Bacillus anthracis factors for phagosomal escape

Abstract

The mechanism of phagosome escape by intracellular pathogens is an important step in the infectious cycle. During the establishment of anthrax, Bacillus anthracis undergoes a transient intracellular phase in which spores are engulfed by local phagocytes. Spores germinate inside phagosomes and grow to vegetative bacilli, which emerge from their resident intracellular compartments, replicate and eventually exit from the plasma membrane. During germination, B. anthracis secretes multiple factors that can help its resistance to the phagocytes. Here the possible role of B. anthracis toxins, phospholipases, antioxidant enzymes and capsules in the phagosomal escape and survival, is analyzed and compared with that of factors of other microbial pathogens involved in the same type of process.

Keywords: Bacillus anthracis; anthrax; anthrolysin; capsule; catalase; germination; phagocytes; phospholipase C; spore; superoxide dismutase; toxins.

Figure 1

Factors produced by B. anthracis having a possible role in helping bacterial survival inside the phagosome. (A) B. anthracis spore is internalized after interaction with membrane receptors, Mac-1 or other receptors (see introduction). It can also interact with anthrax toxin receptors (ATRs) as protective antigen (PA) can be present in the exosporium; (B) Once inside the phagosome, the spore, in response to intracellular factors, is stimulated to germinate and activate a program of protein production different from that activated in in vitro culture; (C) The microorganism releases factors that prevent the maturation of the phagosome and help the bacterium to leave it. LF and EF inhibit the fusion of the phagosome with the lysosome (see text). This fusion can also be inhibited by the polyglutamic acid of the capsule that moreover inhibits the action of antibacterial alpha- and beta-defensins. The increase of oxidant species (ROS) into the phagosome is inhibited by different factors produced by B. anthracis: an arginase and two superoxide-dismutase SODs proteins present into the exosporium, and a catalase (KatB) abundantly produced during the germination phase inside the phagosome. Finally the poly-γ-D-glutamic acid of the capsule, the cytolysin ALO and three PLC proteins can contribute to the destabilization and lysis of the phagosomal membrane and so to the exiting of the bacterium into the cytosol; (D) The B. anthracis phagocytized in the germination phase (grey and black spores) probably activates a different germination program with insufficient production of survival factors.

Figure 2

Conditions that can favor the survival of B. anthracis in the phagosome. (A) The B. anthracis microbes internalized as spores by phagocytes are, in most cases, digested after spore germination. However in some, still not completely understood, circumstances the bacterium can survive the phagosome digestion, leave the phagocyte and give rise to the dangerous bacteremia and toxemia typical of acute anthrax. These conditions can include; (B) high spore charges; (C) internalization by dendritic cells that, coherently with their action of antigen presenting cells, activate a milder digestion process; (D) internalization by receptors that are involved in a different phagosome maturation process.