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J Transl Med ; 18(1): 452, 2020 11 30.
Article in English | MEDLINE | ID: covidwho-948411


BACKGROUND: Dysregulation of transcription and cytokine expression has been implicated in the pathogenesis of a variety inflammatory diseases. The resulting imbalance between inflammatory and resolving transcriptional programs can cause an overabundance of pro-inflammatory, classically activated macrophage type 1 (M1) and/or helper T cell type 1 (Th1) products, such as IFNγ, TNFα, IL1-ß, and IL12, that prevent immune switching to resolution and healing. The low molecular weight fraction of human serum albumin (LMWF5A) is a novel biologic drug that is currently under clinical investigation for the treatment of osteoarthritis and the hyper-inflammatory response associated with COVID-19. This study aims to elucidate transcriptional mechanisms of action involved with the ability of LMWF5A to reduce pro-inflammatory cytokine release. METHODS: ELISA arrays were used to identify cytokines and chemokines influenced by LMWF5A treatment of LPS-stimulated peripheral blood mononuclear cells (PBMC). The resulting profiles were analyzed by gene enrichment to gain mechanistic insight into the biologic processes and transcription factors (TFs) underlying the identified differentially expressed cytokines. DNA-binding ELISAs, luciferase reporter assays, and TNFα or IL-1ß relative potency were then employed to confirm the involvement of enriched pathways and TFs. RESULTS: LMWF5A was found to significantly inhibit a distinct set of pro-inflammatory cytokines (TNFα, IL-1ß, IL-12, CXCL9, CXCL10, and CXCL11) associated with pro-inflammatory M1/Th1 immune profiles. Gene enrichment analysis also suggests these cytokines are, in part, regulated by NF-κB and STAT transcription factors. Data from DNA-binding and reporter assays support this with LMWF5A inhibition of STAT1α DNA-binding activity as well as a reduction in overall NF-κB-driven luciferase expression. Experiments using antagonists specific for the immunomodulatory and NF-κB/STAT-repressing transcription factors, peroxisome proliferator-activated receptor (PPAR)γ and aryl hydrocarbon receptor (AhR), indicate these pathways are involved in the LMWF5A mechanisms of action by reducing LMWF5A drug potency as measured by TNFα and IL-1ß release. CONCLUSION: In this report, we provide evidence that LMWF5A reduces pro-inflammatory cytokine release by activating the immunoregulatory transcription factors PPARγ and AhR. In addition, our data indicate that LMWF5A suppresses NF-κB and STAT1α pro-inflammatory pathways. This suggests that LMWF5A acts through these mechanisms to decrease pro-inflammatory transcription factor activity and subsequent inflammatory cytokine production.

Cytokines/metabolism , Inflammation/prevention & control , Leukocytes, Mononuclear/drug effects , Serum Albumin, Human/pharmacology , Anti-Inflammatory Agents/pharmacology , COVID-19/drug therapy , COVID-19/immunology , COVID-19/pathology , Cells, Cultured , Gene Expression Regulation/drug effects , HEK293 Cells , Humans , Inflammation/genetics , Inflammation/metabolism , Inflammation Mediators/metabolism , Interferon-Stimulated Gene Factor 3/metabolism , Leukocytes, Mononuclear/metabolism , Lipopolysaccharides , Lymphocyte Activation/drug effects , Molecular Weight , NF-kappa B/metabolism , Serum Albumin, Human/chemistry , Signal Transduction/drug effects , Signal Transduction/genetics , Signal Transduction/immunology , Transcription Factors/metabolism
Lancet ; 395(10238): 1727-1734, 2020 05 30.
Article in English | MEDLINE | ID: covidwho-276547


Indigenous communities worldwide share common features that make them especially vulnerable to the complications of and mortality from COVID-19. They also possess resilient attributes that can be leveraged to promote prevention efforts. How can indigenous communities best mitigate potential devastating effects of COVID-19? In Bolivia, where nearly half of all citizens claim indigenous origins, no specific guidelines have been outlined for indigenous communities inhabiting native communal territories. In this Public Health article, we describe collaborative efforts, as anthropologists, physicians, tribal leaders, and local officials, to develop and implement a multiphase COVID-19 prevention and containment plan focused on voluntary collective isolation and contact-tracing among Tsimane forager-horticulturalists in the Bolivian Amazon. Phase 1 involves education, outreach, and preparation, and phase 2 focuses on containment, patient management, and quarantine. Features of this plan might be exported and adapted to local circumstances elsewhere to prevent widespread mortality in indigenous communities.

Communicable Disease Control/methods , Coronavirus Infections/prevention & control , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Population Groups , Social Isolation , Betacoronavirus , Bolivia , COVID-19 , Contact Tracing , Humans , SARS-CoV-2 , Vulnerable Populations
Patient Saf Surg ; 14: 21, 2020.
Article in English | MEDLINE | ID: covidwho-245767


Background: A common complication of viral pulmonary infections, such as in the ongoing COVID-19 pandemic, is a phenomenon described as a "cytokine storm". While poorly defined, this hyperinflammatory response results in diffuse alveolar damage. The low molecular weight fraction of commercial human serum albumin (LMWF5A), a novel biologic in development for osteoarthritis, demonstrates beneficial in vitro immunomodulatory effects complimentary to addressing inflammation, thus, we hypothesize that LMWF5A could improve the clinical outcomes of COVID-19 by attenuating hyperinflammation and the potential development of a cytokine storm. Presentation of the hypothesis: A variety of human in vitro immune models indicate that LMWF5A reduces the production of pro-inflammatory cytokines implicated in cytokine storm associated with COVID-19. Furthermore, evidence suggests LMWF5A also promotes the production of mediators required for resolving inflammation and enhances the barrier function of endothelial cultures. Testing the hypothesis: A randomized controlled trial, to evaluate the safety and efficacy of nebulized LMWF5A in adults with Acute Respiratory Distress Syndrome (ARDS) secondary to COVID-19 infection, was developed and is currently under review by the Food and Drug Administration. Implications of hypothesis: If successful, this therapy may attenuate the cytokine storm observed in these patients and potentially reduce mortality, increase ventilation free days, improve oxygenation parameters and consequently lessen the burden on patients and the intensive care unit. Conclusions: In conclusion, in vitro findings suggest that the immunomodulatory effects of LMWF5A make it a viable candidate for treating cytokine storm and restoring homeostasis to the immune response in COVID-19.