Complement in tuberculosis infection and disease, a battle of two ancients

Tuberculosis continues to kill over a million people every year, with an additional 10 million people falling ill. The ongoing efforts to eradicate the disease are hampered by an incomplete understanding of the mechanisms involved in the defense against tuberculosis. It has become clear that next to the well-known T-cell responses other components of the immune system also play important roles, both protective and detrimental, in the host defense against tuberculosis. In particular, the role of antibodies and complement are increasingly appreciated. However, the contribution of the complement system during Mycobacterium tuberculosis infection and disease remains poorly understood. The complement system is an intricate network of plasma proteins, which upon activation can achieve a powerful cytotoxic effect. Additionally, a range of antimicrobial and immune-modulating effector molecules, such as opsonins and chemoattractants, are generated. As a consequence, the role of the complement system in host defense extends beyond its cytotoxic effect, influencing both the innate and adaptive immune response. In this review, we discuss the many-faceted role of the complement system in tuberculosis, reviewing its involvement in infection, disease progression, and response to therapy, and provide a perspective on how the complement system can be harnessed to improve tuberculosis diagnostics, vaccines and therapeutics.