Date Published: June 15, 2016
Publisher: Public Library of Science
Author(s): Yanyu Wang, Sarah A. Jenkins, Chunfang Gu, Ankita Shree, Margarita Martinez-Moczygemba, Jennifer Herold, Marina Botto, Rick A. Wetsel, Yi Xu, Theresa M. Koehler.
Spores of Bacillus anthracis, the causative agent of anthrax, are known to persist in the host lungs for prolonged periods of time, however the underlying mechanism is poorly understood. In this study, we demonstrated that BclA, a major surface protein of B. anthracis spores, mediated direct binding of complement factor H (CFH) to spores. The surface bound CFH retained its regulatory cofactor activity resulting in C3 degradation and inhibition of downstream complement activation. By comparing results from wild type C57BL/6 mice and complement deficient mice, we further showed that BclA significantly contributed to spore persistence in the mouse lungs and dampened antibody responses to spores in a complement C3-dependent manner. In addition, prior exposure to BclA deletion spores (ΔbclA) provided significant protection against lethal challenges by B. anthracis, whereas the isogenic parent spores did not, indicating that BclA may also impair protective immunity. These results describe for the first time an immune inhibition mechanism of B. anthracis mediated by BclA and CFH that promotes spore persistence in vivo. The findings also suggested an important role of complement in persistent infections and thus have broad implications.
Persistent colonization of the host by microbial pathogens can cause chronic infections, which are often difficult to treat with conventional antibiotics. It is recognized that persistent infection is a unique phase often involving specific virulence factors and pathogenic mechanisms . Identifying and understanding these persistent mechanisms is key to developing new strategies to more effectively combat chronic infections.
In this study we discovered a novel function for the major B. anthracis spore surface protein BclA. We demonstrated that BclA mediated recruitment of CFH to spores, facilitated C3b degradation on the spore surface, inhibited further C3 activation, and reduced C5 cleavage both in vitro and in vivo. We further showed that BclA promoted spore persistence in the host lungs and inhibited antibody responses against spores in a C3-dependent manner. Furthermore, BclA impaired protective immunity against lethal B. anthracis challenges. These results describe for the first time a spore-mediated immune modulatory mechanism through inhibition of complement. The results also suggested an important role of complement in persistent infections, an aspect of pathogen-complement interaction that is poorly understood.