A major limitation of current humanized mouse models is that they primarily enable the analysis of human-specific pathogens that infect hematopoietic cells. However, most human pathogens target other cell types, including epithelial, endothelial and mesenchymal cells. Here, we show that implantation of human lung tissue, which contains up to 40 cell types, including nonhematopoietic cells, into immunodeficient mice (lung-only mice) resulted in the development of a highly vascularized lung implant. We demonstrate that emerging and clinically relevant human pathogens such as Middle East respiratory syndrome coronavirus, Zika virus, respiratory syncytial virus and cytomegalovirus replicate in vivo in these lung implants. When incorporated into bone marrow/liver/thymus humanized mice, lung implants are repopulated with autologous human hematopoietic cells. We show robust antigen-specific humoral and T-cell responses following cytomegalovirus infection that control virus replication. Lung-only mice and bone marrow/liver/thymus-lung humanized mice substantially increase the number of human pathogens that can be studied in vivo, facilitating the in vivo testing of therapeutics.
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This work was supported by NIH grants no. AI103311 (N.J.M.), no. AI123811 (N.J.M.), no. AI110700 (R.S.B.), no. AI100625 (R.S.B.), no. P30 AI027763 (N.G.), no. AI113736 (R.J.P.), no. T32 HL069768 (I.G.N.), no. AI123010 (A.W.), no. AI111899 (J.V.G.), no. AI140799 (J.V.G.), no. MH108179 (J.V.G.), no. CA189479 (P.A.D.) and no. CA170665 (P.A.D) and the North Carolina University Cancer Research Fund (N.J.M.). This work was also supported by the UNC Center for AIDS Research (CFAR) (grant no. P30 AI050410). We thank K. Arend for the generation of HCMV virus stocks used in these experiments. We thank P. Collins and M. Peeples for recombinant RSV expressing GFP and C. O’Connor for recombinant HCMV TB40/E expressing luciferase. We thank G. Clutton for input on the analysis of antigen-specific T-cell responses. The authors thank members of the Garcia laboratory for technical assistance. We thank technicians at the UNC Animal Histopathology Core, The Marsico Lung Institute Tissue and Procurement Core, and the Department of Comparative Medicine. We also thank J. Schmitz and technicians at the UNC Clinical Microbiology/Immunology Laboratories. We thank J. Nelson and technicians at the UNC CFAR Virology Core Laboratory and K. Mollan at the UNC CFAR Biostatistics Core. The authors thank M.T. Heise, L.J. Picker and J.P. Ting for manuscript advice and helpful discussions.
P.A.D. is an inventor of the acoustic angiography imaging technique, and a cofounder of SonoVol, Inc., a company that has licensed this patent.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Integrated supplementary information
Supplementary Figure 1 Histological analysis of the structure and cellular composition of donor matched human lung tissue pre- and post-implantation.
The structure and cellular composition of human lung tissue pre-implantation (n=2 analyzed) and donor matched LoM lung implant harvested 2 months post-implantation (n=4 analyzed) were analyzed by (a) H&E and (b) immunofluorescent staining. In b, co-staining was performed for epithelial cells (cytokeratin 19, magenta) and cilia (alpha-acetylated tubulin, green) or club cells (CC10, green). Arrows show cuboidal cells lining alveoli. In a, scale bars are 100 µm (left panel) and 200 µm (right panel). In b, scale bars are 200 µm (left panels) and 100 µm (right panels).
Supplementary Figure 2 Presence of mouse cells in the human lung implants of LoM and NSG mouse lung.
Immunohistochemical staining for murine epithelial cells, endothelial cells, hematopoietic cells in LoM human lung implants (n=3 analyzed, top panels) and the mouse lung (n=1 analyzed, bottom panels). Images: 10X, scale bars: 100 µm, positive cells: brown. m, mouse.
Supplementary Figure 3 Presence of human immune cells in human lung tissue pre- and post-implantation.
Immunohistochemical staining for human hematopoietic (hCD45) cells including macrophages (hCD68), dendritic cells (hCD11c), B cells (hCD20) and T cells (hCD3) in human donor matched lung tissue pre-implantation (n=1 analyzed, left panels) and two months post-implantation (n=1 analyzed, right panels). Images: 10X, scale bars: 100 µm, positive cells: brown.
Supplementary Figure 4 In vivo gene expression profile of HCMV-infected LoM is consistent with lytic replication.
Total RNA was extracted from human lung implants harvested from HCMV TB40/E infected LoM 14 days post exposure (n=2 TB40/E infected implants). Double stranded cDNA ((ds)cDNA) was generated from ribosomal RNA (rRNA) depleted total RNA. HCMV (ds)cDNA was enriched with custom designed biotinylated probes spanning both strands of the entire HCMV genome and sequenced using next generation sequencing. High quality reads were aligned to the HCMV genome, and viral expression was quantified in read per kilobase per million (rpkm). Values show read counts per gene normalized to gene length read (rpkm).
Supplementary Figure 5 Reconstitution of the peripheral blood of BLT-L mice with human innate and adaptive immune cells.
Levels of (a) human hematopoietic cells (hCD45) including (b) human myeloid cells (hCD33), B cells (hCD19) and T cells (hCD3) as well as the (c) levels of CD4+ (hCD4) and CD8+ (hCD8) T cells and (d) ratio of human CD4:CD8 T cells in the peripheral blood of BLT-L mice (n=11, filled circles). Horizontal lines represent mean ± s.e.m.
Supplementary Figure 6 Levels of human immune cells in the human lung implants and mouse lung of BLT-L mice.
Levels of (a) human hematopoietic cells (hCD45) including (b) human myeloid cells (hCD33), B cells (hCD19) and T cells (hCD3) in the human lung implants (circles; hCD45, hCD33, and hCD3 n=18, hCD19 n=15) and mouse lung (squares, n=11) of BLT-L mice. (c) Levels of CD4+ (hCD4) and CD8+ (hCD8) T cells and (d) ratio of human CD4:CD8 T cells in the human lung implants (circles, n=15) and mouse lungs (squares, n=11) of BLT-L mice. (e) Human CD4+ and CD8+ T cell activation (CD38+HLA-DR+) levels in the human lung implant (circles, n=7) and mouse lung (squares, n=4) of BLT-L mice. Horizontal lines represent mean ± s.e.m. Human immune cell levels in the human lung implants and mouse lung were compared with a two-tailed Mann-Whitney test.
(a-c) The memory phenotype of human T cells in the human lung implants of BLT-L mice (n=4 BLT-L mice, one lung implant per animal). (a) Percent of CD4+ (filled circles) and CD8+ (filled squares) human T cells expressing a memory phenotype (CD45RO+). (b) Percent of memory (CD45RO+) CD4+ (circles) and CD8+ (squares) human T cells expressing an effector memory (Tem, CCR7neg, closed symbols) or central memory (Tcm, CCR7+, open symbols) phenotype. (c) Percent of memory (CD45RO+) CD4+ (filled circles) and CD8+ (filled squares) T cells that are tissue-resident (TRM, CD69+). (d) Flow cytometry gating scheme. Regions identify the following human cell populations: RI (live cells), RII (human hematopoietic cells), RIII (T cells), RIV (CD8+ T cells), RV (CD4+ T cells), RVI (memory CD8+ T cells), RVII (CD8+ Tem), RVIII (CD8+ Tcm), RIX (CD8+ TRM), RX (memory CD4+ T cells), RXI (CD4+ Tem), RXII (CD4+ Tcm) and RXIII (CD4+ TRM). In a-c, horizontal lines represent mean ± s.e.m. (e) Human hematopoietic (hCD45) cells including dendritic cells (hCD11c), macrophages (hCD68), B cells (hCD20) and T cells (hCD3, hCD4 and hCD8) in lymphoid (spleen and lymph nodes) and non-lymphoid (liver and mouse lung) of BLT-L mice by immunohistochemical staining (positive cells: brown). Images shown are at 20X magnification and represent three BLT-L mice (scale bars: 100 µm).
Supplementary Figure 8 Increased plasma human cytokine and chemokine levels in BLT-L mice following HCMV exposure.
Levels of human GM-CSF IFN-γ, IL-6, IL-8, MDC, IP-10, GRO and MCP-1 in the PB plasma of BLT-L mice (n=10 mice, filled circles) pre and 4 days after HCMV TB40/E inoculation. A value of 3.2 pg/ml was graphed for measurements below the limit of detection of the assay (3.2 pg/ml, shown with a dashed line). Human cytokine and chemokine levels pre and post HCMV inoculation were compared with a two-tailed Wilcoxon matched-pairs signed rank test.
(a) HCMV-DNA levels in LoM human lung implants at 4, 7, 14, 21 and 28 days post AD169 exposure (day 4: n=3 implants, days 7, 14, 21 and 28: n=4 implants, filled squares). Horizontal lines represent mean ± s.e.m. (b) HCMV immediate early (IE), early (E) and late (L) proteins in the human lung implant of an AD169-infected LoM 21 days post-exposure (n=1 lung implant analyzed, positive cells: brown). Images shown are at 40X magnification (scale bars: 50 µm). Positive cells in the bottom panel are indicated with black arrows.
Heat-inactivated plasma from naïve (n=1, open blue circles) and repeatedly HCMV TB40/E exposed BLT-L mice (n=6, filled symbols) was incubated with HCMV TB40/E expressing RFP for 1 h prior to the addition of virus to epithelial cells (ARPE-19). Epithelial cells were incubated at 37 °C with the virus/plasma mixture for 2 h at which time the virus/plasma mixture was removed and fresh media added. Shown is the number of HCMV TB40/E-RFP+ epithelial cells 72 h post-infection in quadruplicate wells. Horizontal lines represent mean ± s.e.m. The percent reduction in TB40/E RFP+ cells compared to wells infected with HCMV pre-treated with naïve control plasma is shown in the table.
Supplementary Figure 11 Gating strategies for the identification of HCMV-specific human T cell responses in BLT-L mice by intracellular cytokine staining (ICS) and pentamer staining.
Representative flow cytometry plots indicating the gating used to detect (a) human CD8+ T cells expressing IFN-γ and CD107a and (b) human CD4+ T cells expressing IFN-γ and TNFα by ICS. (c) Representative flow cytometry plots indicating the gating strategy used to detect HLA class1a-restricted HCMV-specific human CD8+ T cells by pentamer staining.
Supplementary Figs. 1–11 and Supplementary Tables 1–10
Three-dimensional rendering of vascularization (red) of a human lung implant (blue).
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Nature Biotechnology (2019)