Toward a humanized mouse model of Pneumocystis pneumonia
Guixiang Dai, Alanna Wanek, Taylor Eddens, Paul Volden, Jay K. Kolls
Guixiang Dai, Alanna Wanek, Taylor Eddens, Paul Volden, Jay K. Kolls
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Research Article Infectious disease Pulmonology

Toward a humanized mouse model of Pneumocystis pneumonia

Abstract

Pneumocystis is an important opportunistic fungus that causes pneumonia in children and immunocompromised individuals. Recent genomic data show that divergence of major surface glycoproteins may confer speciation and host range selectivity. On the other hand, immune clearance between mice and humans is well correlated. Thus, we hypothesized that humanize mice may provide information about human immune responses involved in controlling Pneumocystis infection. CD34-engrafted huNOG-EXL mice controlled fungal burdens to a greater extent than nonengrafted mice. Moreover, engrafted mice generated fungal-specific IgM. Fungal control was associated with a transcriptional signature that was enriched for genes associated with nonopsonic recognition of trophs (CD209) and asci (CLEC7A). These same genes were downregulated in CD4-deficient mice as well as twins with bare lymphocyte syndrome with Pneumocystis pneumonia.

Authors

Guixiang Dai, Alanna Wanek, Taylor Eddens, Paul Volden, Jay K. Kolls

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Figure 5

Lung fungal burden correlated with Pneumocystis GSC1 gene expression and GMS staining.

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Lung fungal burden correlated with Pneumocystis GSC1 gene expression and...
huNOG-EXL mice engrafted with human umbilical cord blood–derived CD34+ hematopoietic stem cells and unengrafted mice were inoculated with approximately 2 × 105 asci of P. murina. Eight weeks after infection, the right middle lung lobes were removed and RNA was extracted in order to assess lung fungal burden and GSC1 gene expression by RT-qPCR. The left lung lobes were taken for GMS staining. Analysis using a 2-tailed, unpaired t test indicated that there were significant differences in the fungal burden (A) and GSC1 gene expression (B) between the huNOG-EXL and NOG-EXL groups; P < 0.001 for fungal burden and P < 0.005 for GSC1 expression. Individual values are shown with a horizontal bar indicating the mean of the group. GMS staining indicated that there were more and extensive but smaller lesions in the lungs of NOG-EXL mice (D) compared with lungs of huNOG-EXL mice (C) (scale bars: 200 μm). At high magnification (original magnification, ×40), GMS-positive asci were well stained (E) (scale bar: 23 μm).