Spatial and Temporal Localization of Immune Transcripts Defines Hallmarks and Diversity in the Tuberculosis Granuloma

Overview

Journal Nat Commun

Specialty Biology

Date 2019 Apr 25

PMID 31015452

Citations 46

Authors

Berit Carow

Thomas Hauling

Xiaoyan Qian

Igor Kramnik

Mats Nilsson

Martin E Rottenberg

Affiliations

Soon will be listed here.

Abstract

Granulomas are the pathological hallmark of tuberculosis (TB) and the niche where bacilli can grow and disseminate or the immunological microenvironment in which host cells interact to prevent bacterial dissemination. Here we show 34 immune transcripts align to the morphology of lung sections from Mycobacterium tuberculosis-infected mice at cellular resolution. Colocalizing transcript networks at <10 μm in C57BL/6 mouse granulomas increase complexity with time after infection. B-cell clusters develop late after infection. Transcripts from activated macrophages are enriched at subcellular distances from M. tuberculosis. Encapsulated C3HeB/FeJ granulomas show necrotic centers with transcripts associated with immunosuppression (Foxp3, Il10), whereas those in the granuloma rims associate with activated T cells and macrophages. We see highly diverse networks with common interactors in similar lesions. Different immune landscapes of M. tuberculosis granulomas depending on the time after infection, the histopathological features of the lesion, and the proximity to bacteria are here defined.

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References

Miller B, Fratti R, Poschet J, Timmins G, Master S, Burgos M . Mycobacteria inhibit nitric oxide synthase recruitment to phagosomes during macrophage infection. Infect Immun. 2004; 72(5):2872-8. PMC: 387846. DOI: 10.1128/IAI.72.5.2872-2878.2004. View

Cardona P, Gordillo S, Diaz J, Tapia G, Amat I, Pallares A . Widespread bronchogenic dissemination makes DBA/2 mice more susceptible than C57BL/6 mice to experimental aerosol infection with Mycobacterium tuberculosis. Infect Immun. 2003; 71(10):5845-54. PMC: 201050. DOI: 10.1128/IAI.71.10.5845-5854.2003. View

Salamon J, Qian X, Nilsson M, Lynn D . Network Visualization and Analysis of Spatially Aware Gene Expression Data with InsituNet. Cell Syst. 2018; 6(5):626-630.e3. DOI: 10.1016/j.cels.2018.03.010. View

Lin P, Ford C, Coleman M, Myers A, Gawande R, Ioerger T . Sterilization of granulomas is common in active and latent tuberculosis despite within-host variability in bacterial killing. Nat Med. 2013; 20(1):75-9. PMC: 3947310. DOI: 10.1038/nm.3412. View

Barnes P, Lu S, Abrams J, Wang E, Yamamura M, Modlin R . Cytokine production at the site of disease in human tuberculosis. Infect Immun. 1993; 61(8):3482-9. PMC: 281026. DOI: 10.1128/iai.61.8.3482-3489.1993. View

Lin P, Rodgers M, Smith L, Bigbee M, Myers A, Bigbee C . Quantitative comparison of active and latent tuberculosis in the cynomolgus macaque model. Infect Immun. 2009; 77(10):4631-42. PMC: 2747916. DOI: 10.1128/IAI.00592-09. View

Lein E, Borm L, Linnarsson S . The promise of spatial transcriptomics for neuroscience in the era of molecular cell typing. Science. 2017; 358(6359):64-69. DOI: 10.1126/science.aan6827. View

Driver E, Ryan G, Hoff D, Irwin S, Basaraba R, Kramnik I . Evaluation of a mouse model of necrotic granuloma formation using C3HeB/FeJ mice for testing of drugs against Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2012; 56(6):3181-95. PMC: 3370740. DOI: 10.1128/AAC.00217-12. View

Larsson C, Grundberg I, Soderberg O, Nilsson M . In situ detection and genotyping of individual mRNA molecules. Nat Methods. 2010; 7(5):395-7. DOI: 10.1038/nmeth.1448. View

10.

Goenawan I, Bryan K, Lynn D . DyNet: visualization and analysis of dynamic molecular interaction networks. Bioinformatics. 2016; 32(17):2713-5. PMC: 5013899. DOI: 10.1093/bioinformatics/btw187. View

11.

Khader S, Guglani L, Rangel-Moreno J, Gopal R, Junecko B, Fountain J . IL-23 is required for long-term control of Mycobacterium tuberculosis and B cell follicle formation in the infected lung. J Immunol. 2011; 187(10):5402-7. PMC: 3208087. DOI: 10.4049/jimmunol.1101377. View

12.

Hunter R . Tuberculosis as a three-act play: A new paradigm for the pathogenesis of pulmonary tuberculosis. Tuberculosis (Edinb). 2016; 97:8-17. PMC: 4795183. DOI: 10.1016/j.tube.2015.11.010. View

13.

CANETTI G . Dynamic aspects of the pathology and bacteriology of tuberculous lesions. Am Rev Tuberc. 1956; 74(2 Part 2):13-21; discussion, 22-7. DOI: 10.1164/artpd.1956.74.2-2.13. View

14.

Jones G, Hill D, Jones S . Understanding Immune Cells in Tertiary Lymphoid Organ Development: It Is All Starting to Come Together. Front Immunol. 2016; 7:401. PMC: 5046062. DOI: 10.3389/fimmu.2016.00401. View

15.

Darwin K, Ehrt S, Gutierrez-Ramos J, Weich N, Nathan C . The proteasome of Mycobacterium tuberculosis is required for resistance to nitric oxide. Science. 2003; 302(5652):1963-6. DOI: 10.1126/science.1091176. View

16.

Tsai M, Chakravarty S, Zhu G, Xu J, Tanaka K, Koch C . Characterization of the tuberculous granuloma in murine and human lungs: cellular composition and relative tissue oxygen tension. Cell Microbiol. 2006; 8(2):218-32. DOI: 10.1111/j.1462-5822.2005.00612.x. View

17.

Scott-Browne J, Shafiani S, Tucker-Heard G, Ishida-Tsubota K, Fontenot J, Rudensky A . Expansion and function of Foxp3-expressing T regulatory cells during tuberculosis. J Exp Med. 2007; 204(9):2159-69. PMC: 2118702. DOI: 10.1084/jem.20062105. View

18.

Sallusto F, Lenig D, Mackay C, Lanzavecchia A . Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes. J Exp Med. 1998; 187(6):875-83. PMC: 2212187. DOI: 10.1084/jem.187.6.875. View

19.

Kramnik I, Beamer G . Mouse models of human TB pathology: roles in the analysis of necrosis and the development of host-directed therapies. Semin Immunopathol. 2015; 38(2):221-37. PMC: 4779126. DOI: 10.1007/s00281-015-0538-9. View

20.

Pichugin A, Yan B, Sloutsky A, Kobzik L, Kramnik I . Dominant role of the sst1 locus in pathogenesis of necrotizing lung granulomas during chronic tuberculosis infection and reactivation in genetically resistant hosts. Am J Pathol. 2009; 174(6):2190-201. PMC: 2684184. DOI: 10.2353/ajpath.2009.081075. View