Seoul Virus Tropism and Pathology in Naturally Infected Feeder Rats

Abstract

Seoul virus (SEOV) is a zoonotic orthohantavirus carried by black and brown rats, and can cause hemorrhagic fever with renal syndrome in humans. Human cases of SEOV virus infection have most recently been reported in the USA, United Kingdom, France and the Netherlands and were primarily associated with contact with pet rats and feeder rats. Infection of rats results in an asymptomatic but persistent infection. Little is known about the cell tropism of SEOV in its reservoir and most available data is based on experimental infection studies in which rats were inoculated via a route which does not recapitulate virus transmission in nature. Here we report the histopathological analysis of SEOV cell tropism in key target organs following natural infection of a cohort of feeder rats, comprising 19 adults and 11 juveniles. All adult rats in this study were positive for SEOV specific antibodies and viral RNA in their tissues. One juvenile rat was seropositive, but negative in the rRT-PCR. Of the 19 adult rats of which subsequently additional organs were tested, SEOV RNA was detected in all lungs, followed by kidney (79%) and liver (74%). Histopathologic changes associated with SEOV infection were primarily found in the liver, consistent with a pathological diagnosis of a mild hepatitis. In conclusion, natural SEOV infection results in mild inflammation of the liver in the absence of clinical disease.

Orthohantavirus Pathogenesis and Cell Tropism

“…In reservoir rodents, orthohantaviruses are also primarily endotheliotropic (Netski et al, 1999 ; Maas et al, 2019 ). However, very little is known about the effect of orthohantavirus infection on the function and host responses by these cells.…”

“…Although this entry route is distinct from what is expected during natural infection, pulmonary cells are also considered a target early in natural infection. In naturally infected rats, SEOV antigen is indeed primarily detected in interstitial ECs of alveolar septal capillaries, and rarely in ECs of larger blood vessels such as pulmonary veins, similar to human infection (Maas et al, 2019 ).…”

“…Almost 40 years ago, the first HFRS orthohantaviral antigens were reported in kidneys of wild rodents (Lee et al, 1982 ; LeDuc et al, 1984 ). To our knowledge, the infected renal cell types have not been specified in reservoir rodents, other than SEOV in microvascular ECs (Maas et al, 2019 ). However, HFRS/NE-associated orthohantaviruses are commonly detected in urine of reservoir hosts (Lee et al, 1981 ; Gavrilovskaya et al, 1983 ; Yanagihara et al, 1985 ; Klein et al, 2001 ; Hardestam et al, 2008 ; Voutilainen et al, 2015 ).…”

“…Intramuscular infections of PUUV in bank voles results in viral antigen in liver ECs and Kupffer cells (Yanagihara et al, 1985 ). Interestingly, natural SEOV infection in rats primarily targets the microvasculature in the liver and results in a mild hepatitis, characterized by an increase in the number of polymorphonuclear cells within the hepatic parenchyma and sinusoids (Maas et al, 2019 ). This suggests that SEOV infects hepatic ECs in both reservoir and diseased host.…”

“…The spleen is a peripheral immune organ that supports merely low levels of virus replication in reservoir rodents (Lee et al, 1982 ; Gavrilovskaya et al, 1983 ; LeDuc et al, 1984 ; Yanagihara et al, 1985 ; Compton et al, 2004 ; Michalski et al, 2014 ). Although evidence is conflicting and cell types are not consistently specified, splenic endothelium and macrophages seem to be the main target cells (Yanagihara et al, 1985 ; Maas et al, 2019 ). During both acute and persistent SEOV infection in spleen tissues, proinflammatory (e.g., IL-1β, IL-6, and TNF-α) and antiviral responses (e.g., IFN-γ) are elevated to stimulate viral clearance, while regulatory responses (e.g., TGF-β) seem unaltered (Easterbrook and Klein, 2008b ).…”