Coronaviruses are members of the Coronaviridae family of the order Nidovirales responsible for a variety of diseases in mammals and birds. The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlights the importance of understanding of the mechanisms by which coronaviruses, even seemingly harmless species, and cause disease. The present dissertation compiled a series of experimental and field studies focused on the porcine hemagglutinating encephalomyelitis virus (PHEV), one of the lesser investigated coronavirus despite the fact that it was the second swine coronavirus discovered after the transmissible gastroenteritis virus (TGEV). Therefore, the second chapter of this thesis provides a comprehensive review of the history and current knowledge on PHEV. This virus is classified as a member of genus Betacoronavirus, and it has been recently merged to the species Betacoronavirus 1. PHEV has been associated with vomiting and wasting disease (VWD) and/or encephalomyelitis in pigs, and it is the only known neurotropic coronavirus affecting pigs. PHEV can infect naïve pigs of any age, but clinical disease, morbidity, and mortality is age-dependent and generally reported only in piglets under 4 weeks of age. The first clinical outbreak was reported in 1957 in swine herds in Ontario, Canada, and the virus was isolated in 1961 from the brain of a neonatal piglets showing encephalomyelitis.Although subclinical PHEV infections are thought to be common, there is a paucity of information concerning the ecology of PHEV in commercial swine herds. Chapter 3 described the development and evaluation of a serum IgG antibody enzyme-linked immunosorbent assay (ELISA) based on the PHEV S1 protein. Assessment of the diagnostic performance of the PHEV S1 ELISA using serum samples of precisely known status (n = 924) showed that a sample-to-positive cutoff value of ≥ 0.6 was both sensitive and specific, i.e., all PHEV-inoculated pigs were seropositive from day post-inoculation 10 to 42 and no cross reactivity was observed in samples from other groups. This ELISA was then used to estimate PHEV seroprevalence in U.S. sow herds (19 states) using 2,756 serum samples from breeding females (> 28 weeks old) on commercial farms (n = 104) with no history of PHEV-associated disease. This study demonstrated that PHEV infection is endemic and highly prevalent in U.S, with an overall seroprevalence of 53.35%, and a herd seroprevalence of 96.15%. Results from this study raised questions for future studies regarding the impact of endemic PHEV on swine health and the mechanisms by which this virus circulates in endemically infected populations. PHEV infections in older pigs are generally considered subclinical, but are poorly characterized in the refereed literature. Therefore, Chapter 4, describe the characterization of the dynamic of the infection (i.e., clinical signs, viremia, and virus shedding) and immune response (i.e., humoral response, cytokine/chemokine response, and changes on immune cell subpopulations) to PHEV in grower pigs (7-week-old) experimentally inoculated with PHEV strain 67N (or Mengeling strain) over the course of 42 days post-inoculation (dpi). No clinical signs were observed in PHEV inoculated pigs, but virus was detected in oral fluid (1-21 dpi) and feces (2-7 dpi). No viremia was detected, but a significant IFN-α response was observed in serum at 3 dpi, followed by the detection of IgM (dpi 7), and IgA/IgG (dpi 10). Flow cytometry revealed a one-off increase in cytotoxic T cells at 21 dpi. This study demonstrated that exposure of grower pigs to PHEV results in subclinical infection characterized by active viral replication and shedding followed by an effective humoral and cell-mediated immune response that attenuates the course of the infection and results in viral clearance. The PHEV infection process has not yet been fully characterized from the perspective of the scientific methods and technologies available at present. Thus, Chapter 5 presented a characterization of the PHEV infection, pathogenesis and immune response in caesarean-derived, colostrum-deprived (CDCD) neonatal pigs. PHEV (67N strain) oronasally inoculated animals developed mild respiratory, enteric, and neurological clinical signs between 2 to 13 days post-inoculation (dpi). PHEV did not produce viremia, but virus shedding was detected in nasal secretions (1-10 dpi) and feces (2-7 dpi) by RT-qPCR. Viral RNA was detected in all tissues except liver, but the detection rate and RT-qPCR Ct values decreased over time. The highest concentration of virus was observed in inoculated piglets necropsied at 5 dpi in turbinate and trachea, followed by tonsils, lungs, tracheobronchial lymph nodes, and stomach. The most representative microscopic lesions were gastritis lymphoplasmacytic, moderate, multifocal, with perivasculitis, and neuritis with ganglia degeneration. A moderate inflammatory response, characterized by increased levels of IFN-α in plasma (5 dpi) and infiltration of T lymphocytes and macrophages was also observed. Coinciding with the progressive resolution of the infection, increased plasma levels of IL-8 were detected at 10 and 15 dpi. A robust antibody response was also detected by 10 dpi. Moreover, a robust antibody response was detected by 10 dpi. An ex vivo air-liquid CDCD-derived porcine respiratory cells culture (ALI-PRECs) system showed virus replication in ALI-PRECs and cytopathic changes and disruption of ciliated columnar epithelia, thereby confirming the upper respiratory tract as a primary site of infection for PHEV. This study provides a platform for further multidisciplinary studies of coronavirus infections.