Placenta as a site of HEV replication and inflammatory cytokines modulating the immunopathogenesis of HEV in pregnant women

• Published in: Journal of medical virology 2022-07, Vol.94 (7), p.3457-3463
• Main Authors: Ratho, Radha Kanta, Thakur, Vikram, Arya, Shallu, Singh, Mini P, Suri, Vanita, Das, Ashim
• Format: Article
• Language: English
• Subjects: Antigens; Blood; Complications; Cytokines; Enzyme-linked immunosorbent assay; Female; Fetuses; Fibrin; Gene expression; Hepatitis; Hepatitis Antibodies; Hepatitis E; hepatitis E virus; Hepatitis E virus - genetics; HEV antigen; Humans; IgG antibody; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Immunohistochemistry; Immunopathogenesis; Inflammasomes; Inflammation; Interleukin-18; Interleukins; Leukocytes, Mononuclear; Liver diseases; Liver Failure, Acute - complications; Necrosis; Pathogenesis; Peripheral blood mononuclear cells; Placenta; Pregnancy; Pregnancy complications; Pregnancy Complications, Infectious; Pregnant Women; Replication; Ribonucleic acid; RNA; Stillbirth; Tissues; Virology; Viruses
• ISSN: 0146-6615; 1096-9071
• DOI: 10.1002/jmv.27699

Viral hepatitis E is an under‐estimated clinical entity with high mortality (20%–30%), especially in the third trimester of pregnancy. As complications due to hepatitis E virus (HEV) in pregnancy is much greater, it is hypothesized that HEV may cross the placenta and replicate in placental tissues even weeks after clearance from the blood, and cytokines may play a role in the immunopathogenesis of HEV in pregnancy. A total of 12 pregnant women with features of acute viral hepatitis/acute liver failure and positive for either HEV‐immunoglobulin M (IgM)/HEV‐RNA and 30 pregnant women negative for HEV RNA/IgM/immunoglobulin G were enrolled as study subjects and healthy controls, respectively. Following delivery, 5 ml blood was collected from the mother for HEV‐RNA. Replicative RNA and viral load in placental tissue were detected through Real‐Time PCR. Placental tissues from the maternal/fetal sides were stained for HEV antigen using HEV‐open reading frame‐2 antibody by immunohistochemistry (IHC) and for histopathological changes by haematoxylin and eosin. Plasma samples were tested for interleukin (IL)‐1β and IL‐18 cytokine levels using Duo‐R&D ELISA kit, whereas peripheral blood mononuclear cells were used to study the inflammasomes and IL‐1β and IL‐18 cytokine genes expression.Of the 10 HEV RNA‐positive sera, 9 had HEV RNA either in the maternal/fetal side of the placenta with the mean viral load of 137.4 IU/ml. Of the 10 HEV RNA‐positive pregnant women, stillbirth in two and fetal and maternal death in one case was reported. IHC revealed strong brownish cytoplasmic staining (HEV antigen) in cytotrophoblasts and syncytiotrophoblast cells in positive samples. The maternal/fetal side of the infected placenta showed irregular intervillous fibrin deposition as well as tissue necrosis. The mean levels of IL‐1β and IL‐18 cytokines in serum of infected subjects were significantly higher than the healthy controls (17.31 ± 4.462 vs. 8.85 ± 4.36 pg/ml; p