PE_PGRS33 Contributes to Mycobacterium tuberculosis Entry in Macrophages through Interaction with TLR2

Area of Science:

• Microbiology
• Immunology
• Molecular Biology

Background:

• PE_PGRS proteins are abundant in Mycobacterium tuberculosis (Mtb).
• The function of PE_PGRS proteins in Mtb pathogenesis remains largely unknown.
• PE_PGRS33 is a representative member of this protein family.

Purpose of the Study:

• To investigate the role of PE_PGRS33 in Mtb infection.
• To elucidate the mechanism of Mtb entry into host cells mediated by PE_PGRS33.

Main Methods:

• Generation and characterization of an Mtb H37Rv mutant lacking PE_PGRS33 (MtbΔ33).
• Complementation of the MtbΔ33 strain with functional deletion mutants of PE_PGRS33.
• Assessment of Mtb entry efficiency into macrophages and pneumocytes.
• Analysis of Mtb entry in TLR2-deficient mice and in the presence of wortmannin or anti-CR3 antibody.

Main Results:

• The MtbΔ33 mutant showed a tenfold lower efficiency in entering macrophages compared to the parental strain.
• PE_PGRS33's C-terminal PGRS domain, specifically amino acids 140-260, is essential for macrophage entry.
• Mtb entry into macrophages mediated by PE_PGRS33 was dependent on Toll-like receptor 2 (TLR2) and complement receptor 3 (CR3).
• The lack of PE_PGRS33 did not impact intracellular growth within macrophages or pneumocyte infection efficiency.

Conclusions:

• PE_PGRS33 is a key virulence factor for Mtb macrophage invasion.
• The PGRS domain of PE_PGRS33 mediates Mtb entry via TLR2 and CR3 interactions.
• Targeting PE_PGRS33 interactions could be a strategy to control Mtb infections.