rs1051838 Promotes Intracellular Survival of Mycobacterium tuberculosis H37Ra by Regulating DUSP14 Expression

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major global health burden. Host genetic factors play a critical role in TB susceptibility, but the underlying mechanisms are not fully understood. Genome-wide association studies have identified DUSP14 as a TB susceptibility gene, and the single nucleotide polymorphism (SNP) rs1051838 in DUSP14 seems to be associated with TB risk. Using in vitro models including THP-1-derived macrophages, A549 cells, and HEK293T cells, we investigated how rs1051838 regulates DUSP14 expression and modulates macrophage responses to Mtb infection. We found that the G allele of rs1051838 exhibits higher transcriptional activity than the A allele in reporter assays. The G allele creates a CpG dinucleotide that is subject to methylation-mediated repression. Mtb infection reduced CpG methylation across this region to upregulate DUSP14, leading to suppressed JNK phosphorylation via its phosphatase activity, reduced pro-inflammatory cytokine production, and promoted intracellular bacterial survival. Knockdown of DUSP14 decreases bacterial burden and increases cytokine secretion. These findings reveal a functional link between genetic variation and immune response in TB and point to DUSP14 as a potential target for host directed therapy, although further validation in primary cells or using virulent strains and in vivo models is needed.