Bacillus anthracis: a multi-faceted role for anthrax lethal toxin in thwarting host immune defenses

Lethal factor (LF), along with its receptor-binding partner protective antigen (PA), forms lethal toxin (LT), a critical virulence factor for Bacillus anthracis. LF is a Zn(2+) protease that cleaves specific mitogen activated protein kinase kinases (MAPKKs), inactivating signal transduction intermediates required for normal immune function. Initial research emphasized the role of LT in attenuating pro-inflammatory responses by macrophages, the primary targets of infection. More recent studies have revealed that LT affects a broad range of immune cells. In addition to direct effects on macrophages and neutrophils, LT suppresses the costimulatory functions of dendritic cells, thereby impeding essential cross-talk between innate and adaptive immune responses. Moreover, LT acts directly on T and B lymphocytes, blocking antigen receptor-dependent proliferation, cytokine production and Ig production. In this manner, LT mounts a broad-based attack on host immunity, thus providing B. anthracis with multiple mechanisms for avoiding protective host responses.