Talaromyces marneffei Mp1 Protein, a Novel Virulence Factor, Carries Two Arachidonic Acid-Binding Domains To Suppress Inflammatory Responses in Hosts

Talaromyces marneffei ( T. marneffei ) infection causes talaromycosis (previously known as penicilliosis), the second most-deadly opportunistic systematic mycosis in immuno-compromised patients. Different virulence mechanisms in T. marneffei had been proposed and investigated. In the sera of patients with talaromycosis, Mp1 protein (Mp1p), a secretory galactomannoprotein antigen encoding two tandem ligand-binding domains (Mp1p-LBD1 and Mp1p-LBD2), was found to be abundant. Mp1p-LBD2 was reported to possess a hydrophobic cavity to bind co-purified palmitic acid (PLM). It was hypothesized that capturing of lipids from human hosts by expressing large quantity of Mp1p may be a possible virulence mechanism of T. marneffei. It was shown that expression of Mp1p enhanced the intracellular survival of T. marneffei by suppressing pro-inflammatory responses. Mechanistic study of Mp1p-LBD2 suggested that arachidonic acid (AA), precursor of paracrine signaling molecules for regulations of inflammatory responses, is the major physiological target of Mp1p-LBD2. In this study, we use crystallographic and biochemical techniques to further demonstrate that Mp1p-LBD1, the previously unsolved first lipid binding domain of Mp1p, is also a strong AA-binding domain in Mp1p. These studies on Mp1p-LBD1 support that the highly-expressed Mp1p is an effective AA-capturing protein. Each Mp1p can bind up to 4 AA molecules. The crystal structure of Mp1p-LBD1-LBD2 has also been solved, showing that both LBDs are likely to function independently with a flexible linker in between. T. marneffei and potentially other pathogens highly expressing and secreting proteins similar to Mp1p can severely disturb hosts9 signaling cascades during pro-inflammatory responses, by reducing the availabilities of important paracrine signaling molecules.