Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 19 de 19
Filter
1.
Life Sci ; 294: 120392, 2022 Apr 01.
Article in English | MEDLINE | ID: covidwho-1670857

ABSTRACT

The SARS coronavirus 2 (SARS CoV-2) causes Coronavirus Disease (COVID-19), is an emerging viral infection. SARS CoV-2 infects target cells by attaching to Angiotensin-Converting Enzyme (ACE2). SARS CoV-2 could cause cardiac damage in patients with severe COVID-19, as ACE2 is expressed in cardiac cells, including cardiomyocytes, pericytes, and fibroblasts, and coronavirus could directly infect these cells. Cardiovascular disorders are the most frequent comorbidity found in COVID-19 patients. Immune cells such as monocytes, macrophages, and T cells may produce inflammatory cytokines and chemokines that contribute to COVID-19 pathogenesis if their functions are uncontrolled. This causes a cytokine storm in COVID-19 patients, which has been associated with cardiac damage. Tregs are a subset of immune cells that regulate immune and inflammatory responses. Tregs suppress inflammation and improve cardiovascular function through a variety of mechanisms. This is an exciting research area to explore the cellular, molecular, and immunological mechanisms related to reducing risks of cardiovascular complications in severe COVID-19. This review evaluated whether Tregs can affect COVID-19-related cardiovascular complications, as well as the mechanisms through which Tregs act.


Subject(s)
COVID-19/immunology , Cardiovascular Diseases/immunology , Cardiovascular Diseases/prevention & control , SARS-CoV-2 , T-Lymphocytes, Regulatory/physiology , Adoptive Transfer , Animals , Cardiovascular Diseases/virology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/prevention & control , Humans , Inflammation/immunology , T-Lymphocytes, Regulatory/immunology
2.
Front Immunol ; 12: 808064, 2021.
Article in English | MEDLINE | ID: covidwho-1649357

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in pregnancy is associated with a higher risk for severe morbidity and mortality when compared with infection in non-pregnant women of childbearing age. An increasing number of countries recommend immunization against SARS-CoV-2 in pregnant women. Recent studies provide preliminary and supportive evidence on safety, immunogenicity and effectiveness of coronavirus disease 2019 (COVID-19) vaccines in pregnant women; however, important knowledge gaps remain which warrant further studies. This collaborative consensus paper provides a review of the current literature on COVID-19 vaccines in pregnant women, identifies knowledge gaps and outlines priorities for future research to optimize protection against SARS-CoV-2 in the pregnant women and their infants.


Subject(s)
Antibodies, Viral/immunology , COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/immunology , COVID-19/prevention & control , Maternal-Fetal Exchange/immunology , SARS-CoV-2/immunology , /adverse effects , /adverse effects , Adoptive Transfer , /immunology , COVID-19/immunology , Female , Humans , Infectious Disease Transmission, Vertical/prevention & control , Milk, Human/immunology , Pregnancy , Pregnancy Complications, Infectious/immunology , Pregnancy Complications, Infectious/prevention & control , Pregnancy Complications, Infectious/virology , Spike Glycoprotein, Coronavirus/immunology , Vaccination , /statistics & numerical data
3.
Front Immunol ; 12: 751869, 2021.
Article in English | MEDLINE | ID: covidwho-1634057

ABSTRACT

BACKGROUND: Immunological characteristics of COVID-19 show pathological hyperinflammation associated with lymphopenia and dysfunctional T cell responses. These features provide a rationale for restoring functional T cell immunity in COVID-19 patients by adoptive transfer of SARS-CoV-2 specific T cells. METHODS: To generate SARS-CoV-2 specific T cells, we isolated peripheral blood mononuclear cells from 7 COVID-19 recovered and 13 unexposed donors. Consequently, we stimulated cells with SARS-CoV-2 peptide mixtures covering spike, membrane and nucleocapsid proteins. Then, we culture expanded cells with IL-2 for 21 days. We assessed immunophenotypes, cytokine profiles, antigen specificity of the final cell products. RESULTS: Our results show that SARS-CoV-2 specific T cells could be expanded in both COVID-19 recovered and unexposed groups. Immunophenotypes were similar in both groups showing CD4+ T cell dominance, but CD8+ and CD3+CD56+ T cells were also present. Antigen specificity was determined by ELISPOT, intracellular cytokine assay, and cytotoxicity assays. One out of 14 individuals who were previously unexposed to SARS-CoV-2 failed to show antigen specificity. Moreover, ex-vivo expanded SARS-CoV-2 specific T cells mainly consisted of central and effector memory subsets with reduced alloreactivity against HLA-unmatched cells suggesting the possibility for the development of third-party partial HLA-matching products. DISCUSSION: In conclusion, our findings show that SARS-CoV-2 specific T cell can be readily expanded from both COVID-19 and unexposed individuals and can therefore be manufactured as a biopharmaceutical product to treat severe COVID-19 patients. ONE SENTENCE SUMMARY: Ex-vivo expanded SARS-CoV-2 antigen specific T cells developed as third-party partial HLA-matching products may be a promising approach for treating severe COVID-19 patients that do not respond to previous treatment options.


Subject(s)
Adoptive Transfer , CD4-Positive T-Lymphocytes/transplantation , CD8-Positive T-Lymphocytes/transplantation , COVID-19/therapy , SARS-CoV-2/immunology , Adult , Antibodies, Viral/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Cell- and Tissue-Based Therapy , Coronavirus Nucleocapsid Proteins/immunology , Epitopes, T-Lymphocyte/immunology , Female , Humans , Immunophenotyping , Leukocytes, Mononuclear/immunology , Male , Middle Aged , Phosphoproteins/immunology , Spike Glycoprotein, Coronavirus/immunology , Viral Matrix Proteins/immunology , Young Adult
4.
Scand J Immunol ; 95(2): e13131, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1583260

ABSTRACT

The role of the immune system against coronavirus disease 2019 (COVID-19) is unknown in many aspects, and the protective or pathologic mechanisms of the immune response are poorly understood. Pro-inflammatory cytokine release and a consequent cytokine storm can lead to acute respiratory distress syndrome (ARDS) and result in multi-organ failure. There are many T cell subsets during anti-viral immunity. The Th17-associated response, as a pro-inflammatory pathway, and its consequent outcomes in many autoimmune disorders play a fundamental role in progression of systemic hyper-inflammation during COVID-19. Therapeutic strategies based on immunomodulation therapy could be helpful for targeting hyper-inflammatory immune responses in COVID-19, especially Th17-related inflammation and hyper-cytokinemia. Cell-based immunotherapeutic approaches including mesenchymal stem cells (MSCs), tolerogenic dendritic cells (tolDCs) and regulatory T cells (Tregs) seem to be promising strategies as orchestrators of the immune response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this review, we highlight Th17-related immunopathology of SARS-CoV-2 infection and discuss cell-based immunomodulatory strategies and their mechanisms for regulation of the hyper-inflammation during COVID-19.


Subject(s)
COVID-19/pathology , COVID-19/therapy , Cytokine Release Syndrome/pathology , Immunomodulation/immunology , Th17 Cells/immunology , Adoptive Transfer/methods , COVID-19/immunology , Cell- and Tissue-Based Therapy/methods , Cytokines/blood , Dendritic Cells/transplantation , Humans , Mesenchymal Stem Cell Transplantation , SARS-CoV-2/immunology , T-Lymphocytes, Regulatory/transplantation
5.
Immunology ; 165(2): 234-249, 2022 02.
Article in English | MEDLINE | ID: covidwho-1511321

ABSTRACT

COVID-19 disease is the manifestation of syndrome coronavirus 2 (SARS-CoV-2) infection, which is causing a worldwide pandemic. This disease can lead to multiple and different symptoms, being lymphopenia associated with severity one of the most persistent. Natural killer cells (NK cells) are part of the innate immune system, being fighting against virus-infected cells one of their key roles. In this study, we determined the phenotype of NK cells after COVID-19 and the main characteristic of SARS-CoV-2-specific-like NK population in the blood of convalescent donors. CD57+ NKG2C+ phenotype in SARS-CoV-2 convalescent donors indicates the presence of 'memory'/activated NK cells as it has been shown for cytomegalovirus infections. Although the existence of this population is donor dependent, its expression may be crucial for the specific response against SARS-CoV-2, so that, it gives us a tool for selecting the best donors to produce off-the-shelf living drug for cell therapy to treat COVID-19 patients under the RELEASE clinical trial (NCT04578210).


Subject(s)
Adoptive Transfer , Blood Donors , COVID-19/immunology , Convalescence , Immunologic Memory , Killer Cells, Natural/immunology , SARS-CoV-2/immunology , Adult , Female , Humans , Male , Middle Aged
6.
J Immunol ; 207(10): 2399-2404, 2021 11 15.
Article in English | MEDLINE | ID: covidwho-1450887

ABSTRACT

Immunity to pulmonary infection typically requires elicitation of lung-resident T cells that subsequently confer protection against secondary infection. The presence of tissue-resident T cells in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) convalescent patients is unknown. Using a sublethal mouse model of coronavirus disease 2019, we determined if SARS-CoV-2 infection potentiated Ag-specific pulmonary resident CD4+ and CD8+ T cell responses and if these cells mediated protection against secondary infection. S protein-specific T cells were present in resident and circulating populations. However, M and N protein-specific T cells were detected only in the resident T cell pool. Using an adoptive transfer strategy, we found that T cells from SARS-CoV-2 immune animals did not protect naive mice. These data indicate that resident T cells are elicited by SARS-CoV-2 infection but are not sufficient for protective immunity.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Lung/immunology , SARS-CoV-2/physiology , Adoptive Transfer , Angiotensin-Converting Enzyme 2/genetics , Animals , Cells, Cultured , Disease Models, Animal , Disease Resistance , Humans , Mice , Mice, Inbred C57BL , Mice, Transgenic , Spike Glycoprotein, Coronavirus/immunology , T-Cell Antigen Receptor Specificity
7.
Hum Immunol ; 83(1): 86-98, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1401492

ABSTRACT

The global outbreak of coronavirus-2019 (COVID-19) still claims more lives daily around the world due to the lack of a definitive treatment and the rapid tendency of virus to mutate, which even jeopardizes vaccination efficacy. At the forefront battle against SARS-CoV-2, an effective innate response to the infection has a pivotal role in the initial control and treatment of disease. However, SARS-CoV-2 subtly interrupts the equations of immune responses, disrupting the cytolytic antiviral effects of NK cells, while seriously activating infected macrophages and other immune cells to induce an unleashed "cytokine storm", a dangerous and uncontrollable inflammatory response causing life-threatening symptoms in patients. Notably, the NK cell exhaustion with ineffective cytolytic function against the sources of exaggerated cytokine release, acts as an Achilles' heel which exacerbates the severity of COVID-19. Given this, approaches that improve NK cell cytotoxicity may benefit treatment protocols. As a suggestion, adoptive transfer of NK or CAR-NK cells with proper cytotolytic potentials and the lowest capacity of cytokine-release (for example CD56dim NK cells brightly express activating receptors), to severe COVID-19 patients may provide an effective cure especially in cases suffering from cytokine storms. More intriguingly, the ongoing evidence for persistent clonal expansion of NK memory cells characterized by an activating phenotype in response to viral infections, can benefit the future studies on vaccine development and adoptive NK cell therapy in COVID-19. Whether vaccinated volunteers or recovered patients can also be considered as suitable candidates for cell donation could be the subject of future research.


Subject(s)
Adoptive Transfer , COVID-19/therapy , Cytokine Release Syndrome/therapy , Cytokines/immunology , Killer Cells, Natural/transplantation , SARS-CoV-2/immunology , Adoptive Transfer/adverse effects , Animals , COVID-19/immunology , COVID-19/metabolism , COVID-19/virology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/metabolism , Cytokine Release Syndrome/virology , Cytokines/metabolism , Cytotoxicity, Immunologic , Host-Pathogen Interactions , Humans , Immunologic Memory , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Killer Cells, Natural/virology , SARS-CoV-2/pathogenicity , Treatment Outcome
8.
Blood ; 138(25): 2702-2713, 2021 12 23.
Article in English | MEDLINE | ID: covidwho-1365304

ABSTRACT

Multiple organ dysfunction is the most severe outcome of sepsis progression and is highly correlated with a worse prognosis. Excessive neutrophil extracellular traps (NETs) are critical players in the development of organ failure during sepsis. Therefore, interventions targeting NET release would likely effectively prevent NET-based organ injury associated with this disease. Herein, we demonstrate that the pore-forming protein gasdermin D (GSDMD) is active in neutrophils from septic humans and mice and plays a crucial role in NET release. Inhibition of GSDMD with disulfiram or genic deletion abrogated NET formation, reducing multiple organ dysfunction and sepsis lethality. Mechanistically, we demonstrate that during sepsis, activation of the caspase-11/GSDMD pathway controls NET release by neutrophils during sepsis. In summary, our findings uncover a novel therapeutic use for disulfiram and suggest that GSDMD is a therapeutic target to improve sepsis treatment.


Subject(s)
Extracellular Traps/genetics , Gene Deletion , Intracellular Signaling Peptides and Proteins/genetics , Multiple Organ Failure/genetics , Phosphate-Binding Proteins/genetics , Sepsis/genetics , Acetaldehyde Dehydrogenase Inhibitors/therapeutic use , Adoptive Transfer , Aged , Animals , Cells, Cultured , Disulfiram/therapeutic use , Female , Humans , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Male , Mice, Inbred C57BL , Middle Aged , Multiple Organ Failure/pathology , Multiple Organ Failure/therapy , Phosphate-Binding Proteins/antagonists & inhibitors , Sepsis/pathology , Sepsis/therapy
9.
Sci Immunol ; 6(60)2021 06 18.
Article in English | MEDLINE | ID: covidwho-1276879

ABSTRACT

The nutrient-sensing mammalian target of rapamycin (mTOR) is integral to cell fate decisions after T cell activation. Sustained mTORC1 activity favors the generation of terminally differentiated effector T cells instead of follicular helper and memory T cells. This is particularly pertinent for T cell responses of older adults who have sustained mTORC1 activation despite dysfunctional lysosomes. Here, we show that lysosome-deficient T cells rely on late endosomes rather than lysosomes as an mTORC1 activation platform, where mTORC1 is activated by sensing cytosolic amino acids. T cells from older adults have an increased expression of the plasma membrane leucine transporter SLC7A5 to provide a cytosolic amino acid source. Hence, SLC7A5 and VPS39 deficiency (a member of the HOPS complex promoting early to late endosome conversion) substantially reduced mTORC1 activities in T cells from older but not young individuals. Late endosomal mTORC1 is independent of the negative-feedback loop involving mTORC1-induced inactivation of the transcription factor TFEB that controls expression of lysosomal genes. The resulting sustained mTORC1 activation impaired lysosome function and prevented lysosomal degradation of PD-1 in CD4+ T cells from older adults, thereby inhibiting their proliferative responses. VPS39 silencing of human T cells improved their expansion to pertussis and to SARS-CoV-2 peptides in vitro. Furthermore, adoptive transfer of CD4+ Vps39-deficient LCMV-specific SMARTA cells improved germinal center responses, CD8+ memory T cell generation, and recall responses to infection. Thus, curtailing late endosomal mTORC1 activity is a promising strategy to enhance T cell immunity.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , Endosomes/metabolism , Mechanistic Target of Rapamycin Complex 1/metabolism , SARS-CoV-2/metabolism , Signal Transduction/genetics , Adoptive Transfer/methods , Adult , Aged , Aged, 80 and over , Animals , Autophagy-Related Proteins/deficiency , Autophagy-Related Proteins/genetics , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism , COVID-19/virology , Cells, Cultured , Female , Forkhead Box Protein O1/deficiency , Forkhead Box Protein O1/genetics , Healthy Volunteers , Humans , Large Neutral Amino Acid-Transporter 1/metabolism , Lysosomes/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Signal Transduction/immunology , Transfection , Vesicular Transport Proteins/deficiency , Vesicular Transport Proteins/genetics , Young Adult
10.
Transpl Infect Dis ; 23(4): e13602, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1138251

ABSTRACT

Cellular and humoral response to acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections is on focus of research. We evaluate herein the feasibility of expanding virus-specific T cells (VST) against SARS-CoV-2 ex vivo through a standard protocol proven effective for other viruses. The experiment was performed in three different donors' scenarios: (a) SARS-CoV-2 asymptomatic infection/negative serology, (b) SARS-CoV-2 symptomatic infection/positive serology, and (c) no history of SARS-CoV-2 infection/negative serology. We were able to obtain an expanded VST product from donors 1 and 2 (1.6x and 1.8x increase of baseline VST count, respectively) consisting in CD3 + cells (80.3% and 62.7%, respectively) with CD4 + dominance (60% in both donors). Higher numbers of VST were obtained from the donor 2 as compared to donor 1. T-cell clonality test showed oligoclonal reproducible peaks on a polyclonal background for both donors. In contrast, VST could be neither expanded nor primed in a donor without evidence of prior infection. This proof-of-concept study supports the feasibility of expanding ex vivo SARS-CoV-2-specific VST from blood of convalescent donors. The results raise the question of whether the selection of seropositive donors may be a strategy to obtain cell lines enriched in their SARS-CoV-2-specificity for future adoptive transfer to immunosuppressed patients.


Subject(s)
COVID-19 , SARS-CoV-2 , Adoptive Transfer , CD4-Positive T-Lymphocytes , Humans
11.
J Clin Invest ; 130(12): 6656-6667, 2020 12 01.
Article in English | MEDLINE | ID: covidwho-1112389

ABSTRACT

BACKGROUNDUnderstanding outcomes and immunologic characteristics of cellular therapy recipients with SARS-CoV-2 is critical to performing these potentially life-saving therapies in the COVID-19 era. In this study of recipients of allogeneic (Allo) and autologous (Auto) hematopoietic cell transplant and CD19-directed chimeric antigen receptor T cell (CAR T) therapy at Memorial Sloan Kettering Cancer Center, we aimed to identify clinical variables associated with COVID-19 severity and assess lymphocyte populations.METHODSWe retrospectively investigated patients diagnosed between March 15, 2020, and May 7, 2020. In a subset of patients, lymphocyte immunophenotyping, quantitative real-time PCR from nasopharyngeal swabs, and SARS-CoV-2 antibody status were available.RESULTSWe identified 77 patients with SARS-CoV-2 who were recipients of cellular therapy (Allo, 35; Auto, 37; CAR T, 5; median time from cellular therapy, 782 days; IQR, 354-1611 days). Overall survival at 30 days was 78%. Clinical variables significantly associated with the composite endpoint of nonrebreather or higher oxygen requirement and death (n events = 25 of 77) included number of comorbidities (HR 5.41, P = 0.004), infiltrates (HR 3.08, P = 0.032), and neutropenia (HR 1.15, P = 0.04). Worsening graft-versus-host disease was not identified among Allo recipients. Immune profiling revealed reductions and rapid recovery in lymphocyte populations across lymphocyte subsets. Antibody responses were seen in a subset of patients.CONCLUSIONIn this series of Allo, Auto, and CAR T recipients, we report overall favorable clinical outcomes for patients with COVID-19 without active malignancy and provide preliminary insights into the lymphocyte populations that are key for the antiviral response and immune reconstitution.FUNDINGNIH grant P01 CA23766 and NIH/National Cancer Institute grant P30 CA008748.


Subject(s)
Adoptive Transfer , Antibodies, Viral/blood , COVID-19 , Hematopoietic Stem Cell Transplantation , SARS-CoV-2 , Adult , Aged , Allografts , Autografts , COVID-19/blood , COVID-19/mortality , COVID-19/therapy , Disease-Free Survival , Female , Follow-Up Studies , Humans , Male , Middle Aged , Retrospective Studies , Survival Rate
12.
Nature ; 590(7847): 630-634, 2021 02.
Article in English | MEDLINE | ID: covidwho-960322

ABSTRACT

Recent studies have reported the protective efficacy of both natural1 and vaccine-induced2-7 immunity against challenge with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in rhesus macaques. However, the importance of humoral and cellular immunity for protection against infection with SARS-CoV-2 remains to be determined. Here we show that the adoptive transfer of purified IgG from convalescent rhesus macaques (Macaca mulatta) protects naive recipient macaques against challenge with SARS-CoV-2 in a dose-dependent fashion. Depletion of CD8+ T cells in convalescent macaques partially abrogated the protective efficacy of natural immunity against rechallenge with SARS-CoV-2, which suggests a role for cellular immunity in the context of waning or subprotective antibody titres. These data demonstrate that relatively low antibody titres are sufficient for protection against SARS-CoV-2 in rhesus macaques, and that cellular immune responses may contribute to protection if antibody responses are suboptimal. We also show that higher antibody titres are required for treatment of SARS-CoV-2 infection in macaques. These findings have implications for the development of SARS-CoV-2 vaccines and immune-based therapeutic agents.


Subject(s)
COVID-19/immunology , COVID-19/prevention & control , COVID-19/therapy , Disease Models, Animal , SARS-CoV-2/immunology , Adoptive Transfer , Animals , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/immunology , COVID-19/virology , Female , Immunization, Passive , Immunoglobulin G/administration & dosage , Immunoglobulin G/analysis , Immunoglobulin G/immunology , Macaca mulatta/immunology , Macaca mulatta/virology , Male , Regression Analysis , Viral Load/immunology
13.
Sci Adv ; 6(47)2020 11.
Article in English | MEDLINE | ID: covidwho-887414

ABSTRACT

To affect the COVID-19 pandemic, lifesaving antiviral therapies must be identified. The number of clinical trials that can be performed is limited. We developed mathematical models to project multiple therapeutic approaches. Our models recapitulate off-treatment viral dynamics and predict a three-phase immune response. Simulated treatment with remdesivir, selinexor, neutralizing antibodies, or cellular immunotherapy demonstrates that rapid viral elimination is possible if in vivo potency is sufficiently high. Therapies dosed soon after peak viral load when symptoms develop may decrease shedding duration and immune response intensity but have little effect on viral area under the curve (AUC), which is driven by high early viral loads. Potent therapy dosed before viral peak during presymptomatic infection could lower AUC. Drug resistance may emerge with a moderately potent agent dosed before viral peak. Our results support early treatment for COVID-19 if shedding duration, not AUC, is most predictive of clinical severity.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Adoptive Transfer/methods , Alanine/analogs & derivatives , Antibodies, Viral/therapeutic use , Antiviral Agents/therapeutic use , Broadly Neutralizing Antibodies/therapeutic use , COVID-19/drug therapy , Cell- and Tissue-Based Therapy/methods , Hydrazines/therapeutic use , SARS-CoV-2/physiology , Triazoles/therapeutic use , Virus Shedding/drug effects , Adenosine Monophosphate/pharmacokinetics , Adenosine Monophosphate/therapeutic use , Alanine/pharmacokinetics , Alanine/therapeutic use , Antiviral Agents/pharmacokinetics , COVID-19/immunology , COVID-19/virology , Humans , Killer Cells, Natural/immunology , Models, Theoretical , Time Factors , Treatment Outcome , Viral Load/drug effects
14.
Immunology ; 162(1): 30-43, 2021 01.
Article in English | MEDLINE | ID: covidwho-772420

ABSTRACT

Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2, a novel coronavirus strain. Some studies suggest that COVID-19 could be an immune-related disease, and failure of effective immune responses in initial stages of viral infection could contribute to systemic inflammation and tissue damage, leading to worse disease outcomes. T cells can act as a double-edge sword with both pro- and anti-roles in the progression of COVID-19. Thus, better understanding of their roles in immune responses to SARS-CoV-2 infection is crucial. T cells primarily react to the spike protein on the coronavirus to initiate antiviral immunity; however, T-cell responses can be suboptimal, impaired or excessive in severe COVID-19 patients. This review focuses on the multifaceted roles of T cells in COVID-19 pathogenesis and rationalizes their significance in eliciting appropriate antiviral immune responses in COVID-19 patients and unexposed individuals. In addition, we summarize the potential therapeutic approaches related to T cells to treat COVID-19 patients. These include adoptive T-cell therapies, vaccines activating T-cell responses, recombinant cytokines, Th1 activators and Th17 blockers, and potential utilization of immune checkpoint inhibitors alone or in combination with anti-inflammatory drugs to improve antiviral T-cell responses against SARS-CoV-2.


Subject(s)
COVID-19/immunology , COVID-19/therapy , Immunity, Cellular , Immunotherapy , Lung/immunology , SARS-CoV-2/immunology , T-Lymphocytes/immunology , Adoptive Transfer , Animals , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/virology , COVID-19 Vaccines/therapeutic use , Host-Pathogen Interactions , Humans , Immunity, Cellular/drug effects , Immunologic Factors/therapeutic use , Lung/drug effects , Lung/virology , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity , T-Lymphocytes/drug effects , T-Lymphocytes/transplantation , T-Lymphocytes/virology
15.
Front Immunol ; 11: 1512, 2020.
Article in English | MEDLINE | ID: covidwho-642764

ABSTRACT

Natural Killer (NK) cells are innate immune responders critical for viral clearance and immunomodulation. Despite their vital role in viral infection, the contribution of NK cells in fighting SARS-CoV-2 has not yet been directly investigated. Insights into pathophysiology and therapeutic opportunities can therefore be inferred from studies assessing NK cell phenotype and function during SARS, MERS, and COVID-19. These studies suggest a reduction in circulating NK cell numbers and/or an exhausted phenotype following infection and hint toward the dampening of NK cell responses by coronaviruses. Reduced circulating NK cell levels and exhaustion may be directly responsible for the progression and severity of COVID-19. Conversely, in light of data linking inflammation with coronavirus disease severity, it is necessary to examine NK cell potential in mediating immunopathology. A common feature of coronavirus infections is that significant morbidity and mortality is associated with lung injury and acute respiratory distress syndrome resulting from an exaggerated immune response, of which NK cells are an important component. In this review, we summarize the current understanding of how NK cells respond in both early and late coronavirus infections, and the implication for ongoing COVID-19 clinical trials. Using this immunological lens, we outline recommendations for therapeutic strategies against COVID-19 in clearing the virus while preventing the harm of immunopathological responses.


Subject(s)
Adoptive Transfer/methods , Betacoronavirus/immunology , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Killer Cells, Natural/immunology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , Adrenal Cortex Hormones/therapeutic use , Animals , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Ascorbic Acid/therapeutic use , Betacoronavirus/drug effects , COVID-19 , Coronavirus Infections/mortality , Coronavirus Infections/virology , Cytokines/antagonists & inhibitors , Cytokines/metabolism , Disease Susceptibility/immunology , Humans , Immunity, Innate/drug effects , Immunity, Innate/immunology , Immunologic Memory , Interferon Type I/metabolism , Interferon Type I/therapeutic use , Killer Cells, Natural/drug effects , Mice , Pandemics , Pneumonia, Viral/mortality , Pneumonia, Viral/virology , SARS-CoV-2
16.
Protein Cell ; 11(10): 707-722, 2020 10.
Article in English | MEDLINE | ID: covidwho-626150

ABSTRACT

The 2019 novel coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has occurred in China and around the world. SARS-CoV-2-infected patients with severe pneumonia rapidly develop acute respiratory distress syndrome (ARDS) and die of multiple organ failure. Despite advances in supportive care approaches, ARDS is still associated with high mortality and morbidity. Mesenchymal stem cell (MSC)-based therapy may be an potential alternative strategy for treating ARDS by targeting the various pathophysiological events of ARDS. By releasing a variety of paracrine factors and extracellular vesicles, MSC can exert anti-inflammatory, anti-apoptotic, anti-microbial, and pro-angiogenic effects, promote bacterial and alveolar fluid clearance, disrupt the pulmonary endothelial and epithelial cell damage, eventually avoiding the lung and distal organ injuries to rescue patients with ARDS. An increasing number of experimental animal studies and early clinical studies verify the safety and efficacy of MSC therapy in ARDS. Since low cell engraftment and survival in lung limit MSC therapeutic potentials, several strategies have been developed to enhance their engraftment in the lung and their intrinsic, therapeutic properties. Here, we provide a comprehensive review of the mechanisms and optimization of MSC therapy in ARDS and highlighted the potentials and possible barriers of MSC therapy for COVID-19 patients with ARDS.


Subject(s)
Betacoronavirus , Coronavirus Infections/complications , Mesenchymal Stem Cell Transplantation , Pandemics , Pneumonia, Viral/complications , Respiratory Distress Syndrome/therapy , Adoptive Transfer , Alveolar Epithelial Cells/pathology , Animals , Apoptosis , Body Fluids/metabolism , CD4-Positive T-Lymphocytes/immunology , COVID-19 , Clinical Trials as Topic , Coinfection/prevention & control , Coinfection/therapy , Coronavirus Infections/immunology , Disease Models, Animal , Endothelial Cells/pathology , Extracorporeal Membrane Oxygenation , Genetic Therapy/methods , Genetic Vectors/administration & dosage , Genetic Vectors/therapeutic use , Humans , Immunity, Innate , Inflammation Mediators/metabolism , Lung/pathology , Lung/physiopathology , Mesenchymal Stem Cell Transplantation/methods , Mesenchymal Stem Cells/physiology , Multiple Organ Failure/etiology , Multiple Organ Failure/prevention & control , Pneumonia, Viral/immunology , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/pathology , SARS-CoV-2
17.
Shock ; 54(5): 586-594, 2020 11.
Article in English | MEDLINE | ID: covidwho-618627

ABSTRACT

Coronavirus disease 2019 (COVID-19) is a life-threatening respiratory illness caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Its clinical presentation can vary from the asymptomatic state to acute respiratory distress syndrome (ARDS) and multi-organ dysfunction. Due to our insufficient understanding of its pathophysiology and lack of effective treatment, the morbidity and mortality of severe COVID-19 patients are high. Patients with COVID-19 develop ARDS fueled by exaggerated neutrophil influx into the lungs and cytokine storm. B-1a cells represent a unique subpopulation of B lymphocytes critical for circulating natural antibodies, innate immunity, and immunoregulation. These cells spontaneously produce natural IgM, interleukin (IL)-10, and granulocyte-monocyte colony stimulating factor (GM-CSF). Natural IgM neutralizes viruses and opsonizes bacteria, IL-10 attenuates the cytokine storm, and GM-CSF induces IgM production by B-1a cells in an autocrine manner. Indeed, B-1a cells have been shown to ameliorate influenza virus infection, sepsis, and pneumonia, all of which are similar to COVID-19. The recent discovery of B-1a cells in humans further reinforces their potentially critical role in the immune response against SARS-CoV-2 and their anticipated translational applications against viral and microbial infections. Given that B-1a cells protect against ARDS via immunoglobulin production and the anti-COVID-19 effects of convalescent plasma treatment, we recommend that studies be conducted to further examine the role of B-1a cells in the pathogenesis of COVID-19 and explore their therapeutic potential to treat COVID-19 patients.


Subject(s)
Adoptive Transfer , B-Lymphocyte Subsets/transplantation , Betacoronavirus/pathogenicity , Coronavirus Infections/therapy , Pneumonia, Viral/therapy , Adoptive Transfer/adverse effects , Animals , B-Lymphocyte Subsets/immunology , Betacoronavirus/immunology , COVID-19 , Coronavirus Infections/diagnosis , Coronavirus Infections/immunology , Coronavirus Infections/virology , Host-Pathogen Interactions , Humans , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , SARS-CoV-2
19.
J Immunother Cancer ; 8(1)2020 05.
Article in English | MEDLINE | ID: covidwho-220167

ABSTRACT

The pandemic caused by the novel coronavirus SARS-CoV-2 has placed an unprecedented burden on healthcare systems around the world. In patients who experience severe disease, acute respiratory distress is often accompanied by a pathological immune reaction, sometimes referred to as 'cytokine storm'. One hallmark feature of the profound inflammatory state seen in patients with COVID-19 who succumb to pneumonia and hypoxia is marked elevation of serum cytokines, especially interferon gamma, tumor necrosis factor alpha, interleukin 17 (IL-17), interleukin 8 (IL-8) and interleukin 6 (IL-6). Initial experience from the outbreaks in Italy, China and the USA has anecdotally demonstrated improved outcomes for critically ill patients with COVID-19 with the administration of cytokine-modulatory therapies, especially anti-IL-6 agents. Although ongoing trials are investigating anti-IL-6 therapies, access to these therapies is a concern, especially as the numbers of cases worldwide continue to climb. An immunology-informed approach may help identify alternative agents to modulate the pathological inflammation seen in patients with COVID-19. Drawing on extensive experience administering these and other immune-modulating therapies, the Society for Immunotherapy of Cancer offers this perspective on potential alternatives to anti-IL-6 that may also warrant consideration for management of the systemic inflammatory response and pulmonary compromise that can be seen in patients with severe COVID-19.


Subject(s)
Coronavirus Infections/complications , Coronavirus Infections/drug therapy , Immunotherapy , Interleukin-6/antagonists & inhibitors , Interleukin-6/immunology , Pneumonia, Viral/complications , Pneumonia, Viral/drug therapy , Respiratory Distress Syndrome/complications , Respiratory Distress Syndrome/drug therapy , Societies, Medical , Adoptive Transfer , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/pathology , Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Humans , Inflammation/complications , Inflammation/drug therapy , Inflammation/immunology , Inflammation/pathology , Interferon-gamma/antagonists & inhibitors , Interleukin-1/antagonists & inhibitors , Interleukin-17/antagonists & inhibitors , Interleukin-23/antagonists & inhibitors , Interleukin-6/genetics , Interleukin-6/metabolism , Janus Kinases/antagonists & inhibitors , Neoplasms/immunology , Neoplasms/therapy , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/pathology , STAT Transcription Factors/antagonists & inhibitors , Severe Acute Respiratory Syndrome/pathology , Signal Transduction/drug effects , Tumor Necrosis Factor-alpha/antagonists & inhibitors
SELECTION OF CITATIONS
SEARCH DETAIL