Immunopathogenesis of Mycobacterium bovis Infection of Cattle

Infection with the tubercle bacillus, and the ensuing immunopathogenesis, is a quintessential example of the complex and ancient interplay between host and pathogen (reviewed in Reece and Kaufmann, 2012 and Cooper and Torrado, 2012). Upon entry into the host, Mycobacterium tuberculosis has a unique ability to delay onset of adaptive immune responses in mice or humans (reviewed in Ottenhoff, 2012). Likewise, adaptive responses are delayed with Mycobacterium bovis infection of cattle (Vordermeier et al., 2009; Waters et al., 2009). This delay in the adaptive response likely gives the pathogen both a foothold for infection (a critical mass of tubercle bacilli) and a defined niche to dictate the ensuing response (Cooper, 2009). The tubercle bacillus is also armed with a multitude of immune evasion tactics enabling intracellular survival and persistence. Examples include: (1) inhibition of important host defense mechanisms such as phagosome maturation and phagolysosome fusion, autophagy, antigen processing and presentation, apoptosis, interferon (IFN)-? receptor signaling; (2) capacity to escape from the hostile phagosome to the cytoplasm; and, (3) mechanisms to inhibit and scavenge toxic oxygen and nitrogen intermediates (Ottenhoff, 2012). Once infection is established, primarily lymphocytes and macrophages are recruited to the site of infection in humans and cattle, forming granulomas. Granulomas are dynamic structures with continual movement of host cells into and out of the structure, orchestrated both by the host as well as the pathogen (Ramakrishnan, 2012). With humans, various stages of tuberculosis are recognized including active (either primary or post-primary), latent, and reactivation or secondary disease (Hunter, 2011). Primary disease occurs when immunocompetent individuals are first infected with M. tuberculosis. With this form, the bacillus typically spreads from the initial site of infection to regional lymph nodes (and potentially elsewhere) until immunity develops and the infection is controlled. Only 5 – 10 % of individuals infected with M. tuberculosis develop clinical manifestations of primary tuberculosis within 2 years after exposure. The majority of infected individuals develop latent tuberculosis, defined as having evidence of M. tuberculosis infection by tuberculin skin test or IFN-? release assay [IGRA]) without clinical signs of disease (Lin and Flynn, 2010). Latent infection is a dynamic equilibrium in which the host controls but does not clear the bacillus. With M. bovis infection of cattle, the disease is generally considered slowly progressive, without clear delineation of the various stages associated with tuberculosis of humans (Pollock et al., 2006). As with human tuberculosis (originally described in Bayle, 1810 and Laënnec, 1837), the disease in cattle may be defined microscopically according to the degree of fibrosis, necrosis, caseation, and mineralization (Wangoo et al., 2005). Thus, there are many similarities in the immunopathogenesis of bovine and human tuberculosis, and a few distinct differences. Aerosol and intratracheal inoculation are routinely used for experimental biology purposes to infect cattle with virulent M. bovis, each resulting primarily in a respiratory tract infection including lungs and lung-associated lymph nodes (reviewed in (Vordermeier, 2010)). Disease severity is dose and time dependent, closely mimicking natural infection of cattle (Buddle et al., 1994; Palmer et al., 2002). Recently, unique insights into M. bovis transmission have been gained through “in contact” studies in which sentinel cattle are exposed to M. bovis-infected cattle in a model of natural infection (Khatri et al., 2012). With each of these routes of exposure, experimental approaches permit disease confirmation through postmortem examination with laboratory analysis by histopathology and bacterial culture, defining the relationship between dose and route of infection, immune response, and the pathogenesis of infection (Waters et al., 2012). The bovine infection model also provides significant opportunities to investigate the basis of genetic susceptibility and impacts of co-infection on pathogenesis and diagnostic techniques (Flynn et al., 2009; Kao et al., 2007). Finally, access to naturally infected cattle provides a unique opportunity to evaluate vaccine and ante-mortem testing strategies, particularly as animals are often available for post-mortem inspection for infection confirmation as well as for gross and microscopic assessment of lesions. Thus, intervention strategies may be directly assessed, as opposed to being inferred based upon immunologic and clinical parameters.