Toll-like receptor 1 N248S single-nucleotide polymorphism is associated with leprosy risk and regulates immune activation during mycobacterial infection.

Abstract

Conflicting findings about the association between leprosy and TLR1 variants N248S and I602S have been reported. Here, we performed case-control and family based studies, followed by replication in 2 case-control populations from Brazil, involving 3162 individuals. Results indicated an association between TLR1 248S and leprosy in the case-control study (SS genotype odds ratio [OR], 1.81; P = .004) and the family based study (z = 2.02; P = .05). This association was consistently replicated in other populations (combined OR, 1.51; P < .001), corroborating the finding that 248S is a susceptibility factor for leprosy. Additionally, we demonstrated that peripheral blood mononuclear cells (PBMCs) carrying 248S produce a lower tumor necrosis factor/interleukin-10 ratio when stimulated with Mycobacterium leprae but not with lipopolysaccharide or PAM3cysK4. The same effect was observed after infection of PBMCs with the Moreau strain of bacillus Calmette-Guerin but not after infection with other strains. Finally, molecular dynamics simulations indicated that the Toll-like receptor 1 structure containing 248S amino acid is different from the structure containing 248N. Our results suggest that TLR1 248S is associated with an increased risk for leprosy, consistent with its hypoimmune regulatory function.

• Authors: Carolinne de Sales Marques, Vânia N Brito-de-Souza, Luana Tatiana Albuquerque Guerreiro, João H Martins, Evaldo P Amaral, Cynthia C Cardoso, Ida Maria Foschiani Dias-Batista, Weber Laurentino da Silva, José Augusto C Nery, Priscila Medeiros, Patricia Gigliotti, Ana Paula Campanelli, Marcos Virmond, Euzenir Nunes Sarno, Marcelo T Mira, Francisco C F Lana, Ernesto Raúl Caffarena, Antonio G Pacheco, Ana Carla Pereira, Milton Ozório Moraes
• Journal: The Journal of infectious diseases (J Infect Dis) Vol. 208 Issue 1 Pg. 120-9 (Jul 2013) ISSN: 1537-6613 [Electronic] United States
• PMID: 23547143 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Toll-Like Receptor 1

Topics

• Adult
• Case-Control Studies
• Enzyme-Linked Immunosorbent Assay
• Female
• Flow Cytometry
• Gene Frequency (genetics)
• Genotype
• Haplotypes
• Heterozygote
• Humans
• Immunity (genetics)
• Leprosy (genetics, immunology)
• Leukocytes, Mononuclear (immunology)
• Middle Aged
• Mycobacterium leprae (immunology)
• Polymorphism, Single Nucleotide (genetics, physiology)
• Risk Factors
• Toll-Like Receptor 1 (genetics, physiology)