The greatest regulation of insulin levels will probably be food related and therefore it is important to look at how immunity and feeding behaviour interact. As flies eat less, circulating sugar levels will fall and insulin should also fall. Having seen that insulin signalling is altered by an infection and that insulin signalling can alter the outcome of infections it is easy to predict that feeding regulation will have large effects on immunity.
Unsurprisingly, outright starvation alters the immune response in bad ways. For example, starvation of Rhodnius prolixus reduces its ability to fight Enterobacter cloacae infections (Azambuja et al.,
1997). Likewise, the restriction of dietary yeast reduces a larval Drosophila's chances of killing a parasitoid wasp egg (Vass and Nappi, 1998).
In nature, feeding levels presumably don't have just two states: unlimited food and starvation. Unfortunately there are not a lot of papers describing the effects of more subtle nutritional changes on the innate immune response of insects. One place to start is the field of dietary restriction; diet restriction, the physiological state during which animals fed a small diet can increase their lifespan, was shown to have no effect on the realized innate immune response for Drosophila against E. faecalis and S. aureus (Libert et al., 2008). This is surprising because diet restriction is anticipated to reduce insulin signalling and a reduction in insulin signalling alone was shown to increase the ability of these flies to defend against these two microbes. As an explanation, Libert and colleagues proposed that diet restriction suppressed the activation of defences that were induced by a loss of insulin signalling.
It appears that some sick insect larvae engage in a type of self-induced chemotherapy; for example, larvae of Estigmene acrea sequester antiparasitic plant-derived pyrrolizidin alkaloids (Bernays and Singer, 2005). These authors demonstrated that taste sensitivity of parasitized caterpillars increases towards these antiparasitic compounds while at the same time they show decreased responsiveness to normally deterrent chemicals. This suggests that infected caterpillars might switch to food that would be unpalatable to an uninfected caterpillar with the purpose of eating more antiparasitic compounds.
Certainly, drug-containing foods can alter immunity but the general quality of the food has effects as well; Lee and coworkers (2006) found that Spodoptera literalis larvae fed protein-rich diets were better able to survive nuclear polyhedrosis virus infections. When caterpillars were allowed to choose their own diets, those choosing protein-rich diets were also better able to survive the infections. Infected larvae tended to choose a higher level of dietary protein late during infections. This suggests that these insects can deliberately change the structure of their diet in a way that helps them fight infections.
Infections can produce more prosaic changes in appetite than an attempt to go out and consume drugs or switch to a more healthy diet; simple infection-induced anorexia has been observed in a number of situations. In some cases the reasons for this anorexia are structural, such as when Pseudomonas entomophila causes gut-blocking lesions when fed to Drosophila larvae (Liehl et al., 2006). In other cases, the activation of the immune response appears to trigger a decrease in appetite (Adamo, 2005; Adamo et al., 2007). Although infection can reduce food intake, in no case has it been shown yet that this decrease in consumption has an effect on immunity.
Given that in the anorexia experiments the insects were not offered a choice of food, we cannot distinguish between the following two responses: 'yuck, this food is not what I want' and 'I don't feel like eating anything.'
In flies, one of the pathways regulating appetite is the neuropeptide F family, which includes NPF and short NPF (sNPF) along with their two receptors. Appetite is positively regulated by sNPF and its receptor (Lee et al., 2004). Inhibition of sNPF signalling by RNAi treatment reduces the appetites of affected flies. sNPF itself is an inducer of insulin signalling (Lee et al., 2008). When flies are hungry, as defined by sNPF expression, they induce insulin. Dilp 1 and 2, two of the seven Drosophila insulin family members, are regulated by sNPF. The regulation of sNPF by insulin has not been tested experimentally but we predict that its activity will be inhibited by high insulin levels.
NPF regulates the fly's response to noxious substances (Wu et al., 2005). High levels of NPF reduce the negative effects of repulsive-tasting chemicals like quinine. NPF signalling is negatively regulated by insulin apparently through an inhibition of signalling through the NPF receptor. When insulin levels are low and NPF levels are high the flies are more likely to eat bad-tasting food; hungry flies will eat anything.
The peptide NPF has other interesting effects on fly behaviour and physiology that might be predicted to change during an infection. NPF is a suppressor of aggression; flies lacking this signalling pathway are more aggressive, as assayed by male flies battling for food and females (Dierick and
Greenspan, 2007). If NPF drops during an infection, flies might be expected to become feistier.
In an uninfected animal we anticipate that low levels of nutrients would lead to low levels of insulin. This would increase NPF induction and we predict would also increase sNPF production. These molecules would raise the appetite of the fly and reduce its avoidance of noxious food. Something different appears to be happening in sick flies, however. Insulin signalling is reduced, but appetite is also reduced. This suggests that the connection between appetite and insulin signalling is altered in these infected animals. The flies should be eating like crazy but are not; why?
There aren't any descriptions in the literature yet where the entire cycle of the immune regulation of appetite and the nutrient regulation of immunity have been completed and both sides were found to be important. However, putting together what we know about immunity and insulin signalling from other models, we can imagine that this apparent conflict between immunity and appetite-regulating systems could lead to physiological collapse. Normally energy depletion increases hunger; in infected flies, energy is being depleted and yet the flies reduce their eating. In the case of an M. marinum infections, this regulatory circuit is expected to lead to a physiological collapse where the fly dies because it wastes away, and this wasting does not help fight the infection. In contrast, we know that reduced insulin signalling is expected to help fight infections caused by E. faecalis and S. aureus. This isn't a perfect counter example, however, because here diet restriction does not affect survival. We anticipate that the fly has evolved in this way because this particular energy-regulation circuit increases fitness when the flies encounter real fly pathogens in the wild. Our laboratory experiments can direct us to those physiological systems that are of interest to the insect immunologist, but they don't tell us how the reactions of these systems help the insects in the field.
There are a several important lessons to be learned from this section that we should apply to our experiments. The first is that food is an important consideration in immunity experiments and thus the exact food composition should be reported in all experiments. The above results suggest a difficulty in performing well-controlled experiments using orally delivered pathogens. If the immune response alters appetite, then the dose of an orally delivered pathogen will vary when immunity mutants are tested. Some immune signalling mutants might appear more susceptible to oral infections but this could be due to an increased uptake of the pathogen, if the anorexia response were blocked. During infections with microbes like S. entomophila, which appear to cause a complete blockage of the gut, other problems can be anticipated; these infected flies are anticipated to be starving and that has been shown to cause enormous changes in the immune responses in all creatures.
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