Activation of Hypoxia Inducible Factor 1 Is a General Phenomenon in Infections with Human Pathogens

Werth, Nadine; Beerlage, Christiane; Rosenberger, Christian; Yazdi, Amir S.; Edelmann, Markus; Amr, Amro; Bernhardt, Wanja M.; Eiff, Christof von; Becker, Karsten; Schäfer, Andrea; Peschel, Andreas; Kempf, Volkhard A. J.

doi:10.1371/journal.pone.0011576

Cited by 153 publications

(139 citation statements)

References 49 publications

(84 reference statements)

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“…During an in vivo viral infection, activated T cells may experience hypoxia due to inflammation and the hyperproliferation of lymphocytes (48,49), a hypothesis that is supported by our data showing hypoxia in the lung, spleen, and lymph nodes of influenza-infected mice. Thus, we provide in vivo evidence that hypoxia may be a crucial activator of T cell autophagy during viral infection.…”

Section: Discussionsupporting

confidence: 79%

Survival of Effector CD8+ T Cells during Influenza Infection Is Dependent on Autophagy

Schlie

Westerback

DeVorkin

et al. 2015

The Journal of Immunology

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The activation and expansion of effector CD8+ T cells are essential for controlling viral infections and tumor surveillance. During an immune response, T cells encounter extrinsic and intrinsic factors, including oxidative stress, nutrient availability, and inflammation, that can modulate their capacity to activate, proliferate, and survive. The dependency of T cells on autophagy for in vitro and in vivo activation, expansion, and memory remains unclear. Moreover, the specific signals and mechanisms that activate autophagy in T effector cells and their survival are not known. In this study, we generated a novel inducible autophagy knockout mouse to study T cell effector responses during the course of a virus infection. In response to influenza infection, Atg5−/− CD8+ T cells had a decreased capacity to reach the peak effector response and were unable to maintain cell viability during the effector phase. As a consequence of Atg5 deletion and the impairment in effector-to-memory cell survival, mice fail to mount a memory response following a secondary challenge. We found that Atg5−/− effector CD8+ T cells upregulated p53, a transcriptional state that was concomitant with widespread hypoxia in lymphoid tissues of infected mice. The onset of p53 activation was concurrent with higher levels of reactive oxygen species (ROS) that resulted in ROS-dependent apoptotic cell death, a fate that could be rescued by treating with the ROS scavenger N-acetylcysteine. Collectively, these results demonstrate that effector CD8+ T cells require autophagy to suppress cell death and maintain survival in response to a viral infection.

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Section: Discussionsupporting

confidence: 79%

Survival of Effector CD8+ T Cells during Influenza Infection Is Dependent on Autophagy

Schlie

Westerback

DeVorkin

et al. 2015

The Journal of Immunology

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“…The oxygen-regulated HIF-␣ subunit (1␣/2␣/3␣) and the ubiquitous HIF-1␤ interact as a complex with HRE-containing gene promoters. However, HIF-1␣ activation under normoxia is a general phenomenon in infection with bacteria, protozoa, and pathogenic viruses (29). HCV induces HIF-1␣ stabilization at late time points postinfection (42)(43)(44).…”

Section: Resultsmentioning

confidence: 99%

Low Oxygen Tension Enhances Hepatitis C Virus Replication

Vassilaki

Kalliampakou

Kotta‐Loizou

et al. 2013

J Virol

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; Applied Molecular Virology, Institut Pasteur Korea, Seongnam-si, South Korea g Low oxygen tension exerts a significant effect on the replication of several DNA and RNA viruses in cultured cells. In vitro propagation of hepatitis C virus (HCV) has thus far been studied under atmospheric oxygen levels despite the fact that the liver tissue microenvironment is hypoxic. In this study, we investigated the efficiency of HCV production in actively dividing or differentiating human hepatoma cells cultured under low or atmospheric oxygen tensions. By using both HCV replicons and infectionbased assays, low oxygen was found to enhance HCV RNA replication whereas virus entry and RNA translation were not affected. Hypoxia signaling pathway-focused DNA microarray and real-time quantitative reverse transcription-PCR (qRT-PCR) analyses revealed an upregulation of genes related to hypoxic stress, glycolytic metabolism, cell growth, and proliferation when cells were kept under low (3% [vol/vol]) oxygen tension, likely reflecting cell adaptation to anaerobic conditions. Interestingly, hypoxia-mediated enhancement of HCV replication correlated directly with the increase in anaerobic glycolysis and creatine kinase B (CKB) activity that leads to elevated ATP production. Surprisingly, activation of hypoxia-inducible factor alpha (HIF-␣) was not involved in the elevation of HCV replication. Instead, a number of oncogenes known to be associated with glycolysis were upregulated and evidence that these oncogenes contribute to hypoxia-mediated enhancement of HCV replication was obtained. Finally, in liver biopsy specimens of HCV-infected patients, the levels of hypoxia and anaerobic metabolism markers correlated with HCV RNA levels. These results provide new insights into the impact of oxygen tension on the intricate HCVhost cell interaction. H epatitis C virus (HCV) infection causes a wide range of clinical manifestations, from a healthy carrier state to acute and chronic hepatitis that can lead to fibrosis, cirrhosis, and hepatocellular carcinoma. Nearly 3% of the world's population is chronically infected with HCV (1, 2), and current therapeutic approaches are not broadly effective (3).HCV is a positive-strand RNA virus with a 9.6-kb genome that is flanked at both termini by conserved, nontranslated regions (NTRs), required for RNA translation and replication. The 5= NTR comprises an internal ribosome entry site (IRES) that directs the expression of a polyprotein precursor (4, 5). The polyprotein is cleaved into structural (core, E1, E2) and nonstructural (p7, NS2, NS3, NS4A, NS4B, NS5A, NS5B) proteins that, in association with cellular factors, form a membrane-associated replicase complex. This copies the viral positive-strand RNA into a negative-strand intermediate that serves as the template for the synthesis of progeny genomes. The alternative reading frame (ARFP) or coreϩ1 and minicore proteins, with as-yet-unknown functions, appear to be synthesized from the core region by alternative translation mechanisms (6, 7).Studies of the...

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“…In the case of group A streptococci, the increased susceptibility to infection was associated with the failure of HIF-1a-deficient mice to upregulate the antimicrobial peptide CRAMP, the murine homolog of cathelicidin (39). However, these mice cannot be used to directly assess the effect of low oxygen tension, because HIF-1a is also activated under normoxic conditions in an inflammatory microenvironment (41), including infections with human pathogens (42).…”

Section: Discussionmentioning

confidence: 99%

Hypoxia Triggers the Expression of Human β Defensin 2 and Antimicrobial Activity against Mycobacterium tuberculosis in Human Macrophages

Nickel

Busch

Mayer

et al. 2012

The Journal of Immunology

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Low oxygen tension is a metabolic hallmark of chronic infection. To investigate the influence of hypoxia on macrophage biology, we analyzed the interaction between the intracellular pathogen Mycobacterium tuberculosis and primary human macrophages. Although the metabolic activity of extracellular M. tuberculosis was reduced at oxygen levels between 0.5 and 10%, the bacilli remained viable throughout the 4 d of culture. Phagocytosis of virulent M. tuberculosis and the pathogen-induced release of inflammatory cytokines by macrophages were not affected by oxygen levels as low as 1%. However, we detected the upregulation of an antimicrobial effector pathway mediated by the vitamin D receptor and human β defensin 2. This finding was functionally relevant, because intracellular mycobacterial growth was inhibited by 58 ± 8% at 1% O2. We conclude that a hypoxic microenvironment, which is characteristic of infected tissue, supports the efficacy of antimicrobial immunity, in part by the upregulation of the antimicrobial peptide human β defensin 2.

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Activation of Hypoxia Inducible Factor 1 Is a General Phenomenon in Infections with Human Pathogens

Cited by 153 publications

References 49 publications

Survival of Effector CD8+ T Cells during Influenza Infection Is Dependent on Autophagy

Survival of Effector CD8+ T Cells during Influenza Infection Is Dependent on Autophagy

Low Oxygen Tension Enhances Hepatitis C Virus Replication

Hypoxia Triggers the Expression of Human β Defensin 2 and Antimicrobial Activity against Mycobacterium tuberculosis in Human Macrophages

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