Human CD46 humanized mice reveal interferon associated pulmonary immune remodeling during human adenovirus type 7 lung infection

Background Human adenovirus type 7(HAdV-7) is a major cause of severe pediatric pneumonia, but the mechanisms linking viral infection to pulmonary immune remodeling and lung pathology remain incompletely understood. Progress has been limited by the lack of physiologically relevant animal models that recapitulate human susceptibility. Methods We generated human CD46 (hCD46) humanized mice and evaluated pulmonary viral burden, recoverable infectious virus, and lung pathology after HAdV-7 infection. Single-cell RNA sequencing was performed on lung tissues from wild type and hCD46 humanized mice under control and infected conditions to characterize cellular composition, transcriptional states, and intercellular communication. Human PBMC bulk transcriptomes from pediatric HAdV infection were further analyzed to assess the systemic relevance of mouse lung derived immune programs. Results hCD46 humanized mice showed increased pulmonary viral burden, recoverable infectious virions, and more severe lung pathology after HAdV-7 infection. Single-cell profiling revealed depletion of resident alveolar macrophages, pronounced expansion of inflammatory macrophage subsets, and remodeling of lymphoid transcriptional states in infected hCD46 lungs. These changes were accompanied by prominent type I/II interferon and interferon associated chemokine programs. B cells and CD4 + and CD8 + T cells showed prominent interferon stimulated genes (ISGs) associated transcriptional states, together with alterations in selected effector- and memory-associated programs and computationally inferred trajectories. Projection of mouse lung derived signatures onto transcriptomes of human peripheral blood mononuclear cell showed that selected interferon associated myeloid and lymphoid programs were also detectable systemically in pediatric HAdV infection. Conclusions HAdV-7 infection in hCD46 humanized mice was associated with an interferon enriched pulmonary inflammatory environment, prominent inflammatory myeloid remodeling, and altered lymphoid transcriptional states. This susceptible mouse model provides a useful experimental tool for studying HAdV-7 associated lung disease and for preclinical evaluation of antiviral, immunomodulatory, and vaccine strategies.