Defensins represents an integral part of the innate immune system serving to ward off potential pathogens and to protect the intestinal barrier from microbial encroachment. In addition to their antimicrobial activities, defensins in general, and human β-defensin 2 (hBD2) in particular, also exhibit immunomodulatory capabilities. In this report, we assessed the therapeutic efficacy of systemically administered recombinant hBD2 to ameliorate intestinal inflammation in three distinct animal models of inflammatory bowel disease; i.e., chemically induced mucosal injury (DSS), loss of mucosal tolerance (TNBS), and T-cell transfer into immunodeficient recipient mice. Treatment efficacy was confirmed in all tested models, where systemically administered hBD2 mitigated inflammation, improved disease activity index, and hindered colitis-induced body weight loss on par with anti-TNF-α and steroids. Treatment of lipopolysaccharide (LPS)-activated human peripheral blood mononuclear cells with rhBD2 confirmed the immunomodulatory capacity in the circulatory compartment. Subsequent analyzes revealed dendritic cells (DCs) as the main target population. Suppression of LPS-induced inflammation was dependent on chemokine receptor 2 (CCR2) expression. Mechanistically, hBD2 engaged with CCR2 on its DC target cell to decrease NF-κB, and increase CREB phosphorylation, hence curbing inflammation. To our knowledge, this is the first study showing in vivo efficacy of a systemically administered defensin in experimental disease.

Objective: Patients with coronary artery disease (CAD) are at increased risk for cardiac death and respiratory failure following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Platelets are crucially involved in pathogenesis of CAD and might also contribute to pathophysiology of SARS-CoV-2 infection. Approach and Results: We enrolled a cohort of 122 participants from February 2020 to July 2020 including 55 patients with preexisting CAD and acute SARS-CoV-2 infection (CAD-SARS-CoV-2 positive ), 28 patients with CAD and without SARS-CoV-2 (CAD-SARS-CoV-2 negative ), and 39 healthy controls. Clinical and cardiac examination of the CAD-SARS-CoV-2 positive group included blood sampling, echocardiography, and electrocardiography within 24 hours after hospital admission. Phenotyping of platelets was performed by flow cytometry; plasma levels of chemokines were analyzed by ELISA. Respiratory failure of patients was stratified by the Horovitz index as moderately/severely impaired when Horovitz index <200 mm Hg. The clinical end point was defined as Horovitz index <200 mm Hg with subsequent mechanical ventilation within a follow-up of 60 days. CAD-SARS-CoV-2 positive patients display a significant enhanced platelet activation and hyper-inflammation early at time of hospital admission. Circulating platelet/leukocyte co-aggregates correlate with plasma levels of cytokines/chemokines like IL (interleukin)-6, CCL2, and CXCL10 as well as activation of platelets is associated with CCL5 and elevation of pulmonary artery pressure. Furthermore, furin is stored and released from activated platelets. High furin plasma levels are associated with poor clinical prognosis in CAD-SARS-CoV-2 positive patients. Conclusions: Patients with CAD and SARS-CoV-2 infection exhibit elevated systemic platelet activation and enhanced plasma levels of the subtilisin-like proprotein convertase furin, which may contribute to an unfavorable clinical prognosis.

Aims To elucidate the prognostic role of monocytes in the immune response of patients with coronary artery disease (CAD) at risk for life-threatening heart and lung injury as major complications of SARS-CoV-2 infection. Methods and Results From February to April 2020, we prospectively studied a cohort of 96 participants comprising 47 consecutive patients with CAD and acute SARS-CoV-2 infection (CAD+SARS-CoV-2), 19 CAD patients without infections, and 30 healthy controls. Clinical assessment included blood sampling, echocardiography, and electrocardiography within 12 hours of admission. Respiratory failure was stratified by the Horovitz Index (HI) as moderately/severely impaired when HI ≤ 200 mmHg. The clinical endpoint (EP) was defined as HI ≤ 200 mmHg with subsequent mechanical ventilation within a follow-up of 30 days. The numbers of CD14dimCD16+ non-classical monocytes in peripheral blood were remarkably low in CAD+SARS-CoV-2 compared to CAD patients without infection and healthy controls (p &lt; 0.0001). Moreover, these CD14dimCD16 monocytes showed decreased expression of established markers of adhesion, migration, and T cell activation (CD54, CD62L, CX3CR1, CD80, HLA-DR). Decreased numbers of CD14dimCD16+ monocytes were associated with the occurrence of EP. Kaplan-Meier curves illustrate that CAD+SARS-CoV-2 patients with numbers below the median of CD14dimCD16+ monocytes (median 1443 cells/mL) reached EP significantly more often compared to patients with numbers above the median (log-rank 5.03, p = 0.025). Conclusion Decreased numbers of CD14dimCD16+ monocytes are associated with rapidly progressive respiratory failure in CAD+SARS-CoV-2 patients. Intensified risk assessments comprising monocyte sub- and phenotypes may help to identify patients at risk for respiratory failure. Translational Perspective Patients with coronary artery disease (CAD) are at risk of life-threatening heart and lung injury accelerated by the pro-inflammatory and pro-thrombotic immune response during SARS-CoV-2 infection. We found substantially low numbers of CD14dimCD16+ non-classical monocytes with an altered phenotype suggesting impaired migration behaviour and T cell activation capacity in peripheral blood of SARS-CoV-2 patients with CAD, compared to CAD patients without infection or healthy controls. Decreased numbers of CD14dimCD16+ monocytes predicted rapidly progressive respiratory failure (Horovitz index ≤ 200 mmHg) with subsequent mechanical ventilation. Therefore, early sub- and phenotyping of CD14dimCD16+ monocytes using simple flow cytometry might predict worsening of respiratory failure at an early stage of SARS-CoV-2 infection in high-risk CAD patients, who require an extensive heart failure and anti-thrombotic therapy to improve their clinical outcome.

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