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Angela Wahl1, Chandrav De2, Maria Abad Fernandez3

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New humanized mouse models enable studying human pathogens beyond blood cells. These models, using human lung implants, support the growth of diverse pathogens and immune responses, aiding therapeutic development.

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Area of Science:

  • * Infectious Diseases
  • * Immunology
  • * Translational Medicine

Background:

  • * Current humanized mouse models are limited to studying pathogens targeting hematopoietic (blood) cells.
  • * Most human pathogens infect non-hematopoietic cells like epithelial, endothelial, and mesenchymal cells, hindering in vivo research.
  • * A need exists for models that accommodate a broader range of human cell types and pathogens.

Purpose of the Study:

  • * To develop a novel humanized mouse model using human lung implants to study non-hematopoietic cell-targeting pathogens.
  • * To assess the capability of this model to support the replication of clinically relevant human viruses.
  • * To evaluate the induction of human immune responses within the lung implant model.

Main Methods:

  • * Implantation of human lung tissue into immunodeficient mice to create vascularized lung implants (lung-only mice).
  • * Infection of lung implants with human pathogens: Middle East respiratory syndrome coronavirus, Zika virus, respiratory syncytial virus, and cytomegalovirus.
  • * Integration of lung implants into bone marrow/liver/thymus humanized mice to allow hematopoietic cell repopulation and assess immune responses.

Main Results:

  • * Human lung implants became highly vascularized and supported the in vivo replication of multiple human viruses.
  • * Lung implants in combined models were repopulated by autologous human hematopoietic cells.
  • * Cytomegalovirus infection elicited robust antigen-specific humoral and T-cell responses that controlled viral replication.

Conclusions:

  • * The developed lung-only and combined humanized mouse models significantly expand the range of human pathogens that can be studied in vivo.
  • * These models facilitate the in vivo investigation of non-hematopoietic cell-targeting pathogens and the testing of novel therapeutics.