The impact of BNT162b2 mRNA vaccine on adaptive and innate immune responses

The mRNA-based BNT162b2 protects against severe disease and mortality caused by SARS-CoV-2 via induction of specific antibody and T-cell responses. Much less is known about its broad effects on immune responses against other pathogens. Here, we investigated the adaptive immune responses induced by BNT162b2 vaccination against various SARS-CoV-2 variants and its effects on the responsiveness of immune cells upon stimulation with heterologous stimuli. BNT162b2 vaccination induced effective humoral and cellular immunity against SARS-CoV-2 that started to wane after six months. We also observed long-term transcriptional changes in immune cells after vaccination. Additionally, vaccination with BNT162b2 modulated innate immune responses as measured by inflammatory cytokine production after stimulation - higher IL-1/IL-6 release and decreased IFN-α production. Altogether, these data expand our knowledge regarding the overall immunological effects of this new class of vaccines and underline the need for additional studies to elucidate their effects on both innate and adaptive immune responses.</p

Dysregulated innate and adaptive immune responses discriminate disease severity in COVID-19

The clinical spectrum of COVID-19 varies and the differences in host response characterizing this variation have not been fully elucidated. COVID-19 disease severity correlates with an excessive pro-inflammatory immune response and profound lymphopenia. Inflammatory responses according to disease severity were explored by plasma cytokine measurements and proteomics analysis in 147 COVID-19 patients. Furthermore, peripheral blood mononuclear cell cytokine production assays and whole blood flow cytometry were performed. Results confirm a hyperinflammatory innate immune state, while highlighting hepatocyte growth factor and stem cell factor as potential biomarkers for disease severity. Clustering analysis reveals no specific inflammatory endotypes in COVID-19 patients. Functional assays reveal abrogated adaptive cytokine production (interferon-gamma, interleukin-17 and interleukin-22) and prominent T cell exhaustion in critically ill patients, whereas innate immune responses were intact or hyperresponsive. Collectively, this extensive analysis provides a comprehensive insight into the pathobiology of severe to critical COVID-19 and highlight potential biomarkers of disease severity

Soluble ST2 plasma concentrations predict mortality in severe sepsis

Patients with sepsis-after surviving the initial hyperinflammatory phase-display features consistent with immunosuppression, including hyporesponsiveness of immunocompetent cells to bacterial agents. Immunosuppression is thought to be facilitated by negative regulators of toll-like receptors, including membrane-bound ST2. We investigated the release of soluble ST2 (sST2), a decoy receptor that inhibits membrane-bound ST2 signaling, during sepsis. The study population comprised 95 patients with severe sepsis admitted to one of two intensive care units (ICUs) at the day the diagnosis of severe sepsis was made. Blood was obtained daily from admission (day 0) until day 7 and finally at day 14. Twenty-four healthy subjects served as controls. sST2 and cytokines were measured in serum. Mortality among patients was 34% in the ICU and 45% in the hospital. On admission, sepsis patients had higher sST2 levels [10,989 (7,871-15,342) pg/ml, geometric mean (95% confidence interval, CI)] than controls [55 (20-145) pg/ml, P < 0.0001]. Serum sST2 remained elevated in patients from day 0 to 14 and correlated with disease severity scores (P < 0.001) and cytokine levels on day 0 and during course of disease (P < 0.0001). Nonsurvivors displayed elevated sST2 levels compared with survivors of the intensive care unit (P < 0.0001). Sepsis results in sustained elevation of serum sST2 levels, which correlates with disease severity and mortalit

Loss of Suppression of Tumorigenicity 2 (ST2) Gene Reverses Sepsis-induced Inhibition of Lung Host Defense in Mice

Rationale: After surviving the initial hyperinflammatory phase, patients with sepsis display features consistent with immunosuppression, which renders the host susceptible to nosocomial infections, in particular bacterial pneumonia. Suppression of tumorigenicity 2 (ST2) is a negative regulator of Toll-like receptor signaling implicated in endotoxin tolerance. Objectives: The present study sought to determine the role of ST2 in modulating host defense in the lung during sepsis, using a murine model of cecal ligation and puncture (CLP) induced sepsis followed by a secondary infection with Pseudomonas aeruginosa via the airways. Methods: CLP or sham surgery was performed on BALB/c wild-type (WT) and ST2 knockout (KO) mice, and 24 hours later animals were challenged with 108 live P. aeruginosa. Measurements and Main Results: CLP mice demonstrated impaired clearance of Pseudomonas from their lungs and reduced pulmonary levels of tumor necrosis factor-a and IL-6 compared with sham mice. After CLP, ST2KO mice with secondary pneumonia displayed a strongly improved survival and a better bacterial clearance compared with WT mice, which was accompanied by enhanced lung inflammation. CLP did not influence the responsiveness of alveolar macrophages toward P. aeruginosa ex vivo irrespective of the st2 genotype. In contrast, CLP resulted in a reduced capacity of WTCD4(+) and CD8(+) T cells to produce IFN-gamma and tumor necrosis factor-a, an immune suppressive effect that was not seen in ST2KO mice. Conclusions: These findings indicate that gene products of ST2 contribute to the immune-compromised state during sepsis and the ensuing disturbed homeostasis of lung host defens

Gene Expression Profiling of Apoptosis Regulators in Patients with Sepsis

Introduction: Sepsis is associated with a dysregulation of apoptosis in immune cells, which has been implicated in both immunosuppression and multiple organ failure. We describe the expression profiles of genes encoding key regulators of apoptosis in highly purified monocytes, granulocytes and CD4+ T lymphocytes. Methods: Sixteen patients with sepsis were recruited from the intensive care unit and were compared with 24 healthy controls. RNA was isolated from highly purified monocyte, granulocyte and CD4+ T-lymphocyte populations. Gene expression profiles were determined using multiplex ligation-dependent probe amplification for the simultaneous detection of 30 pro- and anti-apoptotic target genes. Results: Relative to healthy controls, patients with sepsis showed increased transcription of both pro- and anti-apoptotic genes in peripheral blood leukocytes. Specific monocyte, granulocyte and CD4+ T-lymphocyte mRNA profiles were identified. Anti-apoptotic profiles were found in monocytes and granulocytes, while CD4+ T lymphocytes displayed a foremost pro-apoptotic mRNA profile. Conclusions: These data indicate that in patients with sepsis, the alterations in apoptosis of circulating leukocytes occur in a cell-specific manner. Copyright (C) 2010 S. Karger AG, Base

Lung inflammation induced by lipoteichoic acid or lipopolysaccharide in humans

RATIONALE: Recognition of pathogen-associated molecular patterns by Toll-like receptors (TLRs) is considered to be important for an appropriate immune response against pathogens that enter the lower airways. OBJECTIVES: We studied the effects of two different TLR agonists relevant for respiratory infections in the human lung: lipoteichoic acid (LTA; TLR2 agonist, component of gram-positive bacteria) and lipopolysaccharide (LPS; TLR4-agonist, component of gram-negative bacteria). METHODS: Fifteen healthy subjects were given LPS or LTA: by bronchoscope, sterile saline was instilled into a lung segment followed by instillation of LTA or LPS into the contralateral lung. After 6 hours, a bronchoalveolar lavage was performed and inflammatory parameters were determined. Isolated RNA from purified alveolar macrophages was analyzed by multiplex ligation-dependent probe amplification. In addition, spontaneous cytokine release by alveolar macrophages was measured. MEASUREMENTS AND MAIN RESULTS: Marked differences were detected between LTA- and LPS-induced lung inflammation. Whereas both elicited neutrophil recruitment, only LPS instillation was associated with activation of neutrophils (CD11b surface expression, degranulation product levels) and consistent rises of chemo-/cytokine levels. Moreover, LPS but not LTA activated alveolar macrophages, as reflected by enhanced expression of 10 different mRNAs encoding proinflammatory mediators and increased spontaneous cytokine release upon incubation ex vivo. Remarkably, only LTA induced C5a release. CONCLUSIONS: This is the first study to report the in vivo effects of LTA in men and to compare inflammation induced by LTA and LPS in the human lung. Our data suggest that stimulation of TLR2 or TLR4 results in differential pulmonary inflammation, which may be of relevance for understanding pathogenic mechanisms at play during gram-positive and gram-negative respiratory tract infectio