## 5 Non-NP (Synthetic) Immunomodulators  
The synthetic corticosteroid dexamethasone (DEX) is a well-characterised immunosuppressant which acts as an anti-inflammatory agent by inhibiting phospholipase A(2) (PLA\({}_{2}\)) in the mammalian eicosanoid pathway. A 50 uM DEX treatment was shown to have suppressive effects on the _G. mellonella_ immune system where it significantly (_p_ < 0.05) inhibited haemocyte phagocytosis in vitro [49], suggesting that eicosanoid-dependent phagocytosis is a common pathway in invertebrates and vertebrates alike. Consequently, DEX was used as a positive control immunosuppressiveant when assessing a parasite-host model in larvae [50]. A water-soluble derivative (DEX-21-phosphate (DEX-21P)) was used to suppress _G. mellonella_ immunity prior to bacterial challenge with the objective to create a model to mimic the immunosuppressiveed state of patients suffering from hospital-acquired infections [51]. Treated larvae (200 ug DEX-21P per larva (_n_ = 40) for 10 min prior to bacterial challenge) rendered the insects more susceptible to bacterial infection and significantly increased the subsequent lethality in a dose-dependent manner. The DEX-21P was shown to be non-toxic in this model, and the immunosuppressiveant effect of this corticosteroid was confirmed by an approximate 50% reduction in vitro phagocytosis of fluorescent-labelled bacteria by haemocytes incubated with a clinically equivalent dose of DEX-21P (5 mg/mL). The majority of published studies featuring in this review focus on immunomodulation primarily in the context of how the immune system can be harnessed to enhance the anti-microbial activity of the compound and not how it can serve as an _ipso facto_ immunomododulator. For example, studies have used _G. mellonella_ to primarily assess the efficacy of anti-microbial photodynamic therapy (PDT) with the secondary outcome being the examination of the treatment effect on the insect immune system. In one study, methylene blue (MB)-PDT was shown to confer higher survival rates (75%) in larvae challenged with the human periodontal bacterial pathogen _Porphyromonas gingivalis_ and enhance immunity by inducing a 2.62-fold increase in the total haemocyte count (THC) [52]. In a more recent example, the safety of MB and another frequently used photosensister 5-aminolevulinic acid (ALA) were firstly assessed following topical treatment of larvae (\(n=15\)). ALA-mediated PDT was found to be safer than MB even at high doses (500 mM) and the anti-fungal efficacy of this photosensister-PDT therapy to alleviate fungal dermatological lesions was assessed in this insect model [53]. ALA-mediated PDT almost doubled the larvae lifespan following the fungal challenge (_Fonsecaa monophona_) and induced an enhanced host innate immunity typified by an almost 2-fold increase in THC compared to the untreated group. Interestingly, the PDT-treated haemocytes stimulated in vitro with either bacteria (_S. aureus_) or fungus (_C. albicans_) started to develop morphological changes compatible with enhanced phagocytic activity. The authors concluded that the anti-microbial activity was mediated indirectly via enhancing insect innate immunity. Transition metal chelates containing phenanthroline exert anti-fungal properties through multiple mechanisms of action. [PERSON] et al. (2020) [54] investigated the effects of these compounds on the G. _mellonella_ immune system and found that they exert at least part of their anti-fungal activity by acting as an immunostimulator. Corroborating previous human primary cell culture observations, copper chelates were found to be more toxic than other metals in _G. mellonella_ and manganese compounds exhibited the optimal selectivity index.