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Sci Transl Med ; 13(616): eabj1008, 2021 Oct 20.
Article in English | MEDLINE | ID: covidwho-1518118


Red blood cells (RBCs) are essential for aerobic respiration through delivery of oxygen to distant tissues. However, RBCs are currently considered immunologically inert, and few, if any, secondary functions of RBCs have been identified. Here, we showed that RBCs serve as critical immune sensors through surface expression of the nucleic acid­sensing Toll-like receptor 9 (TLR9). Mammalian RBCs expressed TLR9 on their surface and bound CpG-containing DNA derived from bacteria, plasmodia, and mitochondria. RBC-bound mitochondrial DNA was increased during human and murine sepsis and pneumonia. In vivo, CpG-carrying RBCs drove accelerated erythrophagocytosis and innate immune activation characterized by increased interferon signaling. Erythroid-specific deletion of TLR9 abrogated erythrophagocytosis and decreased local and systemic cytokine production during CpG-induced inflammation and polymicrobial sepsis. Thus, detection and capture of nucleic acid by TLR9-expressing RBCs regulated red cell clearance and inflammatory cytokine production, demonstrating that RBCs function as immune sentinels during pathologic states. Consistent with these findings, RBC-bound mitochondrial DNA was elevated in individuals with viral pneumonia and sepsis secondary to coronavirus disease 2019 (COVID-19) and associated with anemia and severity of disease. These findings uncover a previously unappreciated role of RBCs as critical players in inflammation distinct from their function in gas transport.

Anemia , Immunity, Innate , Toll-Like Receptor 9 , Animals , DNA , Erythrocytes , Humans , Mice
Am J Physiol Lung Cell Mol Physiol ; 321(2): L485-L489, 2021 08 01.
Article in English | MEDLINE | ID: covidwho-1299247


COVID-19, the disease caused by the SARS-CoV-2 virus, can progress to multisystem organ failure and viral sepsis characterized by respiratory failure, arrhythmias, thromboembolic complications, and shock with high mortality. Autopsy and preclinical evidence implicate aberrant complement activation in endothelial injury and organ failure. Erythrocytes express complement receptors and are capable of binding immune complexes; therefore, we investigated complement activation in patients with COVID-19 using erythrocytes as a tool to diagnose complement activation. We discovered enhanced C3b and C4d deposition on erythrocytes in COVID-19 sepsis patients and non-COVID sepsis patients compared with healthy controls, supporting the role of complement in sepsis-associated organ injury. Our data suggest that erythrocytes may contribute to a precision medicine approach to sepsis and have diagnostic value in monitoring complement dysregulation in COVID-19-sepsis and non-COVID sepsis and identifying patients who may benefit from complement targeted therapies.

COVID-19/complications , Complement Activation/immunology , Complement C3b/immunology , Complement C4b/immunology , Erythrocytes/immunology , Peptide Fragments/immunology , Respiratory Insufficiency/diagnosis , Sepsis/diagnosis , COVID-19/immunology , COVID-19/virology , Complement C3b/metabolism , Complement C4b/metabolism , Erythrocytes/metabolism , Erythrocytes/virology , Female , Humans , Male , Middle Aged , Peptide Fragments/metabolism , Respiratory Insufficiency/immunology , Respiratory Insufficiency/metabolism , Respiratory Insufficiency/virology , SARS-CoV-2/isolation & purification , Sepsis/immunology , Sepsis/metabolism , Sepsis/virology
World Dev ; 136: 105104, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-1065653


Food systems are important sites of economic stress, political response and adaptation. Access to food is also an important marker of how well a society distributes its wealth, reflecting the state of political accountability, economic redistribution, and the society's level of commitment to uphold the right to food. The COVID-19 pandemic has exposed the interconnected weaknesses of our food, social and economic systems and offers lessons for building more just and resilient food systems. We focus on three lessons learned anew in the pandemic: (1) food insecurity both reflects and reinforces inequity, (2) food workers are essential yet treated as sacrificial, and (3) racialized migrant food workers face unique forms of inequity. These lessons - chosen for their ethical salience, global relevance, and political urgency - show how interconnected inequities revealed by the pandemic are undermining resilience. We conclude with specific policy recommendations for redress, both within and beyond food systems. This will not be the final global pandemic, nor is it the only shock that regions are currently experiencing. COVID-19 is an opening to think about how societies might center justice and equity in efforts to build back better. Governments should take this opportunity to invest in structural changes to reduce persistent inequities in food access due to poverty, health outcomes, decent work and overall wellbeing, especially for racialized communities and migrants.