Wild-Type Human Adenovirus (Serotype 2)

Severe human adenovirus (HAdV) infections represent an increasing threat to immunosuppressed individuals, particularly those who have undergone stem cell transplantation. It has previously been hypothesized that severe infections may result from reactivation of persistent infection, but this hypothesis has been difficult to test due to the lack of a suitable in vivo model for HAdV infection. Here, researchers establish a humanized mouse model that recapitulates features of both acute and persistent HAdV infection. In this model, acute infection is associated with high mortality, weight loss, liver pathology, and expression of viral proteins in multiple organs. In contrast, persistent infection is asymptomatic and results in the establishment of HAdV-specific adaptive immunity and early viral gene expression exclusively in the bone marrow. These findings demonstrate the feasibility of using humanized mice to study acute and persistent HAdV infection and strongly suggest the presence of a cellular reservoir in the bone marrow.

To generate humanized mice, researchers used NSG transgenic mice expressing human HLA-A2.1, in which the immune system was reconstituted with cord blood–isolated HSPCs. Nine weeks after transplantation, each mouse was infected with 10⁴ or 10⁸ fluorescence-forming units of wild-type HAdV serotype 2 (HAdV2). Animals with suspected disseminated disease showed macroscopic features of liver pathology, including a yellowish appearance, bright spots, hemorrhages, and uneven margins. To better characterize this phenotype, liver sections were examined using specific staining to detect fibrosis, proliferation, and immune cell infiltration, as well as virus-specific antibodies. The livers of acutely infected mice showed severe intrahepatocyte vacuolation (Figure 1A), increased monocyte/macrophage infiltration and activation, increased cell proliferation, and liver fibrosis (Figure 1B). This phenotype was mainly seen in highly engrafted mice infected with 10⁸ fluorescence-forming units of HAdV2. In contrast, humanized asymptomatic infected mice and infected mice that did not receive transplants showed no pathological signs (Figure 1). Notably, HAdV was still detectable in the liver homogenates and sera of two severely ill mice after two passages on A549 cells, indicating that disseminated disease caused by HAdV was present in these animals.

Figure 1. Liver pathology analysis in mice with acute human adenovirus serotype 2 (HAdV2) infection. (Rodríguez E, et al., 2016)