Molecular Mechanism for Protection Against Liver Failure in Human Yellow Fever Infection

Abstract

Yellow fever (YF) is a viral hemorrhagic fever that typically involves the liver. Brazil recently experienced its largest recorded YF outbreak, and the disease was fatal in more than a third of affected individuals, mostly because of acute liver failure. Affected individuals are generally treated only supportively, but during the recent Brazilian outbreak, selected patients were treated with liver transplant. We took advantage of this clinical experience to better characterize the clinical and pathological features of YF‐induced liver failure and to examine the mechanism of hepatocellular injury in YF, to identify targets that would be amenable to therapeutic intervention in preventing progression to liver failure and death. Patients with YF liver failure rapidly developed massive transaminase elevations, with jaundice, coagulopathy, thrombocytopenia, and usually hepatic encephalopathy, along with pathological findings that included microvesicular steatosis and lytic necrosis. Hepatocytes began to express the type 3 isoform of the inositol trisphosphate receptor (ITPR3), an intracellular calcium (Ca2+) channel that is not normally expressed in hepatocytes. Experiments in an animal model, isolated hepatocytes, and liver‐derived cell lines showed that this new expression of ITPR3 was associated with increased nuclear Ca2+ signaling and hepatocyte proliferation, and reduced steatosis and cell death induced by the YF virus. Conclusion: Yellow fever often induces liver failure characterized by massive hepatocellular damage plus steatosis. New expression of ITPR3 also occurs in YF‐infected hepatocytes, which may represent an endogenous protective mechanism that could suggest approaches to treat affected individuals before they progress to liver failure, thereby decreasing the mortality of this disease in a way that does not rely on the costly and limited resource of liver transplantation.

Correlation Between Clinical and Pathological Findings of Liver Injury in 27 Patients With Lethal COVID‐19 Infections in Brazil

“…In order to gain insight about the basis for the pathological findings, these have been correlated with liver tests. We also examined immunostaining for SARS-CoV-2, angiotensin converting enzyme 2 (ACE2), which is thought to be the point of entry of the virus into cells (16), and the type 3 inositol trisphosphate receptor (ITPR3), which increases in acute hepatocellular injury and may relate to the nature of the response to injury (17,18).…”

“…We also examined immunostaining for SARS-CoV-2, angiotensin converting enzyme 2 (ACE2), which is thought to be the point of entry of the virus into cells, (16) and the type 3 inositol trisphosphate receptor (ITPR3), which increases in acute hepatocellular injury and may relate to the nature of the response to injury. (17,18) Brazil, who were hospitalized between March 23 and May 18, 2020, after testing positive for SARs-CoV-2 through quantitative real-time polymerase chain reaction (PCR). Liver specimens of approximately 1 cm 3 were obtained from multiple sites during necropsy and fixed in neutral buffered formalin and embedded in paraffin.…”

Bioengineered Liver Models for Investigating Disease Pathogenesis and Regenerative Medicine

“…109,111 Patients with liver failure often develop jaundice, coagulopathy, thrombocytopenia, steatosis, and necrosis. 112 There are no antivirals approved to treat yellow fever; therefore, human in vitro liver models could provide valuable insights into viral infection and pathogenesis, while enabling the discovery of novel molecular targets for drug development.…”

“…111 In another study, isolated primary hepatocytes and HepG2 cells infected with yellow fever began to express the type 3 isoform of the inositol trisphosphate receptor (ITPR3), an intracellular calcium channel, which has been associated with hepatocyte proliferation and reduced steatosis. 112 Yellow fever usually causes severe hepatocellular damage and steatosis; therefore, this cellular protective mechanism could present a potential therapeutic target for treatment.…”

Inositol 1,4,5‑trisphosphate receptor type 3 is involved in resistance to apoptosis and maintenance of human hepatocellular carcinoma

“…For instance, under physiological conditions type 1 (ITPR1) and 2 (ITPR2) are the predominant isoforms in hepatocytes ( 10 , 11 ), while isoform 3 (ITPR3) is absent or minimally expressed ( 12 ). However, ITPR3 becomes significantly expressed in hepatocytes in acute ( 13 , 14 ) and chronic liver diseases, as well as in HCC and in liver cancer cell lines ( 15 , 16 ). ITPR3 expression is also increased in other malignancies, including cholangiocarcinoma ( 17 ), colon cancer ( 18 ), melanoma ( 19 ), mesothelioma and prostate cancer ( 20 ).…”