Desarrollo y validación del diagnóstico serológico y molecular del Rocahepevirus ratti desde un abordaje One Health

This doctoral thesis focuses on the rat hepatitis E virus (ratHEV), a variant of the hepatitis E virus (HEV) that primarily resides in rodents, especially rats. Initially believed to be specific to rodents, the first confirmed human infection was reported in 2018, revealing its zoonotic potential. Since then, additional human cases have been identified worldwide, highlighting the importance of epidemiological surveillance and rodent population control, particularly in areas with high human-rodent interaction. The main objective of the thesis is to assess the impact of ratHEV on public health and its relevance as a zoonotic threat in Europe. Four specific studies were conducted to address this goal. The first study developed a molecular diagnostic algorithm for detecting ratHEV and assessed its presence in patients with acute hepatitis of unknown origin. It found that 1.4% of patients in the clinical cohort were infected, with 37.5% of them presenting severe acute hepatitis and 50% requiring hospitalization. The strains found in patients were closely related to those identified in rats in Spain. This study demonstrates that ratHEV is an emerging and underdiagnosed agent that should be included in the differential diagnosis of acute hepatitis. The second study monitored wastewater to detect HEV and ratHEV and explored potential correlations with clinical cases. HEV was detected in only one sample (0.9%), while ratHEV was found in 94.3% of the samples. However, no direct correlation was observed between environmental virus detection and clinical cases. Despite this, the study provided valuable epidemiological data, although it suggests that environmental monitoring may not directly reflect clinical incidence. The third study focused on people living with HIV, a high-risk population. A 1.1% prevalence of IgG antibodies against ratHEV was found, with only one active infection case (0.1%). The strain identified was phylogenetically related to others found in patients and rats across Europe. The results suggest a wide geographical distribution of the virus and support its potential as a zoonotic threat, emphasizing the need for surveillance in other vulnerable populations. The fourth study examined the seroprevalence of ratHEV among people who use drugs, a group at increased risk due to factors such as injection drug use and precarious living conditions. A 5% prevalence of antibodies and one active infection case were detected in a 57-year-old homeless woman. Age was the only factor associated with infection. The study highlights the need for targeted research in this population and the development of reliable serological diagnostic tools. Overall, this thesis significantly expands the scientific understanding of ratHEV, reinforces its status as an emerging zoonotic pathogen, and lays the groundwork for future research, monitoring strategies, and public health measures aimed at reducing its impact.