Pathogenesis of hepatitis A in orally inoculated owl monkeys (Aotus trivirgatus)

Abstract

The pathogenesis of hepatitis A virus (HAV) infection was studied in owl monkeys following oral administration of the wild-type HM-175 strain of HAV. Stools were collected daily and blood and pharyngeal swabs twice weekly for viral isolation, and animals were necropsied at various intervals after inoculation. Organs were examined for the presence of virus by isolation in cell culture and for viral antigens by immunofluorescence. Monkeys excreted HAV in the stools for 1-4 days after inoculation, presumably due to the residual unabsorbed inoculum. No virus was found in stools for the next 2-3 days. HAV re-appeared on days 4-7 and then persisted through day 39. Viremia occurred on the 10th day and continued until day 35. Virus was isolated occasionally from throat swabs 1 or 2 weeks after it was detected in stools and blood, and there was no evidence that HAV replicated in the pharyngeal tissues. Animals acquired anti-HAV antibody by the 4th week, and alanine aminotransferase (ALT) was elevated 5-5.5 weeks after inoculation. HAV was isolated from liver 5 days after inoculation; however, viral antigens were first detected in Kupffer cells of the liver at 14 days and in hepatocytes at 21 days. HAV antigen was detected in epithelial cells of the intestinal crypts and in the cells of the lamina propria of the small intestine 3 days postinoculation and thereafter until the 5th week, suggesting that these cells might represent an additional site of HAV replication.

Acute hepatitis A virus infection is associated with a limited type I interferon response and persistence of intrahepatic viral RNA

“…A similar pattern may have occurred in 4x0396. This was not matched by quantitative changes in RNA copy numbers in serum or liver of any animal, suggesting the possibility of an independent gastrointestinal replication compartment as proposed previously (21).…”

Hepatitis A Virus-Specific Immunoglobulin A Mediates Infection of Hepatocytes with Hepatitis A Virus via the Asialoglycoprotein Receptor

“…This information could indicate that IgA production is strongly stimulated, after ingestion of HAV, in the gastrointestinal tract by contact of the virus with the mucosaassociated lymphoid tissue. This notion is supported by the detection of HAV in epithelial cells of the intestinal crypts and in cells of the lamina propria of the small intestine 3 days after oral infection of owl monkeys (2), indicating that accumulation of HAV occurs in the gastrointestinal tract. Immunocomplex formation would then occur in the submucosa, and a certain fraction of invading HAV could be transported to the liver via lymph fluid and blood.…”

“…HAV is transmitted by the fecal-oral route, but at present it is not known how HAV finds its way to the liver (15). Based on the data that no extrahepatic sites for HAV replication could be clearly identified until now (2,6,18), although the putative receptor for HAV is expressed ubiquitously (10) and HAV has the ability to infect a number of nonhepatic cells (9,11), we suggest that a certain fraction of HAV is targeted to the liver by a liver-directed carrier mechanism.…”

“…It was demonstrated that the human homolog is a binding receptor for HAV; it has been suggested that it is also a functional receptor (10). Although cell lines originating from tissues other than liver, such as fibroblasts and kidney cells, are also susceptible to HAV infection (9,11) and although HAV antigen and the putative receptor for HAV could be detected in different organs, such as kidney, spleen, and gastrointestinal tract (2,6,10,18), no extrahepatic sites of HAV replication have been clearly identified. The data on the ubiquitous expression of a receptor for HAV and the ability of HAV to replicate in a number of nonliver cells in cell cultures, but obviously not in the organism, suggest that HAV may be targeted to the liver by a particular mechanism.…”

Immunoglobulin A (IgA) Is a Natural Ligand of Hepatitis A Virus Cellular Receptor 1 (HAVCR1), and the Association of IgA with HAVCR1 Enhances Virus-Receptor Interactions

“…Although it is well established that HAV is transmitted through the fecal-oral route, it is unknown whether there is a primary site of HAV replication in the digestive system or whether the input virus is transported to the blood and then reaches the liver, its target organ (45). HAV initially infects Kupffer cells, which are liver-resident macrophages, and then extends to the hepatocytes (2,25,42). We have previously shown that HAVCR1/TIM1 is a receptor for HAV (13,19), but the exact role of this receptor in the pathogenesis of HAV needs to be fully elucidated.…”