What is the relevance of lung epithelial cells during the dissemination of spores in inhalational anthrax?

A recent paper published by Russell et al. suggests that Bacillus anthracis spores can be taken up by lung epithelial cells that then participate in the transport and diffusion of pathogens (6). In a model of BALB/c mice infected by the Sterne strain, the authors focus on data from 2 and 4 h after infection, which limits their analysis to the very early stages of infection. They analyzed spore-cell contact on a “crude lung cell suspension” by using confocal microscopy. Although a powerful technique, confocal microscopy simply does not enable observation of histological tissue structure or spatial orientation for spore contact. As a result, it cannot be concluded from what is shown that spores traverse (from outside to inside) the lung epithelium in vivo. One of the main questions unanswered is whether spores are only phagocytosed or are phagocytosed and then traverse throughout the epithelial cells. Beside these technical flaws, the number of epithelial cells with intracellular spores is strikingly low, estimated at 20,163 for 3.3 10 epithelial cells (0.62% 0.16%). This is to be compared to 60% of spore-phagocytosing alveolar macrophages after 10 min of infection in a recent report (2). The authors acknowledge in their Discussion that in vivo internalization frequency is only about 0.3% of the total inhaled spores. Although the authors’ observations are interesting, it seems that the capture of anthrax spores by lung epithelial cells is a rather marginal phenomenon. It should be stressed that epithelial cells are not motile per se. As B. anthracis spores and bacilli are not motile either, the bacterial spores need a host-provided vehicle for traversing the epithelial wall in their journey to the draining lymph nodes. The authors’ hypothesis suggesting that “spores may potentially enter the pulmonary capillaries by a paracellular route” is simply not realistic according to what is known about spore and bacillus motility. Most data published so far on inhalational anthrax pathogenesis have shown that either macrophages or dendritic cells play the vehicle role (2–5). Such results mean that even if spores traverse the lung wall through the epithelial cells, the spores still need to be captured by a macrophage or dendritic cell for the rest of their journey to the draining lymph nodes. Clearly, the role of lung epithelial cells in spore transport during inhalational anthrax is still debatable. It does not mean that the lung epithelial cells do not contribute to pathogenesis, because the lung microenvironment certainly plays a crucial role in controlling the immune system (7). Spore capture by the epithelium can subsequently stimulate chemokine secretion (1), leading to the recruitment of proinflammatory cells (polymorphonuclear cells, monocytes) as well as trigger the antimicrobial protein secretion. The lung epithelial cells could then play a central role during the recruitment of immune effectors in the early steps of anthrax infection that facilitates host defense.