Mammarenaviral Infection Is Dependent on Directional Exposure to and Release from Polarized Intestinal Epithelia

Warner, Nikole L.; Jokinen, Jenny D.; Beier, Juliane I.; Sokoloski, Kevin J.; Lukashevich, Igor S.

Epidemiological observations in West Africa indicate that the ingestion of food contaminated with excreta of infected M. natalensis is one of the natural mechanisms of LASV transmission to humans [10] . Up to 45% of individuals living in some LASV endemic regions in Western Africa can be seropositive to the virus; and if re-infection occurs, seropositive individuals can protect themselves from disease onset. However, seronegative individuals may also be protected from disease, due to protection associated with cell-mediated immunity [41] . This implies high prevalence into endemic populations; however, the precise mechanisms behind this phenomenon are unknown. In NHP studies of arenavirus disease, LCMV-WE causes LF-like disease via intravenous (i.v.)-infection, whereas LCMV-ARM shows chronic infection, with no disease onset [23] . Furthermore, high titer i.v. infections of NHPs with LCMV-WE resulted in uniform mortality [23] . Nevertheless, i.g. infection with identical titers showed a variable outcome, ranging from no signs and symptoms to fatal, LF-like disease with elevated aspartate and alanine aminotransferases (ALT/AST) levels [23, 24] . Elevated ALT and AST levels are symptomatic of hepatic tissue damage, and highly elevated levels are associated with lethal LF disease of humans in endemic regions [42] . In addition, some of the surviving animals survived i.v. challenge, indicating that LCMV infection did occur as a competent humoral response was induced [24] . Due to probable infection via the ingestion of contaminated food stuffs, and the variable outcomes of intragastric infection in vivo, we sought to investigate whether or not the patterns of entry and exit when polarized Caco-2 cells were exposed to OW mammarenaviruses apically (intragastric route) or basolaterally (intravenous route).