Biology subjects

Thurman, C. E.

Publications and source records attributed to Thurman, C. E..

3 recordsLinked to original sources

bioRxiv2025

Protocol for Developing a Mouse Model of Post Primary Pulmonary Tuberculosis after Hematogenous Spread in Native Lungs and Lung Implants

This protocol describes a mouse model of post-primary pulmonary tuberculosis (PTB) that develops after hematogenous spread from the primary lesion in native lungs and subcutaneous lung implants. It demonstrates that virulent Mycobacterium tuberculosis (Mtb) disseminates to lymphoid tissue in many organs, but selectively damages the lungs. This approach demonstrates a particular vulnerability of the lung tissue to virulent Mtb independent of the route of infection and provides a robust platform for examining lung-specific mechanisms driving TB pathology. HighlightsO_LIMouse model for studying mechanisms driving post-primary pulmonary TB progression in immune hosts C_LIO_LIModels a hematogenous spread of virulent Mycobacterium tuberculosis to the lungs from a primary site of infection C_LIO_LIAllows for the investigation of lung-specific mechanisms of TB susceptibility using lung tissue implants. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=184 SRC="FIGDIR/small/640830v1_ufig1.gif" ALT="Figure 1"> View larger version (71K): org.highwire.dtl.DTLVardef@1ce5384org.highwire.dtl.DTLVardef@cd3b88org.highwire.dtl.DTLVardef@1ff7ce7org.highwire.dtl.DTLVardef@614598_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2023

Aberrant macrophage activation and failed regeneration of pulmonary epithelium promote tuberculosis progression uniquely in lung tissue

Pulmonary tuberculosis (PTB) represents 85% of the disease burden caused by Mycobacterium tuberculosis (Mtb) and promotes aerosol transmission infecting about a quarter of people globally. Most Mtb infections are effectively limited within primary granulomatous lesions. Containment failures lead to hematogenous spread and the formation of post-primary destructive PTB lesions. Factors that favor Mtb survival and replication in the lungs after hematogenous spread despite systemic immunity represent appealing targets for host-directed TB therapies, but are currently unknown. We developed a novel mouse model that mimics progression of chronic post-primary PTB in humans: wherein PTB lesions form after hematogenous spread from a remote primary lesion in immunocompetent but TB-susceptible B6.Sst1S mice. The B6.Sst1S mice developed PTB lesions featuring granulomatous pneumonia, bronchogenic expansion and broncho-occlusion closely resembling post-primary PTB in humans. Using spatial transcriptomic and fluorescent multiplexed immunochemistry, we demonstrated the expansion of myeloid cell populations with the appearance of alternatively activated macrophages, dissolution of initial lymphoid follicles, and accumulation of de-differentiated lung epithelial cells in the advanced PTB lesions. To determine whether lung parenchymal cells or lung oxygenation were necessary for the pulmonary TB progression, we implanted lung and spleen fragments subcutaneously to serve as potential targets for hematogenous spread. The lung (but not spleen) implants displayed characteristic organized granulomas with necrosis and Mtb replication demonstrating that deleterious interactions of aberrantly activated macrophages with the inflammation-injured lung resident cells, and possibly hypoxia, not oxygenation, are critical determinants of PTB progression in immunocompetent hosts. Necrotic TB lesions also developed in subcutaneous implants of human lung tissue in mice with human immune system after respiratory infection. These animal models may serve to further dissect the lung-specific mechanisms of host susceptibility to virulent Mtb and for testing therapeutic interventions targeting these mechanisms.

immunology↗

bioRxiv2021

Bruton's Tyrosine Kinase Supports Gut Mucosal Immunity and Commensal Microbiome Recognition in Autoimmune Arthritis

Brutons tyrosine kinase (Btk) deficiency preferentially eliminates autoreactive B cells while sparing normal humoral responses, but has not been studied in mucosal immunity. Commensal microbes are essential for arthritis in K/BxN mice, used here to examine how BTK-mediated signaling interfaces with the microbiome. Btk-deficient K/BxN mice were found to have small Peyers Patches with reduced germinal center and IgA+ B cells. Although lamina propria IgA+ plasma cells were numerically normal, intestinal IgA was low and IgA coating of commensal bacteria was reduced. IgA-seq showed a shift in microbes that are normally IgA-coated into the uncoated fraction in Btk-deficient mice. In this altered microbial milieau, the proportion of Parabacteroides distasonis was reduced in Btk-deficient K/BxN mice. To determine whether P. distasonis contributes to arthritis, it was reintroduced into antibiotic-protected K/BxN mice, where it restored disease. This suggests that P. distasonis inability to thrive in Btk-deficient mice may be a factor in disease protection. Thus, BTK supports normal intestinal IgA development, with downstream effects on the microbiome that may contribute to autoimmunity.

immunology↗