Background Practitioners and researchers in the midst of overwhelming coronavirus disease 2019 (COVID-19) outbreaks are calling for new ways of looking at such pandemics, with an emphasis on human behavior and holistic considerations. Viral outbreaks are characterized by socio-behaviorally-oriented public health efforts aimed at reducing exposure and prevention of morbidity/mortality once infected. These efforts involve different points-of-view, generally, than do those aimed to understand the virus’ natural history. Rampant spread of SARS-CoV-2 infection in cities clearly signals that urban areas contain conditions favorable for rapid transmission of the virus. Main text The Critical Medical Ecology model is a multidimensional, multilevel way of viewing pandemics comprehensively, rooted simultaneously in microbiology and in anthropology, with shared priority for evolution, context, stressors, homeostasis, adaptation, and power relationships. Viewing COVID-19 with a Critical Medical Ecological lens suggests three important interpretations: 1) COVID-19 is equally — if not more — a socially-driven disease as much as a biomedical disease, 2) the present interventions available for primary prevention of transmission are social and behavioral interventions, and 3) wide variation in COVID-19 hospitalization/death rates is not expected to significantly be attributable to a more virulent and rapidly-evolving virus, but rather to differences in social and behavioral factors — and power dynamics — rather than (solely) biological and clinical factors. Cities especially are challenged due to logistics and volume of patients, and lack of access to sustaining products and services for many residents living in isolation. Conclusions In the end, SARS-CoV-2 is acting upon dynamic social human beings, entangled within structures and relationships that include but extend far beyond their cells, and in fact beyond their own individual behavior. As a comprehensive way of thinking, the Critical Medical Ecology model helps identify these elements and dynamics in the context of ecological processes that create, shape, and sustain people in their multidimensional, intersecting environments.
Current understanding of B lymphocyte function relies heavily upon in vitro assays. However, standard incubators maintain cells at supraphysiologic oxygen (16–19% oxygen). Physiologic oxygen is far lower (blood 5–10%, secondary lymphoid tissues 1–5%, regions of inflammation, tumor, and bone marrow 0–1%). Previously, we showed that transcripts for hypoxia-induced factor 1 alpha (HIF-1a), an oxygen-sensing transcription factor, are upregulated in peripheral B cells after vaccination1. HIF-1a is also a therapeutic target in multiple myeloma2. Downstream of HIF-1a are genes tied to metabolism, proliferation, and the unfolded protein response. One gene downstream of HIF1a that is critical for B cell migration and function is CXCR4. We set out to determine if room air incubation might affect B cells in vitro, our null hypothesis being that physiologic oxygen would not affect B cell HIF-1a levels or CXCR4 function. We used C-chamber incubator sub-chambers and Pro-Ox 110 gas controllers to control the incubation oxygen and carbon dioxide levels. Setting the reference frame to a range relevant to secondary lymphoid organs (1–5% oxygen), we set the chambers to 5% CO2 and 1% (hypoxic), 4% (physioxic), or 19% (supraphysioxic) oxygen. In primary human B cells and myeloma cell lines, HIF-1a protein levels stabilized at 24 hrs of culture at 1% and 4% oxygen, but not at 19% oxygen. More importantly, B cell migration in response to the CXCR4 ligand, CXCL12, was significantly decreased at low oxygen levels, without affecting cell proliferation or viability, disproving our null hypothesis. This has widespread implications for assessments of B cell function in that incubator oxygen drives HIF-1a degradation and CXCR4 responsiveness in vitro.
B lymphocytes in vitro encounter oxygen levels far in excess of what they experience in vivo. Room air incubator O2 is not 21%, the accepted level for outdoor O2[1]. High CO2 and humidity drive incubator O2 down (16–19%), with variability from door openings. However, in vivo O2 is far lower even (tissues 0–7%, blood 5–10%). Hypoxia-induced factor 1 alpha (HIF-1a) is a tightly regulated transcription factor responsive to O2 levels [2]. Downstream of HIF-1a are genes tied to the unfolded protein response, metabolism, proliferation, and migration. A therapeutic target in multiple myeloma [3], HIF-1a protein is stabilized at low O2 levels and rapidly degraded at higher O2 levels. We previously showed in primary human B cells and myeloma cell lines, that HIF-1a protein levels stabilize at physioxic 1% and 4% oxygen, but not at 19% oxygen. B cell migration in response to the CXCR4 ligand, CXCL12, was decreased at low O2 levels. Here we seek to add direct evidence to HIF-1a participation in B cell migration changes by using a lentiviral vector to produce stable transfectants expressing a HIF-1a shRNA to genetically ablate HIF-1a. We used C-chamber sub-chambers and Pro-Ox 110 gas controllers to stably control the gas levels inside a standard incubator. At 1% O2, HIF-1a shRNA expression resulted in undetectable HIF-1a protein levels, and a correlating increase in CXCR4-mediated B cell migration as compared to a lentiviral control vector or non-transfected cells. This adds genetic evidence that directly links incubator O2 levels, HIF-1a activity and B cell migration in vitro.
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