Interaction between the local and systemic immune response

The local immune response in diverse epithelia and the systemic immune response of the fat body are independent immune mechanisms, as each can be selectively induced depending on the mode of infection. However, some infections may require coordination of both systems to fully control pathogens. Recently, a number of recent studies have identified potential mechanisms that facilitate communication between the different immune compartments of Drosophila (Figure 2.6).

2.4.1 Gut infection and fat body immune response

Both Ecc15 and P. entomophila are able to trigger a strong systemic immune response in Drosophila larvae following oral ingestion, pointing to an integration of both responses at the whole-organism level and the existence of a signalling mechanism between the gut and the fat body (Basset et al., 2000; Vodovar et al, 2005). This immune response correlates with the capacity of these bacterial species to persist and multiply inside the gut and does not appear to rely on physical crossing of the gut wall. Two mechanisms have been proposed to explain the capacity of bacteria that infect through the oral route to induce the systemic immune response.

2.4.1.1 A role for nitric oxide

Nitric oxide (NO) is a signalling molecule implicated in multiple physiological processes in animals, including innate immunity. In vertebrates, NO possesses direct effector functions and is an important signalling molecule that regulates gene expression and influences cell differentiation. NO has also been implicated in gastrointestinal motil-ity, mucosal permeability after bacterial infection, and epithelial-associated pathologies such as colon cancer (Bogdan, 2001). In Drosophila, biochemical modulation of NO signalling has demonstrated its requirement in immune signalling between the gut and fat body. Reduction of nitric oxide syn-thase (NOS) activity in Drosophila using the inhibitor NG-nitro-L-arginine methyl ester (l-NAME), led to increased larval lethality after oral ingestion of Ecc15. In addition, this study demonstrated that exogenous NO in the gut triggers Diptericin expression in the fat body even in the absence of a pathogen (Nappi et al, 2000; Foley and O'Farrell, 2003). According to this model, ingestion of bacteria induces NO in sentinel tissues like the gut, and activates a signalling cascade in haemocytes that leads to induction of the Imd pathway in the fat body by an unknown mechanism. Additionally, mutations in Drosophila calcineurin have shown that NO signalling acts in a calcium-dependent manner (Dijkers and O'Farrell, 2007). Interestingly, NO production is also produced in response to bacterial infection in the Malpighian tubules, and induces AMP production in the same tissue in an autocrine fashion (McGettigan et al, 2005).

2.4.1.2 Translocation of peptidoglycan Alternatively, it has been proposed that this systemic immune response is mediated by the translocation of small peptidoglycan fragments from the gut lumen to the haemolymph. This view is supported by the observation that ingestion of monomeric peptidoglycan can stimulate a strong systemic immune response in PGRP-LB RNAi flies that have reduced amidase activity and are unable to degrade peptidoglycan to its non-immunogenic form (Zaidman-Remy et al, 2006). Transfer of pep-tidoglycan would provide an indirect mechanism for recognition of Gram-negative bacteria that may explain the existence of different PGRP-LC isoforms devoted to the detection of monomeric peptidoglycan that are small enough to efficiently cross the gut barrier.

2.4.2 Other examples of immune response integration

Additional studies support the existence of dialogue between other immune tissues. Larvae mutated for Serpin 77BE have melanized trachea and this local melanization is sufficient to activate the Toll pathway in the fat body (Tang et al., 2008). Therefore, it can be speculated that induction of the Toll pathway by tracheal melanization indicates signalling between the local and systemic immune responses. This communication would serve to alert and prepare the host for potential invasion of internal tissues by pathogens. Such an alarm system could be advantageous for organisms in which pathogens are naturally first encountered at epithelial surfaces. Finally, haemocytes have also been implicated in activation of the systemic response, although this remains an area of active investigation. A previous study using larvae without haemocytes suggested that AMPs are not induced in the fat body in the absence of haemo-cytes (Basset et al., 2000). Likewise, a more recent study suggests that phagocytosis by haemocytes is required for Defensin expression in the fat body upon septic injury (Brennan et al., 2007).

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