In light of the recent accumulated knowledge on SARS-CoV-2 and its mode of human cells invasion, the binding of viral spike glycoprotein to human Angiotensin Converting Enzyme 2 (hACE2) receptor ...plays a central role in cell entry. We designed a series of peptides mimicking the N-terminal helix of hACE2 protein which contains most of the contacting residues at the binding site, exhibiting a high helical folding propensity in aqueous solution. Our best peptide-mimics are able to block SARS-CoV-2 human pulmonary cell infection with an inhibitory concentration (IC
) in the nanomolar range upon binding to the virus spike protein with high affinity. These first-in-class blocking peptide mimics represent powerful tools that might be used in prophylactic and therapeutic approaches to fight the coronavirus disease 2019 (COVID-19).
An unprecedented outbreak of pneumonia caused by a novel coronavirus (CoV), subsequently termed COVID-19 by the World Health Organization, emerged in Wuhan City (China) in December 2019. Despite ...rigorous containment and quarantine efforts, the incidence of COVID-19 continues to expand, causing explosive outbreaks in more than 160 countries with waves of morbidity and fatality, leading to significant public health problems. In the past 20 years, two additional epidemics caused by CoVs have occurred: severe acute respiratory syndrome-CoV, which has caused a large-scale epidemic in China and 24 other countries; and respiratory syndrome-CoV of the Middle East in Saudi Arabia, which continues to cause sporadic cases. All of these viruses affect the lower respiratory tract and manifest as pneumonia in humans, but the novel SARS-Cov-2 appears to be more contagious and has spread more rapidly worldwide. This mini-review focuses on the cellular immune response to COVID-19 in human subjects, compared to other clinically relevant coronaviruses to evaluate its role in the control of infection and pathogenesis and accelerate the development of a preventive vaccine or immune therapies.
Ventilator settings for patients with severe acute respiratory distress syndrome supported by venovenous extracorporeal membrane oxygenation are currently set arbitrarily. The impact on serum and ...pulmonary biotrauma markers of the transition to ultra-protective ventilation settings following extracorporeal membrane oxygenation implantation, and different mechanical ventilation strategies while on extracorporeal membrane oxygenation were investigated.
Randomized clinical trial.
Nine-month monocentric study.
Severe acute respiratory distress syndrome patients on venovenous extracorporeal membrane oxygenation.
After starting extracorporeal membrane oxygenation, patients were switched to the bi-level positive airway pressure mode with 1 second of 24 cm H2O high pressure and 2 seconds of 12 cm H2O low pressure for 24 hours. A computer-generated allocation sequence randomized patients to receive each of the following three experimental steps: 1) high pressure 24 cm H2O and low pressure 20 cm H2O (very high positive end-expiratory pressure-very low driving pressure); 2) high pressure 24 cm H2O and low pressure 5 cm H2O (low positive end-expiratory pressure-high driving pressure); and 3) high pressure 17 cm H2O and low pressure 5 cm H2O (low positive end-expiratory pressure-low driving pressure). Plasma and bronchoalveolar lavage soluble receptor for advanced glycation end-products, plasma interleukin-6, and monocyte chemotactic protein-1 were sampled preextracorporeal membrane oxygenation and after 12 hours at each step.
Sixteen patients on ECMO after 7 days (1-11 d) of mechanical ventilation were included. "Ultra-protective" mechanical ventilation settings following ECMO initiation were associated with significantly lower plasma sRAGE, interleukin-6, and monocyte chemotactic protein-1 concentrations. Plasma sRAGE and cytokines were comparable within each on-ECMO experimental step, but the lowest bronchoalveolar lavage sRAGE levels were obtained at minimal driving pressure.
ECMO allows ultra- protective ventilation, which combines significantly lower plateau pressure, tidalvolume, and driving pressure. This ventilation strategy significantly limited pulmonary biotrauma, which couldtherefore decrease ventilator-induced lung injury. However, the optimal ultra-protective ventilation strategy once ECMO is initiated remains undetermined and warrants further investigations. (Crit Care Med 2019; 47:1505-1512).
The introduction of combined antiretroviral therapies (HAART) has reversed the fatal course of human immunodeficiency virus (HIV) infection. HAART controls virus production and, in most cases, allows ...the quantitative and functional immune defects caused by HIV to be reversed. Here, we review T cell homeostatic mechanisms that drive immune recovery. These homeostatic mechanisms, as well as differences in T cell antigen exposure, explain the distinct patterns of recovery for HIV-specific T cells versus T cells specific for other pathogens. Immune restoration during HAART can, however, have adverse effects. Immune restoration syndrome occurs in some patients as a result of successful but unbalanced immunity.
Objectives
Progressive multifocal leukoencephalopathy (PML) is a very rare and opportunistic encephalitis caused by JC polyomavirus that is linked to profound immunosuppression and is usually fatal ...unless immune function can be restored. Immune checkpoint inhibitors (ICI) are monoclonal antibodies (mAbs) that block either CTLA-4 or PD-1 inhibitor receptors, thus enhancing antiviral T-cell activity. Successful treatment of PML by ICI has recently generated some enthusiasm in case reports/small series of patients. However, the initial enthusiasm was mitigated by some individual case reports that did not show any benefit. More data are thus warranted about efficacy of immune checkpoint inhibitors in the specific context of PML.
Methods and results
We report here the outcomes of six PML patients treated by ICI between 2017 and 2019. Underlying causes of immunosuppression consisted in hematologic malignancies (
n
= 4), primary immune deficiency (
n
= 1) and use of immunosuppressive therapies for myasthenia gravis (
n
= 1). Three patients were alive with a mean follow-up of 21 months (14–33) after first ICI infusion, including one patient with frank clinical response, one with stabilization, and one with initial worsening and further stabilization of PML. The three other patients rapidly died from PML.
Conclusions
Our data suggest that ICI may be effective for PML treatment but were less impressive than the ones previously reported. Larger studies are thus warranted to confirm this efficacy and to identify the predictive factors of response.
Mucosal-associated invariant T lymphocytes (MAIT lymphocytes) are characterized by two evolutionarily conserved features: an invariant T cell antigen receptor (TCR) alpha-chain and restriction by the ...major histocompatibility complex (MHC)-related protein MR1. Here we show that MAIT cells were activated by cells infected with various strains of bacteria and yeast, but not cells infected with virus, in both humans and mice. This activation required cognate interaction between the invariant TCR and MR1, which can present a bacteria-derived ligand. In humans, we observed considerably fewer MAIT cells in blood from patients with bacterial infections such as tuberculosis. In the mouse, MAIT cells protected against infection by Mycobacterium abscessus or Escherichia coli. Thus, MAIT cells are evolutionarily conserved innate-like lymphocytes that sense and help fight off microbial infection.
Post-transplant lymphoproliferative disorders (PTLDs) are life-threatening complications arising after solid organ or hematopoietic stem cell transplantations. Although the majority of these ...lymphoproliferations are of B cell origin, and are frequently associated with primary Epstein-Barr virus (EBV) infection or reactivation in the post-transplant period, rare cases of T cell and natural killer (NK) cell-originated PTLDs have also been described. A general assumption is that PTLDs result from the impairment of anti-viral and anti-tumoral immunosurveillance due to the long-term use of immunosuppressants in transplant recipients. T cell impairment is known to play a critical role in the immune-pathogenesis of post-transplant EBV-linked complications, while the role of NK cells has been less investigated, and is probably different between EBV-positive and EBV-negative PTLDs. As a part of the innate immune response, NK cells are critical for protecting hosts during the early response to virus-induced tumors. The complexity of their function is modulated by a myriad of activating and inhibitory receptors expressed on cell surfaces. This review outlines our current understanding of NK cells in the pathogenesis of PTLD, and discusses their potential implications for current PTLD therapies and novel NK cell-based therapies for the containment of these disorders.
: Immune checkpoint inhibitors (ICPi) have shown major therapeutic successes when used in various cancers. In the HIV field a double benefit of such ICPi should result from their dual ability to ...restore in-vitro HIV-specific CD8 T-cell functions and to enhance HIV production from reservoir cells, thus fulfilling the goals of the 'shock and kill' concept proposed as an HIV cure therapeutic strategy. We conducted a systematic review to identify studies reporting the tolerance profile of ICPi and their effects on HIV plasma loads (pVL), CD4 cell count, HIV reservoirs (cell-associated HIV-DNA) and/or HIV-specific CD8 T cells in PLWH. Thirty-one articles were included for a total 176 participants. Twelve percent of the participants experienced severe adverse events and 49% nonsevere adverse events. pVL remained stable in 91.9% participant, showed increases in 5.8% participant, and decreases in 2.3%. CD4 cell count remained stable in 60.7% participants, showed increases in 24.6%, and decreases in 14.7%. Regarding ICPi effects on HIV-DNA and HIV-specific immunity, we identified three distinct profiles: profile I, transient pVL increases followed by a boost in HIV-specific CD8 T cells concomitant to a decrease in HIV-DNA, reported in one participant. Profile II: increase in HIV-specific CD8 T cells without changes in pVL or HIV-DNA, reported in three participants. III: no effect, reported in five participants. In conclusion, the clinical, virological and immunological safety profiles of ICPi reported in about 200 PLWH appear to be favorable but there are still modest results in terms of HIV cure strategy.
Kidney transplant recipients (KTRs) abnormally replicate the Epstein Barr Virus (EBV). To better understand how long-term immunosuppression impacts the immune control of this EBV re-emergence, we ...systematically compared 10 clinically stable KTRs to 30 healthy controls (HCs). The EBV-specific T cell responses were determined in both groups by multiparameter flow cytometry with intra cellular cytokine staining (KTRs n = 10; HCs n = 15) and ELISpot-IFNγ assays (KTRs n = 7; HCs n = 7). The T/B/NK cell counts (KTRs n = 10; HCs n = 30) and the NK/T cell differentiation and activation phenotypes (KTRs n = 10; HCs n = 15/30) were also measured. We show that in KTRs, the Th1 effector CD4+ T cell responses against latent EBV proteins are weak (2/7 responders). Conversely, the frequencies total EBV-specific CD8+T cells are conserved in KTRs (n = 10) and span a wider range of EBNA-3A peptides (5/7responders) than in HCs (5/7responders). Those modifications of the EBV-specific T cell response were associated with a profound CD4+ T cell lymphopenia in KTRs compared to HCs, involving the naïve CD4+ T cell subset, and a persistent activation of highly-differentiated senescent CD8+ T cells. The proportion of total NK / CD8+ T cells expressing PD-1 was also increased in KTRs. Noteworthy, PD-1 expression on CD8+ T cells normalized with time after transplantation. In conclusion, we show modifications of the EBV-specific cellular immunity in long term transplant recipients. This may be the result of both persistent EBV antigenic stimulation and profound immunosuppression induced by anti-rejection treatments. These findings provide new insights into the immunopathology of EBV infection after renal transplantation.
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