Abstract
Hypoxia-inducible factor-1 alpha (HIF-1α) is considered a global regulator of cellular metabolism and innate immune cell functions. Intracellular pathogens such as Leishmania have been reported to manipulate host cell metabolism. Herein, we demonstrate that myeloid cells from myeloid-restricted HIF-1α-deficient mice and individuals with loss-of-function HIF1A gene polymorphisms are more susceptible to L.donovani infection through increased lipogenesis. Absence of HIF-1α leads to a defect in BNIP3 expression, resulting in the activation of mTOR and nuclear translocation of SREBP-1c. We observed the induction of lipogenic gene transcripts, such as FASN, and lipid accumulation in infected HIF-1α-/- macrophages. L.donovani-infected HIF-1α-deficient mice develop hypertriglyceridemia and lipid accumulation in splenic and hepatic myeloid cells. Most importantly, our data demonstrate that manipulating FASN or SREBP-1c using pharmacological inhibitors significantly reduced parasite burden. As such, genetic deficiency of HIF-1α is associated with increased lipid accumulation, which results in impaired host-protective anti-leishmanial functions of myeloid cells.
Highlights
Pathogen-induced hijacking of host cell metabolism results in the dampening of host defense mechanisms and is considered an important host-pathogen interface (Naderer and McConville, 2008; McConville, 2016)
Hypoxia-inducible factor-1 alpha (HIF-1a) Expression Is Associated with Increased Resistance against Leishmania donovani Infection Because HIF-1aÀ/À macrophages are more susceptible to Leishmania major infection (Schatz et al, 2016), we first evaluated HIF-1a transcription levels during in vivo L. donovani infection of three mouse strains with distinct outcomes to visceral leishmaniasis (VL): BALB/c as susceptible, 129/Sv as resistant, and C57BL/6 as intermediate resistant hosts (Bodhale et al, 2018)
L. donovani-infected peritoneal macrophages from both WT and mHIF-1aÀ/À mice displayed a similar level of phagocytosis (Figure 1B), we observed at 5 days post-infection that parasite viability increases in HIF-1aÀ/À macrophages when compared with WT counterparts (Figure 1C)
Summary
Pathogen-induced hijacking of host cell metabolism results in the dampening of host defense mechanisms and is considered an important host-pathogen interface (Naderer and McConville, 2008; McConville, 2016). Nutrient-rich niche for pathogen multiplication and survival, as demonstrated in Trypanosoma cruzi, T. brucei, Toxoplasma gondii, and Leishmania donovani infections (Caradonna et al, 2013; Blume et al, 2015; Ghosh et al, 2015; Smith et al, 2017). Other carbon sources, such as lipids, have been proposed to contribute to the outcome of infection (Bozza et al, 2009). These recently found nutritional alterations may favor pathogen dissemination, which poses a new challenge in the clinics
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