Immune Response to<i>Mycobacterium tuberculosis</i>and Identification of Molecular Markers of Disease

Gonzalez-Juarrero, Mercedes; Kingry, Luke C.; Ordway, Diane; Henao-Tamayo, Marcela; Harton, Marisa; Basaraba, Randall J.; Hanneman, William H.; Orme, Ian M.; Slayden, Richard A.

doi:10.1165/rcmb.2008-0248oc

Cited by 32 publications

(32 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…S4A). Gene profiles described here, which reflect the complex dynamic interplay between host and pathogen at day 28, match kinetic transcriptome profiles reported previously between day 12 and 100 in comparable mouse M. tuberculosis infection models4344.…”

Section: Resultssupporting

confidence: 83%

Controlled Mycobacterium tuberculosis infection in mice under treatment with anti-IL-17A or IL-17F antibodies, in contrast to TNFα neutralization

Segueni¹,

Tritto²,

Bourigault³

et al. 2016

Sci Rep

View full text Add to dashboard Cite

Antibodies targeting IL-17A or its receptor IL-17RA show unprecedented efficacy in the treatment of autoimmune diseases such as psoriasis. These therapies, by neutralizing critical mediators of immunity, may increase susceptibility to infections. Here, we compared the effect of antibodies neutralizing IL-17A, IL-17F or TNFα on murine host responses to Mycobacterium tuberculosis infection by evaluating lung transcriptomic, microbiological and histological analyses. Coinciding with a significant increase of mycobacterial burden and pathological changes following TNFα blockade, gene array analyses of infected lungs revealed major changes of inflammatory and immune gene expression signatures 4 weeks post-infection. Specifically, gene expression associated with host-pathogen interactions, macrophage recruitment, activation and polarization, host-antimycobacterial activities, immunomodulatory responses, as well as extracellular matrix metallopeptidases, were markedly modulated by TNFα blockade. IL-17A or IL-17F neutralization elicited only mild changes of few genes without impaired host resistance four weeks after M. tuberculosis infection. Further, the absence of both IL-17RA and IL-22 pathways in genetically deficient mice did not profoundly compromise host control of M. tuberculosis over a 6-months period, ruling out potential compensation between these two pathways, while TNFα-deficient mice succumbed rapidly. These data provide experimental confirmation of the low clinical risk of mycobacterial infection under anti-IL-17A therapy, in contrast to anti-TNFα treatment.

show abstract

Section: Resultssupporting

confidence: 83%

Controlled Mycobacterium tuberculosis infection in mice under treatment with anti-IL-17A or IL-17F antibodies, in contrast to TNFα neutralization

Segueni¹,

Tritto²,

Bourigault³

et al. 2016

Sci Rep

View full text Add to dashboard Cite

show abstract

“…SLAMF8 mRNA is reported to be upregulated by 5-fold in pulmonary CD8 T-cells in BALB/c mice inoculated with MTB antigen 85A (Ad85A) intra-nasally as compared to intra-dermal route [46]. A progressive upregulation of SLAMF8 mRNA was reported in mouse lungs inoculated with MTB at 20, 40 and 100 days of the infection [47]. Class II, major histocompatibility complex, transactivator ( CIITA) encodes a nuclear protein, which regulates the expression of class II major histocompatibility complex genes [48,49], was identified to be upregulated by 28-fold in the present study.…”

Section: Resultsmentioning

confidence: 99%

Gene Expression Profiling of Tuberculous Meningitis Co-infected with HIV

Kumar

Venugopal

Kashyap

et al. 2012

JPB

View full text Add to dashboard Cite

Tuberculous meningitis (TBM) is a fatal form of Mycobacterium tuberculosis infection of the central nervous system (CNS). The similarities in the clinical and radiological findings in TBM cases with or without HIV make the diagnosis very challenging. Identification of genes, which are differentially expressed in brain tissues of HIV positive and HIV negative TBM patients, would enable better understanding of the molecular aspects of the infection and would also serve as an initial platform to evaluate potential biomarkers. Here, we report the identification of 796 differentially regulated genes in brain tissues of TBM patients co-infected with HIV using oligonucleotide DNA microarrays. We also performed immunohistochemical validation and confirmed the abundance of four gene products-glial fibrillary acidic protein (GFAP), serpin peptidase inhibitor, clade A member 3 (SERPINA3), thymidine phosphorylase (TYMP/ECGF1) and heat shock 70 kDa protein 8 (HSPA8). Our study paves the way for understanding the mechanism of TBM in HIV positive patients and for further validation of potential disease biomarkers.

show abstract

“…Genes characteristically induced by mycobacteria, such as Tlr2/4 and Indo (IDO) [32], were not highly expressed in lung i.n. samples.…”

Section: Resultsmentioning

confidence: 99%

Chemokine gene expression in lung CD8 T cells correlates with protective immunity in mice immunized intra-nasally with Adenovirus-85A

et al. 2010

View full text Add to dashboard Cite

BackgroundImmunization of BALB/c mice with a recombinant adenovirus expressing Mycobacterium tuberculosis (M. tuberculosis) antigen 85A (Ad85A) protects against aerosol challenge with M. tuberculosis only when it is administered intra-nasally (i.n.). Immunization with Ad85A induces a lung-resident population of activated CD8 T cells that is antigen dependent, highly activated and mediates protection by early inhibition of M. tuberculosis growth. In order to determine why the i.n. route is so effective compared to parenteral immunization, we used microarray analysis to compare gene expression profiles of pulmonary and splenic CD8 T cells after i.n. or intra-dermal (i.d.) immunization.MethodTotal RNA from CD8 T cells was isolated from lungs or spleens of mice immunized with Ad85A by the i.n. or i.d. route. The gene profiles generated from each condition were compared. Statistically significant (p ≤ 0.05) differentially expressed genes were analyzed to determine if they mapped to particular molecular functions, biological processes or pathways using Gene Ontology and Panther DB mapping tools.ResultsCD8 T cells from lungs of i.n. immunized mice expressed a large number of chemokines chemotactic for resting and activated T cells as well as activation and survival genes. Lung lymphocytes from i.n. immunized mice also express the chemokine receptor gene Cxcr6, which is thought to aid long-term retention of antigen-responding T cells in the lungs. Expression of CXCR6 on CD8 T cells was confirmed by flow cytometry.ConclusionsOur microarray analysis represents the first ex vivo study comparing gene expression profiles of CD8 T cells isolated from distinct sites after immunization with an adenoviral vector by different routes. It confirms earlier phenotypic data indicating that lung i.n. cells are more activated than lung i.d. CD8 T cells. The sustained expression of chemokines and activation genes enables CD8 T cells to remain in the lungs for extended periods after i.n. immunization. This may account for the early inhibition of M. tuberculosis growth observed in Ad85A i.n. immunized mice and explain the effectiveness of i.n. compared to parenteral immunization with this viral vector.

show abstract

Immune Response toMycobacterium tuberculosisand Identification of Molecular Markers of Disease

Cited by 32 publications

References 67 publications

Controlled Mycobacterium tuberculosis infection in mice under treatment with anti-IL-17A or IL-17F antibodies, in contrast to TNFα neutralization

Controlled Mycobacterium tuberculosis infection in mice under treatment with anti-IL-17A or IL-17F antibodies, in contrast to TNFα neutralization

Gene Expression Profiling of Tuberculous Meningitis Co-infected with HIV

Chemokine gene expression in lung CD8 T cells correlates with protective immunity in mice immunized intra-nasally with Adenovirus-85A

Contact Info

Product

Resources

About