Innate Immunity vs. Anthrax
To use a historical metaphor, if the macrophages are the brave and noble cavalry of the innate immune system, then bacillus anthracis are the tanks and planes that blind them with superior technology. The complicated interactions between B. anthracis and the innate immune system are some of the most complicated and well researched aspects of the disease. Some researchers suggest that, rather than protecting the body from infection, macrophages become the vehicle of its agency, as mice depleted of macrophages become resistant to the lethal toxin produced by B. anthracis (8). Still other researchers suggest that B. anthracis simply silences activated macrophages so that it can go about proliferating without interruption (14).
Bacillus Anthracis Invades the Macrophage
The first step of anthrax pathogenesis is the bacterial spore’s entry into a macrophage via phagocytosis (1,4,9). Once inside the macrophage, the cells become vegetative, rapidly dividing cells (1,7,8,9). Macrophage-conditioned media has been found to promote transition of B. anthracis from spores to the vegetative state (7). This process is mediated by the gerH operon, as when this locus is deleted from the bacterium, the transition does not (7).
While the macrophages help B. anthracis divide, the bacterium is able to escape death by moving from the phagolysosome to the macrophage cytoplasm, where it can safely hide out (10). The bacteria can leave the infected macrophages in one of two ways. The first involves a gene on the plasmid pXO1 called atxA that allows the bacteria to exit the membrane. Strains of B. anthracis without pXO1 simply divide until, through the sheer volume of bacteria within the macrophage, they disrupt the macrophage membrane and burst the cell (10).
Hijacking the Macrophage
B. anthracis stimulates a the release of a cocktail of cytokines (11). Because the molecular factors of anthrax pathogenesis all act in concert, it is difficult to study their individual roles, though recent research suggests that anthrax stands to gain from inhibiting cytokine response. For example, several studies have suggested that purified B. anthracis lethal toxin (LeTx) disables the cytokine response (12,13,14). Erwin et al found that LeTx inhibited the transcription of cytokine mRNA (12). Prince and Moayeri et. al. investigated the role of LeTx in murine toxicity and found it to be independent of the action of TNF-a (13,14).
The issue is complicated by investigations that suggest that B. anthracis uses the macrophage to flood the host with cytokines. Pickering et. al., observed an increase in TNF-a and IL-6 secretion in murine macrophages upon exposure to whole B. anthracis cells, as well as IL-1b, IL-8, and IL-12 in human dendritic cells (11). Hoover et al found that edema toxin (ET), the other virulence factor in B. anthracis, upregulated intracellular cAMP, affecting production of TNF-a and IL-6 (15). Hanna et al suggest that production of cytokines is increased by the action of the macrophage’s oxidative burst. A study found that antioxidants that removed reactive oxygen intermediates were insensitive to effects of LeTx, meaning that they were not killed, nor did they upregulate cytokine production (16). These seemingly contradictory results illustrate the complexity and elegance with which B. anthracis attacks the body.
To add insult to injury, not only does B. anthracis harness the abilities of the macrophage to help kill the host, but it induces apoptosis as well. LeTx induces apoptosis of activated macrophages by destroying MAPK kinases and inhibiting the activation of p38 MAPK. This leads to apoptosis, but only in activated macrophages (17). The authors of this study propose that this mechanism helps B. anthracis multiply in the body undetected until infection is systemic and the immune system is overwhelmed.
Singlaing map of B. anthracis. See Source 9
Attacking the Dendritic Cells
Yet another way that anthrax disables innate immunity is by paralyzing the dendritic cells (9,18). Agrawal et al observed that dendritic cells treated with LeTx and then exposed to LPS do not upregulate con-stimulatory molecules, are not able to upregulate cytokine secretion as would happen during normal dendritic cell function. They also lose the ability to stimulate antigen-specific T-cells (18). By disabling dendritic cells, B. anthracis effectively cuts off the link between innate and adaptive immunity, elegantly allowing the bacteria to go undetected as it proliferates in the body (9).
Schematic of innate immunity suppresion and interaction. See source 9
B. anthracis has evolved to easily deal with challenges posed by the innate immune system. While there is still a debate as to whether the pathogenic action is the upregulation of cytokines or the inhibition of the cytokine response, there is no disagreement that B. anthracis is able to proliferate in the host without difficulty. It does this by disabling almost every aspect of innate immunity (18) It is worth noting that there is no debate over the presence of a systemic increase of cytokines as a part of anthrax pathogenesis; those who believe that B. anthracis inhibits the cytokine response attribute the deluge of cytokines to necrosis, primarily in the liver (14).