Oxygen: Viral Friend Or Foe? Esther Shuyi Gan1* and Eng Eong Ooi1,2,3

Oxygen: Viral Friend Or Foe? Esther Shuyi Gan1* and Eng Eong Ooi1,2,3

Gan and Ooi Virology Journal (2020) 17:115 https://doi.org/10.1186/s12985-020-01374-2 REVIEW Open Access Oxygen: viral friend or foe? Esther Shuyi Gan1* and Eng Eong Ooi1,2,3 Abstract The oxygen levels organ and tissue microenvironments vary depending on the distance of their vasculature from the left ventricle of the heart. For instance, the oxygen levels of lymph nodes and the spleen are significantly lower than that in atmospheric air. Cellular detection of oxygen and their response to low oxygen levels can exert a significant impact on virus infection. Generally, viruses that naturally infect well-oxygenated organs are less able to infect cells under hypoxic conditions. Conversely, viruses that infect organs under lower oxygen tensions thrive under hypoxic conditions. This suggests that in vitro experiments performed exclusively under atmospheric conditions ignores oxygen-induced modifications in both host and viral responses. Here, we review the mechanisms of how cells adapt to low oxygen tensions and its impact on viral infections. With growing evidence supporting the role of oxygen microenvironments in viral infections, this review highlights the importance of factoring oxygen concentrations into in vitro assay conditions. Bridging the gap between in vitro and in vivo oxygen tensions would allow for more physiologically representative insights into viral pathogenesis. Keywords: Hypoxia, Viruses Background viruses that naturally infect and replicate in tissues with Viral infections are heavily dependent on host cells for high oxygen content are impaired by hypoxic environ- energy, enzymes and metabolic intermediates for suc- ments. Conversely, hypoxia has been shown to increase cessful replication [134]. Factors that influence the state the infection of viruses that naturally infect organs with of a cell, including differential gene expression and path- lower oxygen tensions. way activation, could all impact the outcome of viral pathogenesis. One such factor is the oxygen level in the microenvironment in which cells reside. Oxygen plays Main text key roles in respiration, metabolism and energy produc- Oxygen cascade tion. Given the key role of oxygen in cell function, cells Although oxygen is needed by all human cells, not all have evolved oxygen sensors that regulate the expression cells in our bodies receive similar amounts of oxygen. of a suite of genes in response to lowered oxygen levels. Oxygen levels in most organs, with a few exceptions, are For this discovery, William Kaelin, Gregg Semenza and lower than that of atmospheric oxygen (20–21% or 152- Peter Ratcliffe were awarded the 2019 Nobel Prize for 160 mmHg). This disparity is largely due to blood trans- Physiology and Medicine. Here, we elaborate upon our portation through the vascular anatomy and subse- understanding of how cells react to different oxygen quently vascular beds in tissues [55]. Due to its poor levels and review how oxygen affects the outcome of solubility in liquids, oxygen is transported around the viral infection and disease pathogenesis. In general, body by hemoglobin in red blood cells. Each hemoglobin molecule carries up to a maximum of 4 oxygen mole- cules with its affinity for each oxygen molecule increas- * Correspondence: [email protected] ing as each of its binding sites is occupied [120]. Oxygen 1Programme in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore delivery in the human respiratory system depends on Full list of author information is available at the end of the article several factors such as the partial pressure of oxygen, © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Gan and Ooi Virology Journal (2020) 17:115 Page 2 of 12 efficiency of gas exchange, concentration and affinity of useful to understand how cells adapt to physiological hemoglobin to oxygen and cardiac output [92]. The oxygen tension. highest oxygen concentration is typically found in the respiratory tract. As respired air enters the trachea and The HIF family and molecular mechanisms of oxygen is humidified in the upper respiratory tract, the pressure sensing of oxygen decreases while concentration of water in- In microenvironments with lowered oxygen levels, cells creases, thus altering the partial pressure of oxygen in regulate the expression of genes, such as those involved this gas mixture [92]. Further dilution occurs as oxygen in controlling angiogenesis, iron metabolism and gly- diffuses in and out of arteries. This is best exemplified in colysis, to adapt and survive. To understand the cellular organs such as the spleen and liver. In spleens, oxygen response to lowered oxygen levels, investigators focused concentrations are highest nearest the splenic artery on the regulation of erythropoietin (EPO), that is known (~ 6%) as compared to locations in the spleen distant to be induced in response to lowered oxygen to stimu- from the splenic artery (~ 1%) [16]. In the liver, oxygen late erythropoiesis. Analysis of the cis-acting sequences tensions range from approximately 12% oxygen sur- involved in EPO induction led to the identification of rounding the portal vein to 1% oxygen in the proximity hypoxia inducible factor (HIF) [130, 143, 144]. of the central vein [137]. The average oxygen concentra- tions of different organs observed in humans and animal The HIF family models are summarized in Table 1. Taken collectively, HIF transcription factors are basic helix-loop-helix DNA with the exception of the lungs which are exposed to binding proteins of the PER-ARNT-SIM family [143]. ambient air, median physiological oxygen tensions of or- HIFs form heterodimers, where alpha subunits HIF1α, gans are significantly lower than that of atmospheric HIF2α, HIF3α [39, 49, 130] interact with a constitutively oxygen tensions. This is known as the oxygen cascade. expressed beta subunit HIF1β, also known as the aryl Thus, physiological oxygen concentrations in which viral hydrocarbon receptor nuclear translocator 1 (ARNT1) infection and replication occur can be significantly dif- [145]. HIF1α and HIF2α are oxygen sensitive subunits ferent to the level of oxygen in normal air. It is therefore that share 48% genetic sequence homology [63]. Both dimerize with HIF1β during hypoxic conditions to induce gene transcription [39]. HIF3α is distantly related, sharing Table 1 Summary of oxygen concentrations in various organs less sequence homology and function with HIF1α or α Tissue O2 (%) mmHg Species Reference HIF2 .Ithas6splicevariants[49]. Its function remains α α Atmospheric Air 21.1 160 Human [17] understudied in comparison to HIF1 and HIF2 al- though in vitro studies suggest that the prevailing actions Trachea 19.7 150 Human [17] of HIF3α variants are inhibitory and constitutes a negative Arterial Blood 13.2 100 Human [17] feedback loop for HIF1α and HIF2α [59, 98]. Venous Blood 5.3 40 Human [17] Both HIF1α and HIF2α proteins have multiple con- Brain 4.4 ± 0.3 33.8 ± 2.6 Human [4, 102] served domains involved in DNA binding, protein inter- Normal Lung 5.6 42.8 Human [93] action and dimerization, oxygen-dependent degradation Lung Tumor 0.1–6.1 0.7–46 Human [93] (ODD) and transcriptional activity (N-TAD and C- TAD). HIF3α isoforms are shorter and carry only a N- Skin (Epidermis) 1.1 ± 0.42 8 ± 3.2 Human [147] TAD domain together with a leucine zipper motif with Skin (Dermal Papillae) 3.15 ± 0.8 24 ± 6.4 Human [147] unknown function [99, 115]. HIF1β contains no tran- Liver 7.5 ± 0.7 40.6 ± 5.4 Human [13, 94] scriptional activation domains and requires dimerization Kidney 6.8 ± 0.8 52 ± 6 Human [108] with HIF1α to induce transcription. With 70, 85 and Kidney 5.9–6.6 45–50 Rat [129] 100% homology between their basic helix-loop-helix Placenta 7.4 ± 0.4 56.2 ± 3.2 Human [76] DNA binding and remaining basic domains, it is not sur- prising that HIF1α and HIF2α binds DNA indistinguish- Umbilical cord 2.7–3.9 20–30 Human [47] ably [136]. While extremely similar in both homology Umbilical artery 1.3–1.9 10–15 Human [47] and function, there are subtle differences between HIF1α Bone Marrow 7.22 ± 0.1 54.9 ± 0.98 Human [60] and HIF2α. The C-TAD domains of HIF1α and HIF2α Ovaries 11.6 88 Human [43] control target gene transcription through the recruit- Spleen 10 ± 2.4 80 ± 18 Rats [65] ment of co-factors but target gene selectivity between Lymphoid organs 0.5–4.5 3.8–34.2 Mice [16] the 2 proteins have been postulated to arise from the N- TAD domains which recognize distinct transcriptional Skeletal muscle 3.3 ± 0.58 25 ± 4.4 Human [8] co- factors [3, 32, 38, 67]. Besides differences in protein Adipose tissue 4.7–8.9 36–68 Human [40] domains, the expression of this protein is variable in Gan and Ooi Virology Journal (2020) 17:115 Page 3 of 12 different cell types.

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