Serum lipoproteins and lipoarabinomannan suppress the inflammatory response induced by the mycolactone toxin

Mycobacterium ulcerans is the causative agent of the chronic and debilitating neglected tropical disease Buruli ulcer (BU) that mostly affects children. The early detection and treatment of M. ulcerans infections can significantly minimize life-long disability resulting from surgical intervention. However, the disease is characterized by relatively few systemic symptoms due to complex host-pathogen interactions that have yet to be fully characterized, which has limited the development of both diagnostic and therapeutic approaches to treat BU. In this work, we study the interactions of the host immune system with two principle M. ulcerans virulence factors: mycolactone, an amphiphilic macrolide toxin, and lipoarabinomannan (LAM), a cell wall component of most mycobacterial pathogens. We observe that human lipoproteins have a profound effect on the interaction of both mycolactone and LAM with the immune system. Individually, both molecules are pro-inflammatory in the absence of serum and immunosuppressive in the presence of serum. When combined, mycolactone and LAM are immunosuppressive regardless of serum conditions. We also show that Toll-like receptor 2 (TLR2), a macrophage pathogen pattern recognition receptor, is critical for LAM immune stimulation but aids in mycolactone immunosuppression. These findings are a critical step towards unraveling mycolactone-mediated immunosuppression during BU disease and may facilitate the development of effective diagnostics and therapeutics in the future. ### Competing Interest Statement The authors have declared no competing interest.