Targeting host-derived signalling to activate leukocytes and improve infection outcomes in zebrafish models

Bacterial and fungal infections pose a growing threat to global public health, exacerbated by antimicrobial resistance (AMR). There is an urgent need for alternative treatments to failing antimicrobials, such as host-directed therapies (HDTs) which aim to improve the host immune response to infection. Here, I investigated three potential candidates for HDTs: trib1, hif-1α and arg2, due to their ability to modulate innate immune responses. TRIB1 has previously shown to regulate inflammatory profiles and macrophage function, but its role in infection is unclear. Zebrafish trib1 overexpression decreased bacterial burden in a zebrafish tuberculosis (TB) model, whilst increasing antimicrobial factors such as nitric oxide (NO) and Interleukin-1β. Conversely, trib1 knockdown increased bacterial burden. The host-protective effect of trib1 overexpression was dependant on cop1, a key interacting partner of TRIB1. This data shows a novel role of trib1 in the context of mycobacterial infection and highlight its potential as a therapeutic target to improve infection outcome. Hif-1α is host-protective in multiple experimental models of TB, however its role in fungal infection is understudied. Two clinically relevant zebrafish infection models, for Candida albicans (Ca) and Cryptococcus neoformans (Cn) were utilised, and stabilisation of Hif-1α signalling was host-protective against Ca but not Cn. Hif-1α stabilisation restored the depleted host NO response caused by Ca, a potential mechanism of this host-protective effect. This data expands on pre-existing knowledge and highlight how Hif-1α can also provide protection against fungal infection. Arginase, a key anti-inflammatory factor, can be induced by infection which can be detrimental to the host. To further investigate how and when leukocytes regulate arginase in response to infection, a novel transgenic zebrafish reporter TgBAC(arg2:eGFP)sh571 was utilised to visualise arg2 expression. In response to immune challenge, neutrophils are the primary leukocyte to express arg2, and do so at early time points of infection and injury. This research begins the characterisation of zebrafish arg2 in an infection context and builds upon existing evidence of the timing and localisation of arginase expression in response to immune challenge. To conclude, in this thesis I have added mechanistic in vivo data to the potential of trib1, hif-1α and arg2 as potential HDT targets.