described complication of adenovirus infections in immunocompromised hosts, especially with subgroup C type 5. Adenovirus hepatitis is a particular problem in paediatric liver transplant recipients and may be fatal in these patients 6. In contrast, hepatitis with CMV and human herpesvirus 6 is usually mild to moderate in severity and rarely associated with hepatic failure 1 2.…”

Section: Discussionmentioning

confidence: 99%

Fulminant hepatic failure secondary to acyclovir-resistant herpes simplex virus

Shahani

2016

BMJ Case Reports

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Liver failure is a frequent and serious complication that causes morbidity and mortality in haematopoietic stem cell transplantation (HCT) recipients. Liver dysfunction in these patients can be related to infectious causes, most common viral hepatitis. We report a case of disseminated acyclovir-resistant herpes simplex virus (HSV) infection following HCT that led to acute liver failure and death. Although rare, HSV hepatitis leads to high morbidity and mortality and should be considered in the differential diagnosis of HCT recipients with marked elevation of hepatic transaminase. Acyclovir is a first-line therapy for HSV infection; however, acyclovir-resistant viral strains should be considered and alternative HSV therapies given in HCT recipients whose HSV infection does not improve on acyclovir therapy.

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Fulminant hepatitis due to human adenovirus

Abstract: HAdV hepatitis can manifest as a fulminant illness in immunocompromised hosts. Definitive diagnosis requires liver biopsy. Early consideration of a viral etiology, reduction in immunosuppression, and liver transplantation can be potentially life-saving.

Cited by 81 publications

References 58 publications

Adenovirus Modulates Toll-Like Receptor 4 Signaling by Reprogramming ORP1L-VAP Protein Contacts for Cholesterol Transport from Endosomes to the Endoplasmic Reticulum

Adenovirus Modulates Toll-Like Receptor 4 Signaling by Reprogramming ORP1L-VAP Protein Contacts for Cholesterol Transport from Endosomes to the Endoplasmic Reticulum

The Pathology of Acute Liver Failure

Fulminant hepatic failure secondary to acyclovir-resistant herpes simplex virus

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