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Volume 6
Journal of Infectious Diseases and Therapy
ISSN: 2332-0877
Infection Congress 2018
March 01-02, 2018
Page 38
conference
series
.com
March 01-02, 2018 Berlin, Germany
5
th
International Congress on
INFECTIOUS DISEASES
Zlatko Dembic, J Infect Dis Ther 2018, Volume 6
DOI: 10.4172/2332-0877-C1-037
Tuberculosis risk is spread within the hallmarks of the disease
Statement of the Problem
: Heritable susceptibility to tuberculosis (TB) is complex and polygenic in nature. Only five to ten
percent of humans that come in contact with the bacterium
Mycobacterium tuberculosis
(Mt) will manifest the disease, provided
no acquired- or congenital immunodeficiency were present. We still lack a viable explanation for the observed epidemiologic fact.
Method
: Activation of macrophages via proinflammatory cytokines IFN-v and interleukin (IL)-17 can kill intracellular bacteria
such as Mt. Instead, macrophages stimulated by the Toll-like receptor (TLR)-10 agonists show an anti-inflammatory effect. The
TLR-10 acts by inhibiting the TLR-2 signaling from the cell membrane. The TLR-2 is the Mt-binding protein by which activated
macrophages can internalize (and kill) Mt. Inactivation of the TLR-2 protein might convey a risk for developing the disease. This
was supported by our finding that TLR2 gene polymorphisms, which either inactivate the TLR2 gene product or have a dominant-
negative role in TLR-2-signaling, associated with elevated risk for tuberculosis in the Croatian Caucasian population.
Findings
: The genome-wide study found that three single nucleotide polymorphisms (SNPs) within the HLA class II loci were
significantly associated with TB; suggesting that adaptive immunity is of paramount importance for defense against TB. In our
studied population, SNP in the TLR10 gene was associated with risk for TB, analyzed by the dominant model of inheritance.
However, this was contrasted by the fact that SNPs in the IL17A&F genes were not.
Conclusion & Significance
: Studying genetic risk by association analyses or genome-wide screening led us to propose that
clinical manifestation of TB is a state above certain risk-threshold. Threshold is reached by accumulation of seemingly minor
susceptibilities divided between the hallmarks of the disease (Fig 1). The model suggests that every human population has its own
mosaic of genetic risks for TB.
Recent publications
1. Bretscher P A et al. (2017) Immune class regulation and its medical significance part II of a report of a workshop on
foundational concepts of immune regulation. Scand J Immunol 85:242-250.
2. Sveinbjornsson G. et al. (2016) HLA class II sequence variants influence tuberculosis risk in populations of European
ancestry. Nature genetics 48:318-322.
3. Vrbanec J et al. (2016) Genetic risk of tuberculosis is spread within the hallmarks of the disease. Immunother Open Acc
2:117.
4. Bulat-Kardum L. et al. (2015) Genetic polymorphisms in the toll-like receptor 10, interleukin (IL)17A and IL17F genes
differently affect the risk for tuberculosis in Croatian population. Scand J Immunol 82:63-9.
5. Etokebe G E et al. (2010) Toll-like receptor 2 (P631H) mutant impairs membrane internalization and is a dominant
negative allele. Scand J Immunol. 71:369-381 (2010).
Zlatko Dembic
University of Oslo, Norway