Based on the fast recruitment of innate and innate-like lymphoid cells, it is likely that they provide a potent first line of defense upon HEV infection. T cells in liver damage. In this review, we aimed to highlight different parts of the lymphoid immune response against HEV and point out questions that remain unanswered regarding this underestimated global threat. strong class=”kwd-title” Keywords: hepatitis E virus, solid organ transplantation, innate lymphoid cells, natural killer cells, natural killer T cells, T cells 1. Introduction Worldwide, an infection with the hepatitis E virus (HEV) is one of the main causes for an acute hepatitis. While being asymptomatic 6-Maleimido-1-hexanol in most healthy patients, the infection can lead to severe courses in immunocompromised patients such as solid organ transplant recipients with a high risk of a chronic infection [1,2]. Furthermore, especially in developing countries, a high morbidity and mortality is reported for pregnant women mainly in the third trimester caused by an increased risk for acute liver failure . Historically, HEV was described for the first time in 1983 as a new non-A, non-B hepatitis virus when it was possible to detect novel virus-like particles in stool samples via immune electron microscopy 6-Maleimido-1-hexanol . The first well-documented outbreak of HEV occurred 1955 to 1956 in New Delhi, India, due to contaminated drinking water, though it was yet to be attributed to hepatitis A virus. It took until 1994 to identify HEV as the cause for this outbreak [5,6]. HEV is a single-stranded RNA virus with a size of 7.2 kb. Its particles show a diameter of 27C34 nm and the virions are nonenveloped in feces and bile while circulating 6-Maleimido-1-hexanol in blood in a membrane-associated, quasi-enveloped configuration [7,8,9]. The genome consists of three open reading frames (ORF) encased by noncoding regions, a 5 cap, and a poly-A tail. ORF1 encodes for a nonstructural polyprotein that is essential for the viral replication, ORF2 encodes for the viral capsid protein and ORF3 plays a role in the release of infectious virions from host cells [10,11]. In this review we aimed to outline relevant aspects regarding the versatile lymphoid immune response and point out open questions concerning a globally challenging disease. 2. The Global ThreatCEpidemiological Aspects of HEV By causing an estimated number of 20 million infections per year leading to 3.4 million symptomatic cases and 70,000 deaths plus 3000 stillbirths, HEV is a major burden for health systems around the world . The human affecting species Orthohepevirus A in the family of Hepeviridae is divided into 8 different genotypes, in which HEV-5 and -6 are limited to wild boars and HEV-7 and -8 to dromedary and Bactrian camels. Since there is a report about a liver transplant recipient, whose consumption of camel meat and milk led to a chronic infection caused by HEV-7, humans can be infected by HEV-7 in rare cases [13,14]. Furthermore, recent studies from Hong Kong have shown that patients might also be infected by Orthohepevirus C genotype 1, an HEV species so far believed to be limited to rats, leading to hepatic and extrahepatic manifestations in these patients . However, the genotypes primarily affecting humans are HEV-1 to -4 and they differ widely in geographical distribution, transmission, and disease progression (Figure 1). A recent study showed evidence that the induction of hepatic transcriptomes significantly MCM7 deviates after infection with different HEV genotypes . Open in a separate window Figure 1 Map with the geographical distribution of the four major human pathogen HEV genotypes. Data adapted from WHO and map generated with Datawrapper, Berlin, Germany. HEV-1 and -2 are generally limited to humans and usually transmitted through fecal-contaminated water, in the majority of cases this is the consequence of susceptible hygiene standards in combination with incidents affecting the drinking water supply [12,17]. Especially severe rainfalls and.