**6. References**


carry the RD-1 region (T. A. Halse et al., 2011), suggesting that their differing degrees of virulence might not be directly related to this genomic region. Recent publications have shown the involvement of other RD-1 proteins (EspF, EspG (D. Bottai et al., 2011)) or other genomic regions (RD-2 also lost in attenuated M. bovis BCG (R. A. Kozak et al.,

Mycobacterial cell wall also contributes to virulence. The high content of heterogeneous lipids is a hallmark of mycobacteria. Lipoarabinomanans and lipomanans are two of the major lipidic components that can reduce the activation and cytokine secretion of macrophages. Although limited evidence suggest that cell wall lipids are key in immune response subversion (L. Quintero-Macias et al., 2010; L. M. Rocha-Ramirez et al., 2008), strain-specific lipid characterization during infection represents a challenge yet to be fully engaged. Among the strains used in our experiments, clear differences on the lipid synthesis

On the other hand, a decade of intense research on the mucosal immune system provides an outlook of similar complexity with the interaction of an increasing number of cell types within highly specialized microenvironments. In the case of tuberculosis is necessary to consider that the interaction of at least four histological compartments (alveolar space, lung parenchyma, draining lymph nodes, blood) is affected by the balance between mycobacterial virulence and host resistance. Apparently, virulent mycobacteria would preferentially target lung CD103+ DCs and thus avoid activation of the CD103- DCs. Further research is required to determine whether this constitutes an active evasion mechanism and to clarify the role of lung CD103+ DCs in the induction of Mtb-specific T cells or regulatory

A Silva-Sanchez, J Calderon-Amador, R Hernandez-Pando, S Estrada-Parra, I Estrada-Garcia and L Flores-Romo are members of the National System of Researchers from Mexico (SNI). I. E-G and S. E-P are fellows from COFAA and EDI (IPN). L F-R acknowledges support from the National Council for Science and Technology Conacyt. A S-S, S M-P and F M-T were fellow-holders from Conacyt. R H-P acknowledges support from the European Community (LSHP-CT-2007-037919) TB-adapt, contract number 037919, and the National

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**10** 

*USA* 

**Biofilms of** *Mycobacterium tuberculosis***:** 

*Graduate School of Public Health University of Pittsburgh, Pittsburgh, PA,* 

**1.1 Persistence of the pathogen is the hallmark of TB pathogenesis** 

competent host immune system and antibiotics.

Based on a randomized clinical trial conducted by British Medical Council between 1972 and 1974, the World Health Organization (WHO) and other government agencies implemented a short-course multi-drug regimen for tuberculosis – a disease caused by the infection of *Mycobacterium tuberculosis (BMC, 1972, Fox et al., 1999)*. The regimen is made of three antibiotics, isoniazid, rifampicin and pyrazinamide administered over a period of six months. The extended therapy is essential for sterilizing a small subpopulation of bacilli that presumably acquire phenotypic tolerance to antibiotics (Saltini, 2006, Jindani et al., 2003).

Four decades later, WHO estimates that about 2 billion people in the world still remain asymptomatically infected with *M. tuberculosis*, approximately 5-10% of these visit clinics with symptoms of active tuberculosis, and 1.7 million die of the infection every year (Dye *et al.*, 2009). Moreover, one third of the mortality in HIV-infected patient occurs due to coinfection of *M. tuberculosis*, often with a very high frequency of multi-drug resistant strains (Harrington, 2010, Aaron *et al.*, 2004). It is thus clear that while the existing anti-TB drug regimen has been able to reduce the mortality rate, it has been inadequate in reducing the global burden of the disease. A forward approach towards TB-control must include two critical capabilities: a) to predict and prevent the conversion of asymptomatic infection to active TB, and b) to develop a shorter and more effective therapeutic regimen for active disease. Accomplishing these goals have been difficult because of our limited understanding of the mechanisms employed by *M. tuberculosis* to persist against the challenges of

Although persistence mechanisms of *M. tuberculosis* in the host remain largely unclear, persistence of most, if not all, microbial species is facilitated by growth and existence in surface-associated and organized communities – called biofilms (Costerton *et al.*, 1999, Fux *et al.*, 2005, Hall-Stoodley *et al.*, 2004, Blankenship & Mitchell, 2006, Branda *et al.*, 2005). Several mycobacterial species including *M. tuberculosis* are now known to spontaneously grow *in vitro* as biofilms that harbor drug tolerant bacilli. This raises questions as to whether biofilms

**1. Introduction** 

**New Perspectives of an Old Pathogen** 

Anil K. Ojha1 and Graham F. Hatfull2

*2Department of Biological Sciences* 

*University of Pittsburgh, Pittsburgh, PA,* 

*1Department of Infectious Diseases and Microbiology,* 

Wolf, A. J., Linas, B., Trevejo-Nunez, G. J., Kincaid, E., Tamura, T., Takatsu, K.&Ernst, J. D. (2007). Mycobacterium tuberculosis infects dendritic cells with high frequency and impairs their function in vivo. *J.Immunol.*, Vol. 179, No. 4, pp. (2509-2519).
