Immune Modulation as an Effective Adjunct Post-exposure Therapeutic for B. pseudomallei

Area of Science:

• Infectious Diseases
• Pharmacology
• Immunology

Background:

• Melioidosis, caused by Burkholderia pseudomallei, is a severe, often fatal infectious disease.
• Cyclooxygenase-2 (COX-2) inhibition, specifically reducing prostaglandin E2 (PGE2), shows promise for pulmonary melioidosis treatment.
• Existing COX-2 inhibitors are experimental, necessitating the identification of alternative therapeutic agents.

Purpose of the Study:

• To investigate the efficacy of Tolfenamic acid (TA), a non-steroidal anti-inflammatory drug (NSAID), as a post-exposure treatment for melioidosis.
• To evaluate TA's effects on cell survival, PGE2 production, COX-2, and nuclear factor-kappaB (NF-ĸB) activation in vitro.
• To assess the combined therapeutic potential of TA and ceftazidime (CZ) in a murine model of melioidosis.

Main Methods:

• Utilized RAW 264.7 macrophage cells infected with B. pseudomallei to assess TA's in vitro effects.
• Measured cell viability, PGE2 levels, COX-2, and NF-ĸB protein expression.
• Evaluated post-exposure treatment with TA alone and in combination with sub-therapeutic CZ in BALB/c mice, comparing survival and bacterial load.

Main Results:

• TA treatment increased cell viability in vitro and reduced COX-2 expression, PGE2 production, and NF-ĸB activation.
• Co-treatment with TA and sub-therapeutic CZ significantly improved survival rates in mice.
• Combined TA and CZ therapy effectively cleared bacterial loads in organ tissues.

Conclusions:

• Tolfenamic acid demonstrates therapeutic potential for melioidosis by modulating inflammatory pathways.
• Post-exposure treatment with TA, particularly in combination with sub-therapeutic ceftazidime, offers a viable strategy for melioidosis treatment.
• This study identifies TA as a potential candidate for further investigation in melioidosis therapy.