The relation of host genetics to symptomatic hepatitis E

For most pathogens, there is a wide spectrum of clinical variability in symptoms, ranging from asymptomatic to fatal outcomes. Consequently, a question that looms large in the field of infectious disease: Why do individuals experience infections in such different ways? The answer to the “infection enigma” probably relates to ecological, microbial, immunological, and genetic factors.1 The fate of an infection is shaped by the general condition of the host, deficiencies of acquired somatic or adaptive immunity and host genetics, but also by the pathogens replication cycle itself. Recent efforts especially highlight that inborn errors of germline-encoded immunity can play important roles in vivo.2 In this issue of Hepatology, Saadat et al3 investigated the genomes of patients with HEV infections to examine a potential link between host genetics and clinical outcome. HEV is a single-stranded positive-sense RNA virus, summarizing a variety of different genotypes with a wide range of potential hosts. The dominant genotype 3 (HEV-3) in Europe is of zoonotic origin and is suggested to spill over to humans through the food chain.4 In addition, blood-borne transmissions between humans are possible, mainly documented in transfusion settings.5 When infecting a human host, HEV can manifest with an enormous clinical variability. While most infected individuals do not develop any or only mild symptoms, a few suffer from severe forms of hepatitis, and some experience a panel of neurological symptoms.6 Despite being one of the most common causes of acute viral hepatitis worldwide, the underlying cause of the diverse HEV pathogenesis remains a conundrum. Especially different neurological manifestations, particularly Parsonage-Turner syndrome (PTS), have added a layer of complexity to our understanding of this viral infection.7 Saadat and colleagues have now contributed a new piece to the puzzle of symptom variability by correlating host genetics to clinical outcomes. They analyzed the genomes of patients with acute HEV, including asymptomatic (n=16) and symptomatic cases of hepatitis (n=24) as well as patients suffering from HEV-associated PTS (n=12) (Figure 1). They detected a striking trend: 10 out of 24 symptomatic patients were carriers of inborn errors in type I interferon (IFN) response pathways, while none of these were present in the other 2 groups (Figure 1). Upon infection, recognition of foreign antigens by pattern recognition receptors, including RIG-I, MDA5, and TLR3, represents the first step to initiate a type I IFN response. Signals are forwarded via adaptor proteins, including MyD88 and IRF7 and finally result in the production of IFNs and IFN-stimulated gene-encoded proteins, which are believed to be the effector molecules to combat viral infections.8 The elegance of this study is based on the isolation of the viral HEV strains circulating in Switzerland, designated HEV-3h_s (for Switzerland). Considering the resulting viral homogeneity in the cohort and using the state-of-the-art bioinformatic approaches, the authors were able to readily identify an accumulation of deleterious variants in different innate signaling molecules (including RIG-I, MDA5, TLR3, MyD88, and IRF7) within symptomatic patients. The authors concluded that intrinsic immunity plays a critical role in HEV pathogenesis and that host genetics contribute to the manifestation of symptomatic hepatitis E. The absence of such findings in patients with HEV-associated PTS or asymptomatic blood donors underlines the specificity of these genetic variants to the severe clinical manifestation of HEV infection.FIGURE 1: Host genetics and symptomatic HEV infection. Individuals with confirmed acute HEV infection detected by PCR were enrolled in this study. Individuals were categorized as followed: asymptomatic (n=16), symptomatic hepatitis (n=24) or HEV-associated Parsonage-Turner Syndrome (n=12). Whole genome sequencing revealed inborn errors of type I IFN immunity in the group of patients with severe acute hepatitis E. Abbreviation: IFN, interferon.Their observations are further supported by multiple lines of evidence suggesting that the identified deleterious variants are linked to severe courses of other viral infections, including SARS-CoV-2 and IAV,9 and that the IFN response is critical to restrict HEV infection in vitro.10 However, caveats must be acknowledged. There is a relatively limited number of study participants, which is well accepted in the field due to the limited access to patients and respective control groups. The striking accumulation of rare germline variants (with frequencies between 0.7% and 0.007%) in the genomes of patients with symptomatic HEV implies a significant contribution to the disease manifestation but raises the question of the degree of penetrance of these lesions for symptomatic HEV. Further, the study did not examine functional associations of different variants within the context of HEV infection in vitro. At this stage, there is no way of knowing whether these mutations facilitate HEV replication in hepatocytes or whether they may impair the production of type I IFN by relevant producers like plasmacytoid dendric cells. Also, the connection of neurological symptoms like PTS to HEV infection cannot be answered by this study. Addressing these gaps of knowledge must be a subject of future research and will improve our molecular understanding of HEV pathogenesis. In summary, this important study highlights the importance of deleterious variants in the IFN system during HEV infection in vivo and thus will enhance our comprehension of HEV pathogenesis. Of note, given that approximately 40% of patients with symptomatic hepatitis E carry an inborn error of the IFN-related system, this may indicate that the host’s genetics are integral determinants for the outcome of an HEV infection. At the same time, it leads to the question of whether pegylated IFN might improve the outcome of the patient group with those germline mutations in the IFN system. As commonly used immunosuppressive drugs suppress adaptive T cell responses but not innate IFN responses, it will be interesting in the future to determine whether these germline mutations also contribute to HEV chronicity in immunocompromised patients and whether the lessons learned for the Swiss HEV strain can be translated to other HEV-3 strains or HEV-1.