Adenovirus 14p1 Immunopathogenesis during Lung Infection in the Syrian Hamster

Abstract

Adenovirus (Ad) infections are usually mild and self-limited, with minimal inflammatory responses. During worldwide outbreaks, Ad14p1, an emerging Ad14 variant, has caused severe pulmonary disease, including acute respiratory distress syndrome (ARDS). This increased pathogenicity of Ad14p1 is not completely understood. In initial studies, we observed that infection of Syrian hamsters with Ad14p1 can cause a patchy bronchopneumonia, with an increased intensity of inflammation, compared to wild type Ad14 infection. The current study compared the dynamics of the immunopathogenesis of Ad14 and Ad14p1 infection of hamster lungs through the first two weeks after infection. Little difference was seen in infection-induced inflammation at day 1. Beginning at day 3, Ad14p1-infected hamsters showed marked inflammation that continued through to day 7. The inflammation began to resolve by day 10 but was still detectable at day 14. In contrast, Ad14-infected hamsters showed little inflammation during the 14-day period of observation. Inflammatory cell type analysis revealed that, at day 1, hamsters infected with either virus had predominantly neutrophil infiltration that began to resolve by day 3. However, at day 5, Ad14p1-infected hamsters had a second wave of neutrophil infiltration that was accompanied by edema which persisted to a variable extent through to day 10. These differences were not explained by an increased Ad14p1 replication rate, compared with Ad14 in vitro, but there was prolonged persistence of Ad14p1 in hamster lungs. There were differences in lung tissue cytokine and chemokine responses to Ad14p1 vs. Ad14 infection that might account for the increased leukocyte infiltrates in Ad14p1-infected hamsters. This animal model characterization provides the basis for future translational studies of the viral genetic mechanisms that control the increased immunopathogenesis of the emergent, Ad14p1 strain.

Cytokine Responses to Adenovirus and Adenovirus Vectors

“…Human adenoviruses exhibit species-restricted phenotypes, making studying disease progression in animal models particularly problematic. However, studies of HAdV-B14p1 in the Syrian hamster model have shed some light on virus-mediated immune- and histopathologies [ 19 ]. HAdV-B14p1 is a species B adenovirus (similar to HAdV-B3 and HAdV-B7) implicated in severe pneumonia and ARDS in humans [ 14 ].…”

“…HAdV-B14p1 is a species B adenovirus (similar to HAdV-B3 and HAdV-B7) implicated in severe pneumonia and ARDS in humans [ 14 ]. The infection of Syrian hamsters with HAdV-B14p1 led to a more severe ARDS-like lung pathology compared to infection with the parental HAdV-B14 virus [ 19 ]. In addition to more extensive lung tissue damage, lung immune-pathology in this model included the high expression of pro-inflammatory cytokines IL-1β and TNF-α and chemokines CCL3 and CXCL10 [ 19 ].…”

“…The infection of Syrian hamsters with HAdV-B14p1 led to a more severe ARDS-like lung pathology compared to infection with the parental HAdV-B14 virus [ 19 ]. In addition to more extensive lung tissue damage, lung immune-pathology in this model included the high expression of pro-inflammatory cytokines IL-1β and TNF-α and chemokines CCL3 and CXCL10 [ 19 ]. HAdV-B14p1-infected cells had lower expression of the viral protein E1B 20K, an inhibitor of the host immune response [ 20 ], suggesting that the failure to inhibit pro-inflammatory cytokine production may be responsible for, and lead to, exuberant host pro-inflammatory immune activation and tissue damage [ 19 ].…”

Animal Models in Human Adenovirus Research

“…In recent studies, Radke and colleagues reported that HAdV-B14 and an emerging variant, B14p1, cause severe lung pathogenesis in intratracheally infected in Syrian hamsters characterized by local infiltrations of inflammatory cells developing into bronchopneumonia. However, although the authors did not report clinically apparent disease signs, these studies in conjunction with the studies that Tollefson and colleagues performed in Syrian hamsters allowed for comparisons of the pathogenicity of the different HAdVs and assessment of respective immune responses [ 55 , 56 , 60 , 61 ].…”

Special Issue “Adenovirus Pathogenesis”

“…Certain genotypes of a closely related type, HAdV-B14, cause more severe infections than other genotypes within the same serotype. Here, we learn about distinct inflammatory events caused by different genotypes in the Syrian hamster model [3], which have the potential to be useful for dissection of adenovirus genes associated with mild or severe illness. Adenovirus-induced glycolysis is known to be regulated by the protein encoded by the E4orf1 gene.…”