Wednesday, February 18, 2026 2/18/2026

Molecular mechanisms of MCP-1 polymorphism-mediated susceptibility to pulmonary tuberculosis infection

Award Number: R21AI190812
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/13/2026
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Molecular mechanisms of MCP-1 polymorphism-mediated susceptibility to pulmonary tuberculosis infection - Project Summary/Abstract Tuberculosis (TB) remains a leading global health problem. Though one fourth of the world’s population is infected by Mycobacterium tuberculosis (Mtb), 90% of the people infected with Mtb remain asymptomatic as latent TB infection (LTBI). The reasons why 10% of the infected people progress to active TB are still elusive. Host genetic variations play an important role in TB susceptibility and LTBI reactivation. It has been reported that one single nucleotide polymorphism G/G (SNP-G) at -2518 in the promoter region of monocyte chemoattractant protein-1 (MCP-1) is strongly associated with active pulmonary TB (PTB). The underlying mechanisms of the - 2518 SNP-G-associated PTB susceptibility, however, remain unknown. MCP-1 is one of the key chemokines that regulate migration and infiltration of monocytes and macrophages to the sites of infection. Active TB patients show high levels of MCP-1 compared to people with LTBI and healthy volunteers. Higher levels of MCP-1 have also been used as a biomarker to distinguish active TB from LTBI. Flores-Villanueva, et al. first reported that people harboring the -2518 SNP-G had higher MCP-1 and lower IL-12 in sera and were more likely to develop PTB than individuals carrying the -2518 A/A (SNP-A) haplotype. Two meta-analyses analyzing a total of 5341 active TB cases and 6075 controls in 13 case-control studies report that the -2518 G/G homozygote carriers have a 67% increased risk of TB compared with the A allele carriers and the SNP-G homozygote is a risk factor for PTB. To test whether the SNP-G affected MCP-1 transcription, we cloned the MCP-1 promoter harboring the SNP G/G and SNP A/A into a luciferase vector and checked their luciferase activity in THP1 cells after mycobacterial infection. The SNP-G promoter showed a significant increase in luciferase activity compared to the SNP-A promoter. The MCP-1 transcripts in human macrophages carrying the homozygous SNP-G/G were also the highest than the cells harboring the SNP-A/A and the SNP-A/G after Mtb infection. We also found that BCG induced a strong nuclear binding specifically to the SNP-G and a small group of nuclear proteins called E- box binding protein bound to SNP-G. By reexamining the flanking sequence over the SNP, we found that the SNP-G but SNP-A constitutes the E-box motif (5’-CAGCTG-3’) in the MCP-1 promoter. The E-box-binding proteins are composed of a large superfamily basic helix-loop-helix (bHLH) proteins that transcriptionally regulate many functions in cancer, sex determination and development of the nervous system and muscles. How bHLH proteins regulate MCP-1 expression and affect mycobacterial growth are unknown and will be explored with the following two aims. Aim 1: Identify the E-box-binding proteins that bind to the SNP-G and regulate MCP-1 gene expression in Mtb-infected human macrophages. Aim 2: Explore the molecular mechanisms by which the SNP- G in MCP-1 promoter affects Mtb growth in human macrophages. The results will help us understand the molecular mechanisms of how -2518 G/G homozygote in the MCP-1 promoter contributes to TB susceptibility and reveal a novel role for the E-box binding proteins in control of host defense against Mtb infection.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $192,500 )
2026	2026	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Allergy and Infectious Diseases Research	000	1	2/13/2026	NEW	$192,500
														Subtotal = $192,500

Grand Total All Awards = $192,500

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Molecular mechanisms of MCP-1 polymorphism-mediated susceptibility to pulmonary tuberculosis infection

Award Number: R21AI190812

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/13/2026

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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