Persistence: The Protracted War

Sun TZu also writes ‘There has never been a pro­tracted war from which a country has benefited' (TZu, 19 71, p. 73). In the case of pathogens and

their hosts, one could substitute ‘host’ for coun­try and ‘infection’ for war.

Paratuberculosis may be categorized into three separate states: subclinical infection, subclinical disease and clinical disease (Harris and Lammerding, 2001; Chacon et al., 2004). Since MAP is primarily transmitted by the fae­cal-oral route, subclinically infected cattle are of particular concern, as shedding and spread may continue unabated until clinical signs surface (Harris and Barletta, 2001; Harris and Lammerding, 2001; Whittington et al., 2001, 2004; Chacon et al., 2004; Crossley et al., 2005; Grewal et al., 2006; Tiwari et al., 2006). Once ingested, MAP gains entrance to subepithelial macrophages by invasion into the lamina propria via microfold cells (M cells) (Momotani et al., 1988; SigurSardottir et al., 1999, 2001, 2004; Tiwari et al., 2006; Wu et al., 2007a; Ponnusamy et al., 2013). Recent studies using a bovine ileal-loop model suggest­ed there is a clear early response to MAP but it is still unclear if early responses result from direct T-cell receptor (TCR)ZToll-Hke receptor (TLR) signalling, other pattern recognition receptors or traditional antigen presentation (Philip Griebel, personal communication).

Interplay between MAP and the mac­rophage may dictate disease progression and outcome; therefore, it is of extreme importance to understand early macrophage responses in order to elucidate pathogenesis.

The most recognizable feature of para­tuberculosis is the atypical diffuse granuloma formation, which is found in the mid- and dis­tal segments of the small intestine (Harris and Barletta, 2001; Tiwari et al., 2006). These atypi­cal granulomatous lesions are thought to repre­sent a late response by the host to control and limit MAP spread to the rest of the intestine and draining lymph nodes. However, it has been sug­gested that mycobacteria may take advantage of granulomas to recruit new macrophages to the site of infection and allow for mycobacte­rial travel through the granuloma (Davis and Ramakrishnan, 2009). Thus MAP may use granulomas as bridges to infect new portions of the intestine as well as other organs, includ­ing the mammary gland and mesenteric lymph node (Sweeney et al., 1992a, b, Sweeney et al., 2006; Patel et al., 2006). Clinical signs, includ­ing malabsorption, malnutrition and decreased milk yield, result within 2-5 years of infection, which may lead to death through either a direct cause or culling (Harris and Barletta, 2001; Tiwari et al., 2006).

9.3