How does Mycobacterium tuberculosis establish infection?

On 16 January 1924, Allen Krause gave an address entitled “The spread of tuberculous infection in the body” before the Bronx County Medical Society, under the auspices of the New York Tuberculosis (TB) Association [1]. He said “few of us, it would seem, think of the possibility of a more general distribution of infection as perhaps the mode of tuberculosis; of bacilli nesting in many places throughout the body, once entrance is made, and causing only minimal or microscopic, in other words, unnoticed changes in many tissues, with only a single visible focus, or a few here and there, to indicate infection; with, maybe, a rather free and frequent moving about of small numbers of germs along the various avenues of dissemination and a consequent repeated new focalization that is widespread, the early focus of relatively many bacilli and of native tissue reaction remaining the only visible process and numerous minute foci of few bacilli remaining concealed with their growth kept in abeyance by the immunity of the body, as long as this holds.” Nearly 90 years later, in the study by Barrios-Payán et al [1a] reported in this issue of The Journal, multiple sensitive techniques were used to probe the presence, location, and viability of Mycobacterium tuberculosis (Mtb) in immunocompetent individuals in Mexico. All subjects died from reasons unrelated to TB and had no evidence or history of clinical TB. The authors provide evidence of latent Mtb infection not only in the lungs but also in the liver, spleen, and kidneys of these individuals. As expected from a TB-endemic setting, a majority of these individuals were latently infected, with Mtb DNA demonstrable in the lungs of approximately 70%. Of importance, almost all of the individuals also had bacterial DNA in the spleen, kidney, and/or liver. Whereas Mtb DNA was present in only extrapulmonary locations in many subjects, none showed infection restricted to only the lungs. Different individuals were infected with different strains of Mtb. Thus, dissemination from the lungs and infection in multiple organs appear fundamental to the establishment of Mtb infection and, as Krause postulated, may indeed be “the mode” of spread of Mtb in the body. Although the BCG-vaccination status of the subjects is not provided, BCG vaccination is routine in Mexico. BarriosPayán et al were unable to detect Mycobacterium bovis BCG DNA in any specimen. Reactivation of BCG in HIVpositive patients occurs, but it is far less frequent than reactivation of latent Mtb. BCG has been shown to be attenuated for dissemination in animal models [2–4]. Moreover, latently infected individuals exhibit immune responses to ESAT6. Although the mechanism underlying attenuated dissemination of BCG is unclear, ESAT6, which is one of the RD1-encoded proteins secreted via ESX1, may play a role in bacterial dissemination from the lungs [2–5]. ESAT6 is a pore-forming toxin that causes cytolysis of both type 1 and type 2 alveolar epithelial cells in vitro, and it is also an adhesin which binds to laminin [5, 6]. Laminin is synthesized by pneumocytes and is a major component of the basement membrane on which these cells rest. It is possible that Mtb organisms replicating in alveolar epithelial cells use ESAT6 for anchoring onto the basolateral laminin-expressing surfaces and cause damage to the cells and the basement membrane, thus participating in their dissemination via the alveolar wall. While the presence of >1 clinical strain in TB patients was reported earlier, Barrios-Payán et al provide evidence for latent infection with multiple Mtb strains in the same individual [7, 8]. Thus, adaptive immune responses elicited by the first infection (which was driven to latency) could not inhibit a second or even a third strain of Mtb from infecting and disseminating. Even robust immune responses, which in most individuals can prevent reactivation of Received 6 March 2012; accepted 20 March 2012; electronically published 25 June 2012. Correspondence: Suman Laal, PhD, NYU School of Medicine, c/o VA Medical Center, 423 East 23rd Street, Room 18123N, New York, NY 10010 ([email protected]). The Journal of Infectious Diseases 2012;206:1157–9 © The Author 2012. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/infdis/jis382