With the rise of antimicrobial resistance (AMR), bacterial infections are a major threat to global public health. Tuberculosis, caused by the human pathogen Mycobacterium tuberculosis, is a case in point, with 1.6 million deaths worldwide (WHO, 2022), many of which are resistant to first- and second-line antibiotic treatments (Allué-Guardia et al., 2021; Hameed et al., 2018; Migliori et al., 2013). To successfully combat AMR there is a pressing and urgent need for alternative treatment strategies to failing antimicrobials. One such approach is offered by the development of host-derived therapies (HDTs), which target systems in the host rather than the pathogen, circumventing AMR (Kaufmann et al., 2018; Kilinç et al., 2021).

One primary immune defence against Mycobacterium tuberculosis (Mtb) is macrophages. Macrophages have a spectrum of phenotypes ranging from proinflammatory to anti-inflammatory, determined in a process known as macrophage polarisation. Mtb is expert at manipulation of macrophage polarisation to its advantage (Ahmad et al., 2022) and can inhibit the polarisation of proinflammatory macrophages, subverting killing mechanisms to promote intracellular survival of the bacteria and subsequent granuloma formation (Hackett et al., 2020). Reprogramming macrophages to better kill Mtb is a potential HDT strategy that may be particularly effective against intracellular pathogens (Sheedy and Divangahi, 2021).

Tribbles genes encode for a family of pseudokinases (TRIB1, TRIB2, and TRIB3; Kiss-Toth et al., 2004), involved in the regulation of core cellular processes, ranging from cell cycle to glucose metabolism (Grosshans and Wieschaus, 2000; Mata et al., 2000; Seher and Leptin, 2000). The TRIB1 isoform has been strongly associated with macrophage roles in inflammation and innate immunity (Johnston et al., 2015; Niespolo et al., 2020). TRIB1 regulates multiple important macrophage regulatory factors, especially controlling the proinflammatory response, such as tumour necrosis factor alpha (TNF-α), interleukin-1beta (IL-1β), and nitric oxide (NO) (Arndt et al., 2018; Liu et al., 2013). Trib1^−/− mice have decreased expression levels of inflammation-related genes such as IL-6, IL-1b, and Nos2 (encodes for inducible nitric oxide synthase, iNOS), and murine Trib1^−/− bone marrow-derived macrophages have defective inflammatory, phagocytic, migratory, and NO responses in vitro (Arndt et al., 2018; Liu et al., 2013).

TRIB1 influences inflammatory and immune processes via multiple mechanisms. The best described is via recruitment and binding of the E3 ubiquitin ligase constitutive photomorphogenic 1 (COP1). The TRIB1 protein possesses two functional binding sites in its C-terminal, one for COP1 and the second for mitogen-activated protein kinase kinase (MEK) binding. TRIB1 can act as a protein scaffold, binding a substrate to its pseudokinase domain, as well as binding in the functional C terminus to create a regulatory complex. Binding of TRIB1 to the E3 ubiquitin ligase COP1 causes a conformational change, enhancing COP1 binding and bringing COP1 into proximity with the substrate allowing ubiquitination and subsequent degradation (Jamieson et al., 2018; Kung and Jura, 2019; Murphy et al., 2015; Zahid et al., 2022). The TRIB1/COP1 complex is responsible for the regulation of multiple targets such as transcription factors, including the tumour suppressor CCAAT/enhancer-binding protein (C/EBPα), which regulates macrophage migration and TNF-α production (Liu et al., 2013; Yoshida et al., 2013).

While TRIB1 has been shown to regulate several inflammatory and innate immune functions in vitro, its role in infection is much less characterised, especially in an in vivo setting. TRIB1 is a predicted target of microRNA–gene interactions that differentiate active and latent TB patients (Wu et al., 2014) and is an overabundant transcript in highly proinflammatory tuberculosis-immune reconstitution inflammatory syndrome patients (Lai et al., 2015). However, despite these reported potential links between Tribbles and TB, interrogation of TRIB isoform transcripts in human mycobacterial datasets had not been performed.

Over the last two decades, the zebrafish has proved a powerful model for understanding host–pathogen interactions, due to its high-fecundity, transparency of larvae and availability of transgenic reporter lines. A human disease-relevant and tractable infection model is the zebrafish model of tuberculosis, utilising the injection of the natural fish pathogen Mycobacterium marinum (Mm), a close genetic relative of Mtb (Davis et al., 2002; van der Sar et al., 2009). This model has shed light on numerous immune pathways involved in host defence, for example hypoxia-inducible factor (HIF) signalling (Elks et al., 2013; Ogryzko et al., 2019; Schild et al., 2020).

Here, we show that Tribbles1 is expressed in human primary monocytes and its expression is increased at the site of a human in vivo mycobacterial antigen challenge, indicative of a role in TB responses. To substantiate the importance of TRIB1 in TB pathogenesis, we report a new, protective role for trib1 in infection defence using an in vivo zebrafish Mycobacterium marinum (Mm) infection model. Overexpression of trib1 significantly reduced Mm burden and increased production of the proinflammatory cytokine il1b and NO. The antimicrobial effect of trib1 overexpression was found to be dependent on cop1. Our findings uncover a role for trib1 in mycobacterial infection defence in vivo, highlighting Trib1 as a potential therapeutic target for manipulation to improve bacterial infection outcomes.

TRIB1 has previously been shown to be a key regulator of multiple inflammatory factors and immune cell function, influencing pathologies with an inflammatory component including cancer and atherosclerosis (Johnston et al., 2015). Innate immunity and production of inflammatory factors are important defence mechanisms against invading pathogens, yet the role of Tribbles in the immune response to infection is poorly understood. Here, we provide evidence that mycobacterial antigen stimulation both in vitro and in vivo induces human TRIB1 and TRIB2 expression independent of TB disease status. We used a zebrafish TB model to show that trib1 expression has functional roles in the innate immune response to infection in vivo. trib1 is required to control Mm infection, associated with increased production of the antimicrobial factors il-1β and NO. We also show a role for cop1, a binding partner of TRIB1, which is required for the host-protective effects of trib1 overexpression. The in vivo tools, developed here to investigate the immune roles of tribbles in zebrafish, create new opportunities to further investigate Tribbles1 as a potential therapeutic target, not only in infection, but in a wider range of disease contexts that have an innate immunity component.

For the first time, we have identified that Tribbles1 is important in the host response to mycobacterial infection, with TRIB1 being upregulated in human monocytes after mycobacterial antigen challenge and overexpression of trib1 being host-protective in a zebrafish TB model. TRIB1 is a well-known regulator of innate immune cells and functions in inflammatory settings playing a key role in the regulation of proinflammatory profiles (Arndt et al., 2018; Niespolo et al., 2020; Ostertag et al., 2010). Trib1^−/− mice have a defective inflammatory response, with reduced proinflammatory gene expression (including Nos2 and Il-1β compared to controls) resulting in bone-marrow-derived macrophages (BMDMs) that produce lower NO and have defective phagocytosis (Arndt et al., 2018). In zebrafish, trib1 overexpression increased production of proinflammatory factors, indicating that similar control of NO and Il-1β by TRIB1 is conserved in fish, although NO was primarily observed in neutrophils rather than macrophages matching previous observations in the zebrafish model (Elks et al., 2014; Elks et al., 2013).

TRIB1 has been associated with inflammation and immune response, whereas TRIB3 is strongly associated with metabolic function, including the regulation of glucose homeostasis (Angyal and Kiss-Toth, 2012; Prudente et al., 2012; Zhang et al., 2013) which also has regulatory roles in innate immune cells such as macrophages (Steverson et al., 2016; Wang et al., 2012). There are robust links between glucose metabolism and innate immune responses, such as the glycolytic switch which is closely related to macrophage polarisation (Zhu et al., 2015). Immune cell glucose and lipid metabolism have important roles in infection defence. Lipid droplets form in macrophages during Mtb infection that are potentially used as source of lipids by Mtb to allow for intracellular growth (Daniel et al., 2011). However, more recent findings suggest that lipid droplets are formed during the immune activation process after macrophage Mtb infection (Knight et al., 2018), that can subsequently influence the dynamic response of macrophage host defence (Menon et al., 2019). In murine atheroma models, Trib1 increased the lipid accumulation in macrophages leading to the formation of foam cells (Johnston et al., 2019). In Drosophila melanogaster, trbl knockdown increased circulating triglyceride levels (Das et al., 2014) and in mice where TRIB3 knockdown in a murine adipose cell line (3T3-L1) increased intracellular triglycerides (Takahashi et al., 2008) and targeted deletion of murine TRIB3 resulted in elevated triglyceride levels in the liver (Örd et al., 2018). Macrophage lipid metabolism and handling during Mtb infection could therefore potentially be influenced by Tribbles.

It is interesting to note that overexpression or knockdown of trib genes did not affect macrophage and neutrophil differentiation in zebrafish larvae. Trib1-deficient mice have been shown to have defects in the differentiation of a number of different immune cells, including an increase in neutrophils due to commitment of the granulocyte precursor lineage to neutrophils at the expense of eosinophils (Mack et al., 2019) and a decrease in M2-like tissue-resident macrophages (Satoh et al., 2013). The effects of Trib1 deficiency on eosinophil/neutrophil differentiation has been shown to be dependent on C/EBP transcription factors (Mack et al., 2019). Similar to mammalian neutrophil differentiation, zebrafish neutrophil differentiation is partially regulated by C/EBP transcription factors including Cebpα (Dai et al., 2016; Yuan et al., 2011), Cebp1 (the functional homolog of mammalian C/EBPε, Kim et al., 2016) and Cebpβ (Wei et al., 2020). It was therefore surprising that trib1 manipulation did not affect neutrophil differentiation in the zebrafish and highlights potential differences between the function of zebrafish trib1 compared to murine TRIB1. An important C/EBP in zebrafish myelopoiesis is a zebrafish-specific isoform called Cebp1 that is myeloid expressed (Lyons et al., 2001). This has a highly conserved carboxy-terminal bZIP domain with mammalian homologues, but the amino-terminal domains are unique. Reduction of Cebp1 did not ablate initial macrophage or granulocyte development in 24 hpf zebrafish larvae (Lyons et al., 2001). Recent findings demonstrate that Cebp1 controls eosinophilopoiesis in zebrafish larvae and has important roles in balancing the neutrophil and eosinophil lineages (Li et al., 2024), as in mice (Mack et al., 2019), however, eosinophils do not emerge until after 5 dpf beyond the stages in our study (Balla et al., 2010; Li et al., 2024). It remains unclear as to whether M2-like macrophages are affected by trib1 modulation in zebrafish as they are in mice (Satoh et al., 2013), as biomarkers/transgenic tools to investigate the existence of M2-like macrophages in larvae have only recently been developed (Hammond et al., 2023), but could be of interest in future studies.

Many of the reported regulatory functions of TRIB1 in immune cells are dependent on COP1 (Kung and Jura, 2019). In our zebrafish Mm model the protective effect of trib1 overexpression was reduced when cop1 was depleted, demonstrating a requirement for cop1 expression to improve the host response to infection. Interestingly, cop1 CRISPants possess a subtly reduced burden compared to controls without the overexpression of trib1, suggesting that cop1 depletion alone may offer a small level of protection. In cancer cell lines infected with Mycobacterium bovis Bacillus Calmette–Guérin (BCG), BCG-induced Sonic Hedgehog signalling increasing COP1 expression, leading to the inhibition of apoptosis in the cell line (Holla et al., 2014), indicating there may be a COP1 response to mycobacterial infection. The TRIB1/COP1 complex is responsible for the regulation of multiple targets, including C/EBPs (Liu et al., 2013; Yoshida et al., 2013). The lack of changes observed in neutrophil and macrophage numbers in trib1/cop1 knockdowns in our zebrafish studies, discussed above, may be suggestive of C/EBP independent mechanisms. There is evidence suggesting that COP1 and C/EBP have distinct binding sites on TRIB1, potentially unlinking their activity in some biological situations and this may be the case in zebrafish haematopoeisis (Murphy et al., 2015). There are many other candidate pathways other than C/EBPs that Trib1 and Cop1 interactions can influence that could lead to the host-protective effect observed, with examples including mitogen-activated protein kinases (Niespolo et al., 2020), serine threonine kinases (Durzynska et al., 2017), JAK/STAT (Arndt et al., 2018), and beta-Catenin (Zahid et al., 2022), likely context and cell dependent. For example, the neutrophil NO response generated by trib1 overexpression in zebrafish could be produced through JAK/STAT signalling which, in mice, regulates macrophage NO via TRIB1 control of STAT3 and STAT6 (Arndt et al., 2018). The zebrafish will be a useful in vivo model to investigate and dissect these pathways further.

If proinflammatory signals are initiated early in infection, this can reduce infection burden and improve infection outcomes. An example of this is control of the proinflammatory response by HIF-1α, where early stabilisation and activation of HIF-1α signalling is host beneficial in mycobacterial infection (Elks et al., 2013; Lewis and Elks, 2019; Ogryzko et al., 2019). The host-protective effect of trib1 overexpression closely mimicked the effects of Hif-1α stabilisation, with an increase in the production of antimicrobial factors NO and il-1β and a decrease in Mm infection burden (Elks et al., 2013; Ogryzko et al., 2019). TRIB3 has been associated with HIF-1α in renal cell carcinoma patients with HIF-1α binding to multiple regions in the TRIB3 promoter resulting in upregulation of TRIB3 expression (Hong et al., 2019). In lung adenocarcinoma cells, TRIB3 knockdown decreased levels of HIF-1α (Xing et al., 2020), indicating a feedback loop between TRIB3 and HIF-1α, where one can regulate the other. In common with TRIB3, a potential link between TRIB2 and HIF-1α has been reported, as depletion of TRIB2 significantly decreased the effect of TNF-α on HIF-1α stability and accumulation in multiple cancer cell lines (Schoolmeesters et al., 2012). However, there is no current link identified between TRIB1 and HIF-1α and this was reflected in our findings showing that trib1 overexpression did not lead to an increase in a well-validated Hif-α reporter line (Santhakumar et al., 2012).

Together our findings show a potential therapeutic application of targeting Trib1 to improve infection outcomes. We demonstrate il-1b and NO control by Trib1, suggesting that Trib1 controls multiple immune pathways and that therapeutic Trib1 manipulation may be more effective than targeting individual immune pathways alone. Due to its potential functions in multiple pathways, any targeting of Trib1 must be carefully controlled. For example, overexpression of TRIB1 in chronic mycobacterial infections may be beneficial against infection, but could trigger immunopathology. The concept of host immunomodulation is an emerging therapeutic avenue for infectious disease, especially with the continually increasing problem of AMR in multiple pathogens, and could potentially be used alongside antimicrobial drug treatment. To aid the efficiency of host immunomodulation, and to help avoid off-target effects, specific targeting methods can be used. Polymersomes have been shown to be a promising avenue for drug delivery to immune cells and could be utilised for the delivery of host immunomodulatory compounds and factors (Dal et al., 2020). Further research into TRIB1 as a target for host-derived therapies could potentially improve infection outcome of mycobacterial infection via pharmacological targeted delivery methods and transient manipulation through genetic approaches.

All data generated or analysed during this study are included in the manuscript, supporting files and source data. Expression data was derived from publicly available transcriptomic data deposited in EBI ArrayExpress repository (datasets E-MTAB-8162 and E-MTAB-6816 respectively - https://www.ebi.ac.uk/biostudies/arrayexpresshttps://www.ebi.ac.uk/biostudies/arrayexpress). Original gel images can be found in Figure 4—figure supplement 2—source data 1,2, Figure 4—figure supplement 3—source data 1 and Figure 8—figure supplement 1—source data 1. Figure 1—source data 1–9, Figure 4—source data 1–5, Figure 4—figure supplement 3—source data 2, Figure 5—source data 1–6, Figure 6—source data 1,2, Figure 8—source data 1,2, and Figure 8—figure supplement 1—source data 2 contain the numerical data used to generate the figures.

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Author details

1. Ffion R Hammond

   The Bateson Centre, School of Medicine and Population Health, Faculty of Health, University of Sheffield, Sheffield, United Kingdom

   Contribution

   Conceptualization, Resources, Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing - original draft, Writing - review and editing

   Competing interests

   No competing interests declared

2. Amy Lewis

   The Bateson Centre, School of Medicine and Population Health, Faculty of Health, University of Sheffield, Sheffield, United Kingdom

   Contribution

   Conceptualization, Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing - original draft, Project administration, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-1156-3592

3. Gabriele Pollara

   Division of Infection & Immunity, University College London, London, United Kingdom

   Contribution

   Conceptualization, Resources, Data curation, Formal analysis, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing - original draft, Writing - review and editing

   Competing interests

   No competing interests declared

4. Gillian S Tomlinson

   Division of Infection & Immunity, University College London, London, United Kingdom

   Contribution

   Conceptualization, Resources, Data curation, Formal analysis, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-4342-3161

5. Mahdad Noursadeghi

   Division of Infection & Immunity, University College London, London, United Kingdom

   Contribution

   Conceptualization, Resources, Data curation, Formal analysis, Funding acquisition, Validation, Investigation, Visualization, Methodology, Project administration, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-4774-0853

6. Endre Kiss-Toth

   The Bateson Centre, School of Medicine and Population Health, Faculty of Health, University of Sheffield, Sheffield, United Kingdom

   Contribution

   Conceptualization, Data curation, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing - original draft, Project administration, Writing - review and editing

   For correspondence

   e.kiss-toth@sheffield.ac.uk

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-4406-4017

7. Philip M Elks

   The Bateson Centre, School of Medicine and Population Health, Faculty of Health, University of Sheffield, Sheffield, United Kingdom

   Contribution

   Conceptualization, Resources, Data curation, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing - original draft, Project administration, Writing - review and editing

   For correspondence

   p.elks@sheffield.ac.uk

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-1683-0749

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