HIF1α is required for NK cell metabolic adaptation during virus infection

Abstract

Natural killer (NK) cells are essential for early protection against virus infection, and must metabolically adapt to the energy demands of activation. Here, we found upregulation of the metabolic adaptor hypoxia inducible factor-1α (HIF-1α) is a feature of mouse NK cells during murine cytomegalovirus (MCMV) infection in vivo. HIF-1 α -deficient NK cells failed to control viral load, causing increased morbidity. No defects were found in effector functions of HIF-1α KO NK cells however, their numbers were significantly reduced. Loss of HIF-1 α did not affect NK cell proliferation during in vivo infection and in vitro cytokine stimulation. Instead, we found HIF-1α -deficient NK cells showed increased expression of the pro-apoptotic protein Bim and glucose metabolism was impaired during cytokine stimulation in vitro. Similarly, during MCMV infection HIF-1α -deficient NK cells upregulated Bim and had increased caspase activity. Thus, NK cells require HIF-1α-dependent metabolic functions to repress Bim expression and sustain cell numbers for an optimal virus response.

Metabolism of NK cells during viral infections

“…This model is characterized by the proliferation and function of virus-specific NK cells that eliminate infected cells ( 63 ). In response to HCMV, NK cells activate the NKG2C receptor and rapidly expand and persist; these cells display enhanced responses ( 64 ). In mice, during the first two days of CMV infection, NK cells are activated through a strong host-cytokine response.…”

“…In this context, cells activate different metabolic regulators, such as HIF1α, to adapt to new conditions. Murine models demonstrate that CMV infection upregulates HIF1α to protect against morbidity, control viral load, and support the survival of NK cells by providing optimal glucose metabolism during pathogen infection ( 64 ).…”

Emerging role of hypoxia-inducible factor-1α in inflammatory autoimmune diseases: A comprehensive review

“…Natural killer (NK) cells mainly maintain anti-tumor and anti-infection effects in innate immune response ( 64 ). In human cardiomyocytes (HCMS), HIF-1α up-regulates expression of major histocompatibility complexes I-related molecule A/B (MICA/B), and then enhances the cytotoxicity of NK cells during hypoxia-reoxygenation ( 65 ).…”

“…Loss of HIF-1α in NK cells leads to nonproductive angiogenesis to suppress tumors ( 66 ). HIF-1α -/- NK cells fail to control cytomegalovirus viral load, resulting in increased morbidity ( 64 ). In addition, IL-15 activates STAT3 pathway and IL-2 activates PI3K/mTOR signaling, which then stabilize HIF-1α expression, and maintain natural defense against microbial infection and tumor development ( 67 , 68 ).…”

NK Cells Under Hypoxia: The Two Faces of Vascularization in Tumor and Pregnancy

“…Accordingly, mouse VHL -/- NK cells showed the opposite phenotype to HIF-1α -/- NK cells ( 64 ). In a mouse model of MCMV infection, HIF-1α was required in NK cells for metabolic adaptation and survival to the virus infection ( 65 ). In the TME context, there is a wide variety of tumor-associated bacteria (the tumor microbiome) ( 66 ).…”