Hif‐1alpha stabilisation is protective against infection in zebrafish comorbid models

Abstract

Multi‐drug‐resistant tuberculosis is a worldwide problem, and there is an urgent need for host‐derived therapeutic targets, circumventing emerging drug resistance. We have previously shown that hypoxia‐inducible factor‐1α (Hif‐1α) stabilisation helps the host to clear mycobacterial infection via neutrophil activation. However, Hif‐1α stabilisation has also been implicated in chronic inflammatory diseases caused by prolonged neutrophilic inflammation. Comorbid infection and inflammation can be found together in disease settings, and it remains unclear whether Hif‐1α stabilisation would be beneficial in a holistic disease setting. Here, we set out to understand the effects of Hif‐1α on neutrophil behaviour in a comorbid setting by combining two well‐characterised in vivo zebrafish models – TB infection (Mycobacterium marinum infection) and sterile injury (tailfin transection). Using a local Mm infection near to the tailfin wound site caused neutrophil migration between the two sites that was reduced during Hif‐1α stabilisation. During systemic Mm infection, wounding leads to increased infection burden, but the protective effect of Hif‐1α stabilisation remains. Our data indicate that Hif‐1α stabilisation alters neutrophil migration dynamics between comorbid sites and that the protective effect of Hif‐1α against Mm is maintained in the presence of inflammation, highlighting its potential as a host‐derived target against TB infection.

The Role of Macrophages During Zebrafish Injury and Tissue Regeneration Under Infectious and Non-Infectious Conditions

“…Epimorphic regeneration in zebrafish has been poorly explored in the presence of pathogens. A few rare studies have examined injuries under infectious conditions, but they have focused primarily on neutrophils ( 85 ). To the best of our knowledge, only one study has specifically studied the cellular mechanisms associated with regeneration, the MФ response and their polarization in the presence of the bacterial pathogen, Listeria monocytogenes ( 57 ).…”

Lactate Metabolism and Signaling in Tuberculosis and Cancer: A Comparative Review

“…Multiple studies have demonstrated that HIF-1a is expressed and active during Mtb infection (Shi et al, 2015;Braverman et al, 2016;Prosser et al, 2017;Baay-Guzman et al, 2018;Knight and Stanley, 2019;Resende et al, 2020). In zebrafish infection models using Mycobacterium marinum, HIF-1a stabilization enhances IL-1b expression, and helps clear infections via activating neutrophils (Elks et al, 2013;Ogryzko et al, 2019;Schild et al, 2020). Deletion of HIF-1a in myeloid cells accelerates granuloma necrosis and impairs host responses to Mycobacterium avium infection in mouse models (Cardoso et al, 2015).…”

“…Further, lactate suppresses the induction of the NLRP3 inflammasome and IL1b via GPR81 activation, regulates TLR activation via interactions with arrestin B2 downstream of GPR81, and protects against inflammatory injury in pancreatitis and hepatitis models through GPR81 signaling (Hoque et al, 2014). Mtb infection has been demonstrated to inhibit NLRP3 inflammasome activation and (Hanahan and Weinberg, 2011;Vaupel et al, 2019) • Regulated by HIF-1a, which controls expression of LDHA (Ivan et al, 2001;Jaakkola et al, 2001;Kaluz et al, 2006) • LDHA is a poor prognostic indicator and correlated to increased tumor size (Koukourakis et al, 2003;Koukourakis et al, 2005;Kolev et al, 2008) • Lactate accumulates within the tumor microenvironment (Walenta and Mueller-Klieser, 2004) • Glycolysis enhanced early during in vitro Mtb infection (Shi et al, 2015;Qualls and Murray, 2015;Gleeson et al, 2016;Shi et al, 2019) • HIF-1a expressed and active during Mtb infection (Shi et al, 2015;Braverman et al, 2016;Prosser et al, 2017;Baay-Guzman et al, 2018;Knight and Stanley, 2019;Resende et al, 2020) • Deletion of HIF-1a impacts granuloma necrosis, host responses, and chronic inflammation (Elks et al, 2013;Cardoso et al, 2015;Ogryzko et al, 2019;Schild et al, 2020) • LDHA increased in Mtb infection within macrophages and T cells (Shi et al, 2015) • Increased serum and BAL LDH within TB patients (Emad and Rezaian, 1999;Sharma et al, 2010) • Increased lactate within TB granulomas (Somashekar et al, 2011;Somashekar et al, 2012) • Increased CSF lactate in tuberculous meningitis correlates with disease severity…”

If it’s not one thing, HIF’s another: immunoregulation by hypoxia inducible factors in disease

“…For example, it was recently shown in a model of chronic inflammation of the cornea (Herpes Stromal Keratitis) that HIF‐1α was high in the myeloid lineage, whereas HIF‐2α was higher in epithelial cells, highlighting how different cell types in close proximity regulate HIF signalling differently and may need to be targeted separately in disease [71]. The potential of HIF‐1α stabilisation to contribute to inflammatory and infectious comorbidities has recently been explored in zebrafish models, where it was shown that although Hif‐1α stabilisation delays neutrophil inflammation resolution, a host‐protective effect against mycobacterial infection remains [72]. A potentially important step in immunoregulatory therapies would be cell‐specific targeting of HIF drugs in a timely way.…”