Immune Immunomodulation in Coronavirus Disease 2019 (COVID-19): Strategic Considerations for Personalized Therapeutic Intervention

Abstract We are learning that the host response to severe acute respiratory syndrome coronavirus 2 ( SARS-CoV-2) infection is complex and highly dynamic. Effective initial host defense in the lung is associated with mild symptoms and disease resolution. Viral evasion of the immune response can lead to refractory alveolar damage, ineffective lung repair mechanisms, and systemic inflammation with associated organ dysfunction. The immune response in these patients is highly variable and can include moderate to severe systemic inflammation and/or marked systemic immune suppression. There is unlikely to be a “one size fits all” approach to immunomodulation in patients with coronavirus disease 2019 (COVID-19). We believe that a personalized, immunophenotype-driven approach to immunomodulation that may include anticytokine therapy in carefully selected patients and immunostimulatory therapies in others is the shortest path to success in the study and treatment of patients with critical illness due to COVID-19.

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Concurrent Immune Suppression and Hyperinflammation in Patients With Community-Acquired Pneumonia

Frontiers in Immunology ◽

10.3389/fimmu.2020.00796 ◽

2020 ◽

Vol 11 ◽

Cited By ~ 1

Author(s):

Xanthe Brands ◽

Bastiaan W. Haak ◽

Augustijn M. Klarenbeek ◽

Natasja A. Otto ◽

Daniël R. Faber ◽

...

Keyword(s):

Systemic Inflammation ◽

Immune Suppression ◽

Host Response ◽

Cell Activation ◽

Acute Infection ◽

Community Acquired Pneumonia ◽

Endothelial Cell Activation ◽

Blood Leukocytes ◽

Tnf Α ◽

Neutrophil Degranulation

BackgroundThe nature and timing of the host immune response during infections remain uncertain and most knowledge is derived from critically ill sepsis patients. We aimed to test the hypothesis that community-acquired pneumonia (CAP) is associated with concurrent immune suppression and systemic inflammation.MethodsBlood was collected from 79 CAP patients within 24 h after hospitalization and 1 month after discharge; 42 age- and sex-matched subjects without acute infection served as controls. Blood leukocytes were stimulated with lipopolysaccharide (LPS) or Klebsiella pneumoniae, and cytokines were measured in supernatants. Fifteen plasma biomarkers reflective of key host response pathways were compared between CAP patients with the strongest immune suppression (lowest 25% blood leukocyte tumor necrosis factor (TNF)-α production in response to LPS) and those with the least immune suppression (highest 25% of LPS-induced TNF-α production).ResultsBlood leukocytes of CAP patients (relative to control subjects) showed a reduced capacity to release TNF-α, interleukin (IL)-1β, IL-6 and IL-10 upon stimulation with LPS or K. pneumoniae, with a concurrently enhanced ability to release the anti-inflammatory mediator IL-1 receptor antagonist, irrespective of the presence of sepsis (18.9% of cases). Low (relative to high) TNF-α producers displayed higher plasma levels of biomarkers reflecting systemic inflammation, neutrophil degranulation, endothelial cell activation, a disturbed vascular barrier function and coagulation activation.ConclusionCAP replicates a common feature of immune suppression in sepsis. The coexistence of immune suppression and hyperinflammation in CAP argues against the theory of two distinct phases during the host response to sepsis.

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Early Upregulation of Acute Respiratory Distress Syndrome-Associated Cytokines Promotes Lethal Disease in an Aged-Mouse Model of Severe Acute Respiratory Syndrome Coronavirus Infection

Journal of Virology ◽

10.1128/jvi.00127-09 ◽

2009 ◽

Vol 83 (14) ◽

pp. 7062-7074 ◽

Cited By ~ 101

Author(s):

Barry Rockx ◽

Tracey Baas ◽

Gregory A. Zornetzer ◽

Bart Haagmans ◽

Timothy Sheahan ◽

...

Keyword(s):

Immune Response ◽

Acute Respiratory Distress Syndrome ◽

Severe Acute Respiratory Syndrome ◽

Respiratory Distress Syndrome ◽

Respiratory Distress ◽

Host Response ◽

Molecular Mechanisms ◽

Distress Syndrome ◽

Aged Mice ◽

Young Mice

ABSTRACT Several respiratory viruses, including influenza virus and severe acute respiratory syndrome coronavirus (SARS-CoV), produce more severe disease in the elderly, yet the molecular mechanisms governing age-related susceptibility remain poorly studied. Advanced age was significantly associated with increased SARS-related deaths, primarily due to the onset of early- and late-stage acute respiratory distress syndrome (ARDS) and pulmonary fibrosis. Infection of aged, but not young, mice with recombinant viruses bearing spike glycoproteins derived from early human or palm civet isolates resulted in death accompanied by pathological changes associated with ARDS. In aged mice, a greater number of differentially expressed genes were observed than in young mice, whose responses were significantly delayed. Differences between lethal and nonlethal virus phenotypes in aged mice could be attributed to differences in host response kinetics rather than virus kinetics. SARS-CoV infection induced a range of interferon, cytokine, and pulmonary wound-healing genes, as well as several genes associated with the onset of ARDS. Mice that died also showed unique transcriptional profiles of immune response, apoptosis, cell cycle control, and stress. Cytokines associated with ARDS were significantly upregulated in animals experiencing lung pathology and lethal disease, while the same animals experienced downregulation of the ACE2 receptor. These data suggest that the magnitude and kinetics of a disproportionately strong host innate immune response contributed to severe respiratory stress and lethality. Although the molecular mechanisms governing ARDS pathophysiology remain unknown in aged animals, these studies reveal a strategy for dissecting the genetic pathways by which SARS-CoV infection induces changes in the host response, leading to death.

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Adjunct corticosteroid treatment in patients with pneumonia: A precision medicine approach

Bosnian Journal of Basic Medical Sciences ◽

10.17305/bjbms.2019.3977 ◽

2019 ◽

Author(s):

Srdjan Gavrilovic ◽

Ana Andrijevic ◽

Aida Mujakovic ◽

Yewande Odeyemi ◽

Belma Paralija ◽

...

Keyword(s):

Immune Response ◽

Respiratory Failure ◽

Precision Medicine ◽

Cause Of Death ◽

Immune Suppression ◽

Host Response ◽

Corticosteroid Treatment ◽

Microbial Invasion

Pneumonia is the leading infectious cause of death worldwide. While inflammation is critically important in host response to microbial invasion, exaggerated inflammation can damage the lungs, contributing to respiratory failure and mortality. Corticosteroids are effective in reducing inflammation and can also cause immune suppression. Presently, clinicians are unable to reliably distinguish between exaggerated and appropriate immune response and thus cannot rapidly identify patients most likely to benefit from adjunctive corticosteroids. In this review, we propose a biomarker-guided, precision medicine approach to corticosteroid treatment, aimed to give these medications at appropriate dose and time and only to patients who have exaggerated inflammation.

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COVID-19: a review of current knowledge regarding exposure, quarantine, isolation and other preventive measures

Therapeutic Advances in Infectious Disease ◽

10.1177/20499361211032039 ◽

2021 ◽

Vol 8 ◽

pp. 204993612110320

Author(s):

Robert Rosolanka ◽

Andres F. Henao-Martinez ◽

Larissa Pisney ◽

Carlos Franco-Paredes ◽

Martin Krsak

Keyword(s):

Immune Response ◽

Severe Acute Respiratory Syndrome ◽

Clinical Response ◽

Preventive Measures ◽

Current Knowledge ◽

Therapeutic Options ◽

Exposure Control ◽

Knowledge Gaps ◽

Vaccination Strategies ◽

Speed Up

Deeper understanding of the spread, morbidity, fatality, and development of immune response associated with coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2, is necessary in order to establish an appropriate epidemiological and clinical response. Exposure control represents a key part of the combat against COVID-19, as the effectiveness of current therapeutic options remains partial. Since the preventive measures have not been sufficiently able to slow down this pandemic, in this article we explore some of the pertinent knowledge gaps, while overall looking to effective vaccination strategies as a way out. Early on, such strategies may need to rely on counting the convalescents as protected in order to speed up the immunization of the whole population.

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The host transcriptional response to Candidemia is dominated by neutrophil activation and heme biosynthesis and supports novel diagnostic approaches

Genome Medicine ◽

10.1186/s13073-021-00924-9 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Julie M. Steinbrink ◽

Rachel A. Myers ◽

Kaiyuan Hua ◽

Melissa D. Johnson ◽

Jessica L. Seidelman ◽

...

Keyword(s):

Immune Response ◽

Bacterial Infection ◽

Viral Infection ◽

Fungal Infection ◽

Host Response ◽

Hospitalized Patients ◽

Neutrophil Activation ◽

Heme Biosynthesis ◽

Transcriptional Analysis ◽

Diagnostic Approaches

Abstract Background Candidemia is one of the most common nosocomial bloodstream infections in the United States, causing significant morbidity and mortality in hospitalized patients, but the breadth of the host response to Candida infections in human patients remains poorly defined. Methods In order to better define the host response to Candida infection at the transcriptional level, we performed RNA sequencing on serial peripheral blood samples from 48 hospitalized patients with blood cultures positive for Candida species and compared them to patients with other acute viral, bacterial, and non-infectious illnesses. Regularized multinomial regression was utilized to develop pathogen class-specific gene expression classifiers. Results Candidemia triggers a unique, robust, and conserved transcriptomic response in human hosts with 1641 genes differentially upregulated compared to healthy controls. Many of these genes corresponded to components of the immune response to fungal infection, heavily weighted toward neutrophil activation, heme biosynthesis, and T cell signaling. We developed pathogen class-specific classifiers from these unique signals capable of identifying and differentiating candidemia, viral, or bacterial infection across a variety of hosts with a high degree of accuracy (auROC 0.98 for candidemia, 0.99 for viral and bacterial infection). This classifier was validated on two separate human cohorts (auROC 0.88 for viral infection and 0.87 for bacterial infection in one cohort; auROC 0.97 in another cohort) and an in vitro model (auROC 0.94 for fungal infection, 0.96 for bacterial, and 0.90 for viral infection). Conclusions Transcriptional analysis of circulating leukocytes in patients with acute Candida infections defines novel aspects of the breadth of the human immune response during candidemia and suggests promising diagnostic approaches for simultaneously differentiating multiple types of clinical illnesses in at-risk, acutely ill patients.

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Lactobacillus rhamnosus HDB1258 modulates gut microbiota-mediated immune response in mice with or without lipopolysaccharide-induced systemic inflammation

BMC Microbiology ◽

10.1186/s12866-021-02192-4 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Sang-Kap Han ◽

Yeon-Jeong Shin ◽

Dong-Yeon Lee ◽

Kyung Min Kim ◽

Seo-Jin Yang ◽

...

Keyword(s):

Immune Response ◽

Gut Microbiota ◽

Oral Administration ◽

Systemic Inflammation ◽

Nk Cell ◽

Lactobacillus Rhamnosus ◽

Expression Ratio ◽

Macrophage Phagocytosis ◽

Tnf Α ◽

Gut Microbiota Composition

Abstract Background Gut microbiota closely communicate in the immune system to maintain a balanced immune homeostasis in the gastrointestinal tract of the host. Oral administration of probiotics modulates gut microbiota composition. In the present study, we isolated Lactobacillus rhamnosus HDB1258, which induced tumor necrosis factor (TNF)-α and interleukin (IL)-10 expression in macrophages, from the feces of breastfeeding infants and examined how HDB1258 could regulate the homeostatic immune response in mice with or without lipopolysaccharide (LPS)-induced systemic inflammation. Results Oral administration of HDB1258 significantly increased splenic NK cell cytotoxicity, peritoneal macrophage phagocytosis, splenic and colonic TNF-α expression, TNF-α to IL-10 expression ratio, and fecal IgA level in control mice, while Th1 and Treg cell differentiation was not affected in the spleen. However, HDB1258 treatment significantly suppressed peritoneal macrophage phagocytosis and blood prostaglandin E2 level in mice with LPS-induced systemic inflammation. Its treatment increased LPS-suppressed ratios of Treg to Th1 cell population, Foxp3 to T-bet expression, and IL-10 to TNF-α expression. Oral administration of HDB1258 significantly decreased LPS-induced colon shortening, myeloperoxidase activity and NF-κB+/CD11c+ cell population in the colon, while the ratio of IL-10 to TNF-α expression increased. Moreover, HDB1258 treatment shifted gut microbiota composition in mice with and without LPS-induced systemic inflammation: it increased the Cyanobacteria and PAC000664_g (belonging to Bacteroidetes) populations and reduced Deferribacteres and EU622763_s group (belonging to Bacteroidetes) populations. In particular, PAC001066_g and PAC001072_s populations were negatively correlated with the ratio of IL-10 to TNF-α expression in the colon, while the PAC001070_s group population was positively correlated. Conclusions Oral administered HDB1258 may enhance the immune response by activating innate immunity including to macrophage phagocytosis and NK cell cytotoxicity in the healthy host and suppress systemic inflammation in the host with inflammation by the modulation of gut microbiota and IL-10 to TNF-α expression ratio in immune cells.

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Immunological imprinting of the antibody response in COVID-19 patients

Nature Communications ◽

10.1038/s41467-021-23977-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Teresa Aydillo ◽

Alexander Rombauts ◽

Daniel Stadlbauer ◽

Sadaf Aslam ◽

Gabriela Abelenda-Alonso ◽

...

Keyword(s):

Immune Response ◽

Severe Acute Respiratory Syndrome ◽

Antibody Response ◽

Humoral Immune Response ◽

Nucleocapsid Protein ◽

Spike Protein ◽

Ongoing Research ◽

Variable Regions ◽

Humoral Immune ◽

Human Coronaviruses

AbstractIn addition to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), humans are also susceptible to six other coronaviruses, for which consecutive exposures to antigenically related and divergent seasonal coronaviruses are frequent. Despite the prevalence of COVID-19 pandemic and ongoing research, the nature of the antibody response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unclear. Here we longitudinally profile the early humoral immune response against SARS-CoV-2 in hospitalized coronavirus disease 2019 (COVID-19) patients and quantify levels of pre-existing immunity to OC43, HKU1 and 229E seasonal coronaviruses, and find a strong back-boosting effect to conserved but not variable regions of OC43 and HKU1 betacoronaviruses spike protein. However, such antibody memory boost to human coronaviruses negatively correlates with the induction of IgG and IgM against SARS-CoV-2 spike and nucleocapsid protein. Our findings thus provide evidence of immunological imprinting by previous seasonal coronavirus infections that can potentially modulate the antibody profile to SARS-CoV-2 infection.

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POS-027 Critical illness and systemic inflammation are key risk factors of severe AKI in patients with COVID-19

Kidney International Reports ◽

10.1016/j.ekir.2021.03.033 ◽

2021 ◽

Vol 6 (4) ◽

pp. S12

Author(s):

J.H.B. HARDENBERG ◽

H. Stockmann ◽

A. Aigner ◽

K.U. Eckardt ◽

K. Schmidt-Ott

Keyword(s):

Risk Factors ◽

Critical Illness ◽

Systemic Inflammation

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521. Similarities and Differences in Transcriptomic Host Response between SARS-CoV-2 and Other Viral Infections

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.715 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S326-S327

Author(s):

Simone A Thair ◽

Yudong He ◽

Yehudit Hasin-Brumshtein ◽

Suraj Sakaram ◽

Rushika R Pandya ◽

...

Keyword(s):

Immune Response ◽

B Cells ◽

Nk Cells ◽

Pathway Analysis ◽

Host Response ◽

Viral Infections ◽

Cell Types ◽

Gene Signature ◽

Gene Signatures ◽

Similarities And Differences

Abstract Background COVID-19 is a pandemic caused by the SARS-CoV-2 virus that shares and differs in clinical characteristics of known viral infections. Methods We obtained RNAseq profiles of 62 prospectively enrolled COVID-19 patients and 24 healthy controls (HC). We collected 23 independent studies profiling 1,855 blood samples from patients covering six viruses (influenza, RSV, HRV, Ebola, Dengue and SARS-CoV-1). We studied host whole-blood transcriptomic responses in COVID-19 compared to non-COVID-19 viral infections to understand similarities and differences in host response. Gene signature threshold was absolute effect size ≥1, FDR ≤ 0.05%. Results Differential gene expression of COVID-19 vs HC are highly correlated with non-COVID-19 vs HC (r=0.74, p< 0.001). We discovered two gene signatures: COVID-19 vs HC (2002 genes) (COVIDsig) and non-COVID-19 vs HC (635 genes) (nonCOVIDsig). Pathway analysis of over-expressed signature genes in COVIDsig or nonCOVIDsig identified similar pathways including neutrophil activation, innate immune response, immune response to viral infection and cytokine production. Conversely, for under-expressed genes, pathways indicated repression of lymphocyte differentiation and activation (Fig1). Intersecting the two gene signatures found two genes significantly oppositely regulated (ACO1, ATL3). We derived a third gene signature using COCONUT to compare COVID-19 to non-COVID-19 viral infections (416 genes) (Fig2). Pathway analysis did not result in significant enrichment, suggesting identification of novel biology (Fig1). Statistical deconvolution of bulk transcriptomic data found M1 macrophages, plasmacytoid dendritic cells, CD14+ monocytes, CD4+ T cells and total B cells changed in the same direction across COVID-19 and non-COVID-19 infections. Cell types that increased in COVID-19 relative to non-COVID-19 were CD56bright NK cells, M2 macrophages and total NK cells. Those that decreased in non-COVID-19 relative to COVID-19 were CD56dim NK cells & memory B cells and eosinophils (Fig3). Figure 1 Figure 2 Figure 3 Conclusion The concordant and discordant responses mapped here provide a window to explore the pathophysiology of COVID-19 vs other viral infections and show clear differences in signaling pathways and cellularity as part of the host response to SARS-CoV-2. Disclosures Simone A. Thair, PhD, Inflammatix, Inc. (Employee, Shareholder) Yudong He, PhD, Inflammatix Inc. (Employee) Yehudit Hasin-Brumshtein, PhD, Inflammatix (Employee, Shareholder) Suraj Sakaram, MS in Biochemistry and Molecular Biology, Inflammatix (Employee, Other Financial or Material Support, stock options) Rushika R. Pandya, MS, Inflammatix Inc. (Employee, Shareholder) David C. Rawling, PhD, Inflammatix Inc. (Employee, Shareholder) Purvesh Khatri, PhD, Inflammatix Inc. (Shareholder) Timothy Sweeney, MD, PHD, Inflammatix, Inc. (Employee, Shareholder)

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COVID-19: Unmasking Emerging SARS-CoV-2 Variants, Vaccines and Therapeutic Strategies

Biomolecules ◽

10.3390/biom11070993 ◽

2021 ◽

Vol 11 (7) ◽

pp. 993

Author(s):

Renuka Raman ◽

Krishna J. Patel ◽

Kishu Ranjan

Keyword(s):

Immune Response ◽

Monoclonal Antibodies ◽

Severe Acute Respiratory Syndrome ◽

Small Molecules ◽

Viral Vector ◽

Therapeutic Strategies ◽

Convincing Evidence ◽

Plasma Therapy ◽

Therapeutic Monoclonal Antibodies ◽

Increased Susceptibility

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of the coronavirus disease 2019 (COVID-19) pandemic, which has been a topic of major concern for global human health. The challenge to restrain the COVID-19 pandemic is further compounded by the emergence of several SARS-CoV-2 variants viz. B.1.1.7 (Alpha), B.1.351 (Beta), P1 (Gamma) and B.1.617.2 (Delta), which show increased transmissibility and resistance towards vaccines and therapies. Importantly, there is convincing evidence of increased susceptibility to SARS-CoV-2 infection among individuals with dysregulated immune response and comorbidities. Herein, we provide a comprehensive perspective regarding vulnerability of SARS-CoV-2 infection in patients with underlying medical comorbidities. We discuss ongoing vaccine (mRNA, protein-based, viral vector-based, etc.) and therapeutic (monoclonal antibodies, small molecules, plasma therapy, etc.) modalities designed to curb the COVID-19 pandemic. We also discuss in detail, the challenges posed by different SARS-CoV-2 variants of concern (VOC) identified across the globe and their effects on therapeutic and prophylactic interventions.

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