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Cells ; 11(6)2022 03 12.
Article in English | MEDLINE | ID: covidwho-1760408


Lymphatic vessels provide a critical line of communication between peripheral tissues and their draining lymph nodes, which is necessary for robust immune responses against infectious agents. At the same time, lymphatics help shape the nature and kinetics of immune responses to ensure resolution, limit tissue damage, and prevent autoimmune responses. A variety of pathogens have developed strategies to exploit these functions, from multicellular organisms like nematodes to bacteria, viruses, and prions. While lymphatic vessels serve as transport routes for the dissemination of many pathogens, their hypoxic and immune-suppressive environments can provide survival niches for others. Lymphatics can be exploited as perineural niches, for inter-organ distribution among highly motile carrier cells, as effective replicative niches, and as alternative routes in response to therapy. Recent studies have broadened our understanding of lymphatic involvement in pathogenic spread to include a wider range of pathogens, as well as new mechanisms of exploitation, which we summarize here.

Lymph Nodes , Lymphatic Vessels , Autoimmunity , Immunity , Lymphatic System
Purinergic Signal ; 18(1): 13-59, 2022 03.
Article in English | MEDLINE | ID: covidwho-1694363


Hyperinflammation plays an important role in severe and critical COVID-19. Using inconsistent criteria, many researchers define hyperinflammation as a form of very severe inflammation with cytokine storm. Therefore, COVID-19 patients are treated with anti-inflammatory drugs. These drugs appear to be less efficacious than expected and are sometimes accompanied by serious adverse effects. SARS-CoV-2 promotes cellular ATP release. Increased levels of extracellular ATP activate the purinergic receptors of the immune cells initiating the physiologic pro-inflammatory immune response. Persisting viral infection drives the ATP release even further leading to the activation of the P2X7 purinergic receptors (P2X7Rs) and a severe yet physiologic inflammation. Disease progression promotes prolonged vigorous activation of the P2X7R causing cell death and uncontrolled ATP release leading to cytokine storm and desensitisation of all other purinergic receptors of the immune cells. This results in immune paralysis with co-infections or secondary infections. We refer to this pathologic condition as hyperinflammation. The readily available and affordable P2X7R antagonist lidocaine can abrogate hyperinflammation and restore the normal immune function. The issue is that the half-maximal effective concentration for P2X7R inhibition of lidocaine is much higher than the maximal tolerable plasma concentration where adverse effects start to develop. To overcome this, we selectively inhibit the P2X7Rs of the immune cells of the lymphatic system inducing clonal expansion of Tregs in local lymph nodes. Subsequently, these Tregs migrate throughout the body exerting anti-inflammatory activities suppressing systemic and (distant) local hyperinflammation. We illustrate this with six critically ill COVID-19 patients treated with lidocaine.

Adenosine Triphosphate/metabolism , COVID-19/immunology , Cytokine Release Syndrome/etiology , Inflammation/etiology , Lidocaine/therapeutic use , Purinergic P2X Receptor Antagonists/therapeutic use , Receptors, Purinergic/physiology , Anti-Inflammatory Agents/therapeutic use , Critical Care , Cytokine Release Syndrome/drug therapy , Humans , Inflammation/drug therapy , Infusions, Subcutaneous , Lidocaine/administration & dosage , Lidocaine/pharmacology , Lymph Nodes/immunology , Lymphatic System/immunology , Male , Maximum Tolerated Dose , Middle Aged , Models, Immunological , Purinergic P2X Receptor Antagonists/administration & dosage , Purinergic P2X Receptor Antagonists/pharmacology , Receptors, Purinergic/drug effects , Receptors, Purinergic P1/drug effects , Receptors, Purinergic P1/physiology , Receptors, Purinergic P2X7/physiology , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/etiology , Signal Transduction , T-Lymphocytes, Regulatory/immunology
Med Hypotheses ; 144: 110023, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-611691


Consistent observations report increased severity of SARS-CoV-2 infection in overweight men with cardiovascular factors. As the visceral fat possesses an intense immune activity, is involved in metabolic syndrome and is at the crossroad between the intestines, the systemic circulation and the lung, we hypothesized that it plays a major role in severe forms of SARS-CoV-2 infection. SARS-CoV2 presents the ability to infect epithelial cells of the respiratory tract as well as the intestinal tract. Several factors may increase intestinal permeability including direct enterocyte damage by SARS-CoV2, systemic inflammatory response syndrome (SIRS) and epithelial ischemia secondary to SARS-CoV2- associated endothelial dysfunction. This increase permeability further leads to translocation of microbial components such as MAMPs (microbial-associated molecular pattern), triggering an inflammatory immune response by TLR-expressing cells of the mesentery fat (mostly macrophages and adipocytes). The pro-inflammatory cytokines produced by the mesentery fat mediates systemic inflammation and aggravate acute respiratory distress syndrome (ARDS) through the mesenteric lymph drainage.

COVID-19/physiopathology , Lung/physiopathology , Lymphatic System/physiopathology , Obesity/physiopathology , COVID-19/complications , Critical Care , Cytokines/metabolism , Gastrointestinal Microbiome , Humans , Immune System , Inflammation , Intensive Care Units , Intra-Abdominal Fat/pathology , Ischemia/pathology , Male , Metabolic Syndrome/immunology , Models, Theoretical , Obesity/complications , Overweight/complications , Permeability , Risk Factors , Systemic Inflammatory Response Syndrome/immunology