Mycobacterial Diseases
Open Access

Balancing Immune Activation for Effective Treatment of TLR1 and TB

Kasang Arndatas^{* *}Correspondence: Kasang Arndatas, Department of Pathogenesis, Institute of Immunology, University of Münster, Germany, Email:

Author info »

Description

In despite of Tuberculosis (TB) advancements in diagnostics and treatment, understanding the host-pathogen interaction is essential for developing effective prevention and treatment strategies. One of the emerging areas of research is the role of Toll-Like Receptors (TLRs), especially TLR1, in influencing susceptibility to TB [1]. Toll-like receptors are essential components of the innate immune system. They recognize Pathogen Associated Molecular Patterns (PAMPs) on microbes, triggering an immune response. Among the TLR family, TLR1 is particularly significant in TB because it recognizes triacylated lipopeptides from mycobacteria, activating immune signalling pathways to combat the infection [2]. However, variations in TLR1 expression and function can lead to differences in how individuals respond to Mycobacterium tuberculosis (M. tb). High TLR1 expression may amplify inflammatory responses, potentially contributing to tissue damage and facilitating the survival of M. tb within the host.

The link between TLR1 expression and TB susceptibility

Increased TLR1 expression may lead to excessive production of pro-inflammatory cytokines like TNF-α and IL-6. While these cytokines are essential for controlling infection, their overproduction can cause collateral damage to lung tissue, creating an environment conducive to bacterial persistence [3]. Genetic variations in the TLR1 gene, such as Single Nucleotide Polymorphisms (SNPs), can influence its expression and function. Some polymorphisms have been associated with higher TLR1 activity and increased susceptibility to TB [4]. M. tb has evolved strategies to exploit host immune responses. High TLR1- mediated signalling may inadvertently aid the pathogen by creating inflammatory niches or exhausting the immune system. This intricate interplay between TLR1 expression, immune regulation, and M. tb survival underscores the delicate balance required for effective host defense [5]. Over activation of TLR1 can tip the scales, leading to immunopathology rather than protection. Moreover, these findings highlight the need for personalized approaches in TB management, considering genetic and immunological differences among individuals [6]. Targeting TLR1 pathways therapeutically could help modulate inflammation, ensuring efficient bacterial clearance while minimizing tissue damage.

Implications of TLR1 in TB management

Given the dual nature of TLR1 in TB, targeting its signalling pathway requires a nuanced approach. Therapeutic strategies could focus on modulating TLR1 activity to achieve a balance between effective bacterial clearance and controlled inflammation [7]. Potential interventions include, small molecules or biologics could be developed to fine-tune TLR1 activity. These agents might dampen excessive TLR1 signalling in individuals with high expression levels, reducing tissue damage while preserving essential immune responses [8]. Interventions that regulate downstream cytokines, such as TNF-α and IL-6 inhibitors, could mitigate the adverse effects of heightened inflammatory responses associated with increased TLR1 activity. Genetic screening for TLR1 polymorphisms could help identify individuals at higher risk of TB due to altered TLR1 expression or function [9]. Personalized therapeutic regimens could then be designed to address their specific immunological profiles. Vaccines targeting M. tb could be optimized by considering TLR1-mediated immune pathways. Adjuvants that modulate TLR1 activity might enhance vaccine efficacy by stimulating a balanced immune response [10]. Approaches that target the host immune response, rather than the pathogen directly, could be tailored to counteract the detrimental effects of overactive TLR1 signalling. These therapies could work alongside conventional antibiotics to improve outcomes and reduce disease progression.

Conclusion

TLR1 plays a dual role in TB immunity, acting as both a defender against M. tb and, in some cases, a contributor to disease progression. Understanding the factors that influence TLR1 expression and activity can provide valuable insights into TB pathogenesis and pave the way for innovative diagnostic and therapeutic strategies. As the fight against TB continues, unravelling the complexities of host-pathogen interactions, including the role of TLR1, will be important to achieving global TB control and elimination.

References

1. Schurz H, Daya M, Möller M, Hoal EG, Salie M. TLR1, 2, 4, 6 and 9 variants associated with tuberculosis susceptibility: A systematic review and meta-analysis. PLoS One. 2015;10(10):139711.

   [Crossref] [Google Scholar] [PubMed]

2. Mukherjee S, Huda S, Sinha Babu SP. Toll�like receptor polymorphism in host immune response to infectious diseases: A review. Scand J Immunol. 2019;90(1):12771.

   [Crossref] [Google Scholar] [PubMed]

3. Meyer CG, Reiling N, Ehmen C, Ruge G, Owusu-Dabo E, Horstmann RD, et al. TLR1 variant H305L associated with protection from pulmonary tuberculosis. PLoS One. 2016;11(5):0156046.

   [Crossref] [Google Scholar] [PubMed]

4. Mifsud EJ, Tan AC, Jackson DC. TLR agonists as modulators of the innate immune response and their potential as agents against infectious disease. Front Immunol. 2014;5:79.

   [Crossref] [Google Scholar] [PubMed]

5. Peng W, Chen H, Zhao Z, Hu X, Zhou Y, Li Y, et al. TLR1 polymorphisms are significantly associated with the occurrence, presentation and drug-adverse reactions of tuberculosis in Western Chinese adults. Oncotarget. 2018;9(2):1691.

   [Crossref] [Google Scholar] [PubMed]

6. Randhawa AK, Shey MS, Keyser A, Peixoto B, Wells RD, de Kock M, et al. Association of human TLR1 and TLR6 deficiency with altered immune responses to BCG vaccination in South African infants. PLoS Pathog. 2011;7(8):1002174.

   [Crossref] [Google Scholar] [PubMed]

7. Sia JK, Georgieva M, Rengarajan J. Innate immune defenses in human tuberculosis: An overview of the interactions between Mycobacterium tuberculosis and innate immune cells. J Immunol Res. 2015;2015(1):747543.

   [Crossref] [Google Scholar] [PubMed]

8. Qi H, Sun L, Wu X, Jin Y, Xiao J, Wang S, et al. Toll-like receptor 1 (TLR1) Gene SNP rs5743618 is associated with increased risk for tuberculosis in Han Chinese children. Tuberculosis. 2015 ;95(2):197-203.

   [Crossref] [Google Scholar] [PubMed]

9. Garlanda C, Di Liberto D, Vecchi A, La Manna MP, Buracchi C, Caccamo N, et al. Damping excessive inflammation and tissue damage in Mycobacterium tuberculosis infection by Toll IL-1 receptor 8/single Ig IL-1-related receptor, a negative regulator of IL-1/TLR signaling. J Immunol. 2007;179(5):3119-3125.

   [Crossref] [Google Scholar] [PubMed]

10. Richardson ET, Shukla S, Sweet DR, Wearsch PA, Tsichlis PN, Boom WH, et al. Toll-like receptor 2-dependent extracellular signal-regulated kinase signaling in Mycobacterium tuberculosis-infected macrophages drives anti-inflammatory responses and inhibits Th1 polarization of responding T cells. Infect Immun. 2015;83(6):2242-2254.

    [Crossref] [Google Scholar] [PubMed]