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Competing Interests: Conflict of interest disclosure The authors declare no competing financial interests.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a systemic disease affecting not only the lungs but also multiple organ systems. Clinical studies implicate that SARS-CoV-2 infection causes imbalance of cellular homeostasis and immune response that trigger cytokine storm, oxidative stress, thrombosis, and insulin resistance. Mathematical modeling can offer in-depth understanding of the SARS-CoV-2 infection and illuminate how subcellular mechanisms and feedback loops underpin disease progression and multiorgan failure. We report here a mathematical model of SARS-CoV-2 infection pathway network with cytokine storm, oxidative stress, thrombosis, insulin resistance, and nitric oxide (NO) pathways. The biochemical systems theory model shows autocrine loops with positive feedback enabling excessive immune response, cytokines, transcription factors, and interferons, which can imbalance homeostasis of the system. The simulations suggest that changes in immune response led to uncontrolled release of cytokines and chemokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor α (TNFα), and affect insulin, coagulation, and NO signaling pathways. Increased production of NETs (neutrophil extracellular traps), thrombin, PAI-1 (plasminogen activator inhibitor-1), and other procoagulant factors led to thrombosis. By analyzing complex biochemical reactions, this model forecasts the key intermediates, potential biomarkers, and risk factors at different stages of COVID-19. These insights can be useful for drug discovery and development, as well as precision treatment of multiorgan implications of COVID-19 as seen in systems medicine.

Aims: We evaluated physicians' willingness to trade-off benefits, risks and time to infusion for CAR T-cell therapy for relapsed or refractory diffuse large B-cell lymphoma. Materials & methods: In a discrete-choice experiment survey, 150 US oncologists/hematologists chose between two hypothetical CAR T-cell treatments defined by six attributes. Results: Decreasing time to infusion from 113 to 16 days yielded the greatest change in preference weight (1.91). Physicians were willing to accept a >20% increase in risk of severe cytokine release syndrome and 15% increase in risk of severe neurological events in exchange for an increase in the probability of overall survival at 24 months from 40 to 55%. Conclusion: Physicians value reducing time to infusion and will accept incremental increases in serious adverse event risks to gain survival improvements.

Coronavirus disease 2019 (COVID-19) is a highly infectious viral disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Laboratory findings from a significant number of patients with COVID-19 indicate the occurrence of leukocytopenia, specifically lymphocytopenia. Moreover, infected patients can experience contrasting outcomes depending on lymphocytopenia status. Patients with resolved lymphocytopenia are more likely to recover, whereas critically ill patients with signs of unresolved lymphocytopenia develop severe complications, sometimes culminating in death. Why immunodepression manifests in patients with COVID-19 remains unclear. Therefore, the evaluation of clinical symptoms and laboratory findings from infected patients is critical for understanding the disease course and its consequences. In this review, we take a logical approach to unravel the reasons for immunodepression in patients with COVID-19. Following the footprints of the virus within host tissues, from entry to exit, we extrapolate the mechanisms underlying the phenomenon of immunodepression.

SARS-CoV-2 has claimed 2,137,908 lives in more than a year. Some COVID-19 patients experience sudden and rapid deterioration with the onset of fatal cytokine storm syndrome (CSS), which have increased interest in CSS's mechanisms, diagnosis and therapy. Although the prototypic concept of CSS was first proposed 116 years ago, we have only begun to study and understand CSS for less than 30 years. Actually, diseases under CSS umbrella include familial/primary and secondary hemophagocytic lymphohistiocytosis (HLH), macrophage activation syndrome (MAS), infection-associated hemophagocytic syndrome, cytokine release syndrome (CRS), and cytokine storm (CS). Hematologic malignancies and autoimmune diseases that cause CSS are named malignancy-associated hemophagocytic syndrome (MAHS) and MAS, respectively. In-depth research on the pathogenesis of HLH/CSS has greatly increased the number of patients that were able to be definitively diagnosed with HLH/CSS. However, it should be emphasized that HLH/CSS diagnosis is difficult at the early stages due to the non-specific clinical signs and symptoms, which tends to result in missed and incorrect diagnoses. Therefore, clinicians should not only possess extensive clinical experience to ensure high sensitivity to the characteristics of HLH/CSS but must also be familiar with HLH-2004/2009 diagnostic criteria, and HScore methods. The paper concisely comment evolution of CSS classifications, cytokines associated with CSS, evolution of CSS diagnostic criteria and importance of the correct identification of hemophagocytes in diagnosing CSS, which is timely and may benefit clinicians familiar HLH-2004/2009 diagnostic criteria, and HScore methods. In addition, clinicians must also understand that there are some limitations to these diagnostic criteria. Abbreviations: aBMT: autologous bone marrow transplantation; CAR-T: chimeric antigen receptor-engineered T-cell; COVID-19: coronavirus disease 2019; CSS: cytokine storm syndrome; HLH: hemophagocytic lymphohistiocytosis; MAS: macrophage activation syndrome; CRS: cytokine release syndrome; CS: cytokine storm; MAHS: malignancy-associated hemophagocytic syndrome; IAHS: infection-associated hemophagocytic syndrome; fHLH/pHLH: familial/primary hemophagocytic lymphohistiocytosis; sHLH: secondary hemophagocytic lymphohistiocytosis; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TCR-T, T-cell receptor-engineered T-cell.

The coronavirus disease (COVID-19) has once again reminded us of the significance of host immune response and consequential havocs of the immune dysregulation. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) inflicts severe complications to the infected host, including cough, dyspnoea, fever, septic shock, acute respiratory distress syndrome (ARDs), and multiple organ failure. These manifestations are the consequence of the dysregulated immune system, which gives rise to excessive and unattended production of pro-inflammatory mediators. Elevated circulatory cytokine and chemokine levels are accompanied by spontaneous haemorrhage, thrombocytopenia and systemic inflammation, which are the cardinal features of life-threatening cytokine storm syndrome in advanced COVID-19 diseases. Coronavirus hijacked NF-kappa B (NF-κB) is responsible for upregulating the expressions of inflammatory cytokine, chemokine, alarmins and inducible enzymes, which paves the pathway for cytokine storm. Given the scenario, the systemic approach of simultaneous inhibition of NF-κB offers an attractive therapeutic intervention. Targeted therapies with proteasome inhibitor (VL-01, bortezomib, carfilzomib and ixazomib), bruton tyrosine kinase inhibitor (acalabrutinib), nucleotide analogue (remdesivir), TNF-α monoclonal antibodies (infliximab and adalimumab), N-acetylcysteine and corticosteroids (dexamethasone), focusing the NF-κB inhibition have demonstrated effectiveness in terms of the significant decrease in morbidity and mortality in severe COVID-19 patients. Hence, this review highlights the activation, signal transduction and cross-talk of NF-κB with regard to cytokine storm in COVID-19. Moreover, the development of therapeutic strategies based on NF-κB inhibition are also discussed herein., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The epidemic Streptococcus suis ( S. suis ) strain [Sequence type (ST) 7] was gradually evolving from the non-epidemic ST1 strain and got the ability for high expressing of suilysin (SLY). And the high expression of SLY was required for the epidemic strain to cause NLRP3 hyperactivation, which is essential for the induction of cytokines storm, dysfunction of multiple organs, and a high incidence of mortality, the characters of streptococcal toxic shock-like syndrome (STSLS). However, it remains to be elucidated whether acquiring high SLY expression due to genome evolution was sufficient for the non-epidemic strain to cause STSLS. Here, we found that the overexpression of SLY in ST1 strain (P1/7-SLY) could obviously increase the inflammasome activation, which was dependent on NLRP3 signalling. In contrast, the strain (P1/7-mSLY) overexpressing the mutant SLY (protein without hemolytic activity) could not significantly increase the inflammasome activation. Furthermore, similar to the epidemic strain, P1/7-SLY could cause STSLS in nlrp3 +/+ mice but not in nlrp3 -/- mice. In contrast, P1/7-mSLY could not cause STSLS in both nlrp3 +/+ mice and nlrp3 -/- mice. In summary, we demonstrate that genetic evolution enabling S. suis strain to express high level of SLY may be an essential and sufficient condition for NLRP3 inflammasome hyperactivation, which could further cause cytokines storm and STSLS.

CAR-T cells represent a new anti-tumor immunotherapy which has shown its clinical efficacy in B-cell malignancies. The results of clinical trials carried out in this context have shown that certain immunological characteristics of patients before (at the time of apheresis) and after the administration of the treatment, or of the CAR-T cells themselves, are correlated with the response to the treatment or to its toxicity. However, to date, there are no recommendations on the immunological monitoring of patients treated in real life. The objectives of this workshop were to determine, based on data from the literature and the experience of the centers, the immunological analyses to be carried out in patients treated with CAR-T cells. The recommendations relate to the characterization of the patient's immune cells at the time of apheresis, the characterization of the injected CAR-T cells, as well as the monitoring of the CAR-T cells and other parameters of immune reconstitution in the patient after administration of the treatment. Harmonization of practices will allow clinical-biological correlation studies to be carried out in patients treated in real life with the aim of identifying factors predictive of response and toxicity. Such data could have a major medico-economic impact by making it possible to identify the patients who will optimally benefit from these expensive treatments., (Copyright © 2021 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

The coronavirus SARS-CoV-2, the aetiological agent of COVID-19 disease, is representing a worldwide threat for the medical community and the society at large so that it is being defined as "the twenty-first-century disease". Often associated with a severe cytokine storm, leading to more severe cases, it is mandatory to block such occurrence early in the disease course, to prevent the patients from having more severe, sometimes fatal, outcomes. In this framework, early detection of "danger signals", possibly represented by alarmins, can represent one of the most promising strategies to effectively tailor the disease and to better understand the underlying mechanisms eventually leading to death or severe consequences. In light of such considerations, the present article aims at evaluating the role of alarmins in patients affected by COVID-19 disease and the relationship of such compounds with the most commonly reported comorbidities. The conducted researches demonstrated yet poor literature on this specific topic, however preliminarily confirming a role for danger signals in the amplification of the inflammatory reaction associated with SARS-CoV-2 infection. As such, a number of chronic conditions, including metabolic syndrome, gastrointestinal and respiratory diseases, in turn, associated with higher levels of alarmins, both foster the infection and predispose to a worse prognosis. According to these preliminary data, prompt detection of high levels of alarmins in patients with COVID-19 and co-morbidities could suggest an immediate intense anti-inflammatory treatment.Key messageAlarmins have a role in the amplification of the inflammatory reaction associated with SARS-CoV-2 infectiona prompt detection of high levels of alarmins in patients with COVID-19 could suggest an immediate intense anti-inflammatory treatment.

Coronavirus disease 2019 (COVID-19) a global infectious disease caused by severe acute respiratory coronavirus 2 (SARS-CoV-2) affects various organs, primarily the respiratory system, and presented with pulmonary manifestations such as acute lung injury (ALI) and acute respiratory distress syndrome. Levamisole (LVM) is an anthelminthic drug; it has immune-modulating effects through induction of type 1 immune response. Based on these findings several recent studies highlighted that LVM might be effective in preventing and treating SARS-CoV-2 infections. The aim of this report is to illustrate the potential role of LVM in SARS-CoV-2 infection and in the management of COVID-19. Different studies proposed that LVM may inhibit proliferation of SARS-CoV-2 through inhibition of papain-like protease. LVM may prevent ALI and acute kidney injury through activation of glucocorticoid receptors. In general, LVM has strong immune stimulant effects by modulating cellular and humoral immune responses. This effect is beneficial in the early phase of COVID-19 and harmful in the late phase. In the early phase, immune stimulation facilitates SARS-CoV-2 clearance and tissue repair, however, in the late phase, immune stimulation in COVID-19 may increase propagation risk of cytokine storm. In conclusion, LVM therapy in COVID-19 has bidirectional effects, beneficial in the early phase and harmful effects in the late phase of COVID-19. Clinical trial and prospective studies are warranted in this regard to confirm the efficacy and timing administration of LVM in the management of COVID-19.

The virus responsible for coronavirus disease 2019 (COVID-19), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected over 190 million people to date, causing a global pandemic. SARS-CoV-2 relies on binding of its spike glycoprotein to angiotensin-converting enzyme 2 (ACE2) for infection. In addition to fever, cough, and shortness of breath, severe cases of SARS-CoV-2 infection may result in the rapid overproduction of pro-inflammatory cytokines. This overactive immune response is known as a cytokine storm, which leads to several serious clinical manifestations such as acute respiratory distress syndrome and myocardial injury. Cardiovascular disorders such as acute coronary syndrome (ACS) and heart failure not only enhance disease progression at the onset of infection, but also arise in hospitalized patients with COVID-19. Tissue-specific differentiated cells and organoids derived from human pluripotent stem cells (hPSCs) serve as an excellent model to address how SARS-CoV-2 damages the lungs and the heart. In this review, we summarize the molecular basis of SARS-CoV-2 infection and the current clinical perspectives of the bidirectional relationship between the cardiovascular system and viral progression. Furthermore, we also address the utility of hPSCs as a dynamic model for SARS-CoV-2 research and clinical translation., (© 2021. The Author(s).)

The coronavirus disease 19 (COVID-19) caused by the novel coronavirus known as SARS-CoV-2 has caused a global public health crisis. As of 7 January 2021, 87,640,402 confirmed cases and 1,891,692 mortalities have been reported worldwide. Studies focusing on the epidemiological and clinical characteristics of COVID-19 patients have suggested a dysregulated immune response characterized by lymphopenia and cytokine storm in these patients. The exaggerated immune response induced by the cytokine storm causes septic shock, acute respiratory distress syndrome (ARDS), and/or multiple organs failure, which increases the fatality rate of patients with SARS-CoV-2 infection. Herein, we review the recent research progress on epidemiology, clinical features, and system pathology in COVID-19. Moreover, we summarized the recent therapeutic strategies, which are either approved, under clinical trial, and/or under investigation by the local or global health authorities. We assume that treatments should focus on the use of antiviral drugs in combination with immunomodulators as well as treatment of the underlying comorbidities.

The coronavirus disease-19 (COVID-19), at first, was reported in Wuhan, China, and then rapidly became pandemic throughout the world. Cytokine storm syndrome (CSS) in COVID-19 patients is associated with high levels of cytokines and chemokines that cause multiple organ failure, systemic inflammation, and hemodynamic instabilities. Acute respiratory distress syndrome (ARDS), a common complication of COVID-19, is a consequence of cytokine storm. In this regard, several drugs have been being investigated to suppress this inflammatory condition. Purinergic signaling receptors comprising of P1 adenosine and P2 purinoceptors play a critical role in inflammation. Therefore, activation or inhibition of some subtypes of these kinds of receptors is most likely to be beneficial to attenuate cytokine storm. This article summarizes suggested therapeutic drugs with potential anti-inflammatory effects through purinergic receptors.

SARS-CoV-2, as the causative agent of COVID-19, is an enveloped positives-sense single-stranded RNA virus that belongs to the Beta-CoVs sub-family. A sophisticated hyper-inflammatory reaction named cytokine storm is occurred in patients with severe/critical COVID-19, following an imbalance in immune-inflammatory processes and inhibition of antiviral responses by SARS-CoV-2, which leads to pulmonary failure, ARDS, and death. The miRNAs are small non-coding RNAs with an average length of 22 nucleotides which play various roles as one of the main modulators of genes expression and maintenance of immune system homeostasis. Recent evidence has shown that Homo sapiens (hsa)-miRNAs have the potential to work in three pivotal areas including targeting the virus genome, regulating the inflammatory signaling pathways, and reinforcing the production/signaling of IFNs-I. However, it seems that several SARS-CoV-2-induced interfering agents such as viral (v)-miRNAs, cytokine content, competing endogenous RNAs (ceRNAs), etc. preclude efficient function of hsa-miRNAs in severe/critical COVID-19. This subsequently leads to increased virus replication, intense inflammatory processes, and secondary complications development. In this review article, we provide an overview of hsa-miRNAs roles in viral genome targeting, inflammatory pathways modulation, and IFNs responses amplification in severe/critical COVID-19 accompanied by probable interventional factors and their function. Identification and monitoring of these interventional elements can help us in designing the miRNAs-based therapy for the reduction of complications/mortality rate in patients with severe/critical forms of the disease., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The pathophysiological process of the disease, Covid-19, is mediated by innate immunity, with the presence of macrophages responsible for secreting type 1 and 6 interleukins (IL), tumor necrosis factor (TNF) leading to dilation of endothelial cells with a consequent increase in capillary permeability. The treatment of this disease has been much discussed, but the variability in the clinical picture, the difficulties for diagnosis and treatment, especially of those patients who have the most severe clinical condition of the disease. Immunization is an effective tool for controlling the spread and overload of health services, but its effectiveness involves high investments in the acquisition of inputs, development of vaccines, and logistics of storage and distribution. These factors can be obstacles for countries with lower economic, technological, and infrastructure indexes. Reflecting on these difficulties, we raised the possibility of adjuvant therapies with imminent research feasibility, as is the case with the use of carvacrol, a monoterpenic phenol whose has biological properties that serve as a barrier to processes mediated by free radicals, such as irritation and inflammation, due to its antioxidant action. Many authors highlighted the activity of carvacrol as a potent suppressor of COX-2 expression minimizing the acute inflammatory process, decreasing the release of some pro-inflammatory mediators such as IL-1β, TNF-α, PGE2. Anyway, the benefits of carvacrol are numerous and the therapeutic possibilities too. With this description, the question arises: would carvacrol be a supporting treatment option, effective in minimizing the deleterious effects of Covid-19? There is still a lot to discover and research., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The "normal" immune response to an insult triggers a highly regulated response determined by the interaction of various immunocompetent cells with pro- and anti-inflammatory cytokines. Under pathologic conditions, the massive elevation of cytokine levels ("cytokine storm") could not be controlled until the recent development of hemoadsorption devices that are able to extract a variety of different DAMPs, PAMPs, and metabolic products from the blood. CytoSorb ® has been approved for adjunctive sepsis therapy since 2011. This review aims to summarize theoretical knowledge, in vitro results, and clinical findings to provide the clinician with pragmatic guidance for daily practice. English-language and peer-reviewed literature identified by a selective literature search in PubMed and published between January 2016 and May 2021 was included. Hemoadsorption can be used successfully as adjunct to a complex therapeutic regimen for various conditions. To the contrary, this nonspecific intervention may potentially worsen patient outcomes in complex immunological processes. CytoSorb ® therapy appears to be safe and useful in various diseases (e.g., rhabdomyolysis, liver failure, or intoxications) as well as in septic shock or cytokine release syndrome, although a conclusive assessment of treatment benefit is not possible and no survival benefit has yet been demonstrated in randomized controlled trials.

The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has seriously affected public health and social stability. The main route of the transmission is droplet transmission, where the oral cavity is the most important entry point to the body. Due to both the direct harmful effects of SARS-CoV-2 and disordered immune responses, some COVID-19 patients may progress to acute respiratory distress syndrome or even multiple organ failure. Genetic variants of SARS-CoV-2 have been emerging and circulating around the world. Currently, there is no internationally approved precise treatment for COVID-19. Mesenchymal stem cells (MSCs) can traffic and migrate towards the affected tissue, regulate both the innate and acquired immune systems, and participate in the process of healing. Here, we will discuss and investigate the mechanisms of immune disorder in COVID-19 and the therapeutic activity of MSCs, in particular human gingiva mesenchymal stem cells., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Xun Li et al.)

Objective: To investigate the cytokine release syndrome (CRS) condition for central nervous system B-cell acute lymphocytic leukemia (CNS B-ALL) patients after CAR-Ts targeting CD19 with short hairpin RNA (shRNA)-IL-6 gene silencing technology (ssCART-19s) infusion., Methods: This prospective observational research included a total of 12 cases of patients with CNS B-ALL from March 2017 to February 2020. ssCART-19 infusions (5×10 6 cells/kg) were given to patients for 3 consecutive days. After infusion, the temperature of all patients was detected constantly and the CRS was carefully monitored within 1 month after treatment. The serum levels of IL-2, IL-4, IL-6, IL-10, IFN-γ, TNF-α, CRP and IL-17A were tested by enzyme-linked immunosorbent assay (ELISA) within 10 days after infusion., Results: All 12 CNS B-ALL patients showed CRS with 100% incidence rate, with 3 cases (25.00%) of CRS stage I and 9 cases (75.00%) with CRS stage II. No CRS stage III~V was observed. The overall response rate was 91.67% (11/12), with 10 patients (83.33%) showed CR and 1 case (8.33%) of PR. In 9 patients with CRS stage II, the temperature increased persistently, ranging from 4 days to 14 days after infusion, and decreased gradually after 14 days of nursing treatment. The hyperthermia condition started from 1 day after infusion and returned to baseline at the following 2-10 days of nursing treatment. The levels of the inflammatory factors increased markedly after ssCAR-T19s infusion for 2-3 days compared to the baseline, and gradually returned to the baseline after treatment. After 10 days of infusion, all inflammatory factors returned to normal levels., Conclusion: ssCART-19s infusion induced short-term slight CRS with increased temperature and inflammatory factors, and no severe CRS was observed., (© 2021 by the Association of Clinical Scientists, Inc.)

The current pandemic caused by SARS-CoV-2 virus infection is known as Covid-19 (coronavirus disease 2019). This disease can be asymptomatic or can affect multiple organ systems. Damage induced by the virus is related to dysfunctional activity of the immune system, but the activity of molecules such as C-reactive protein (CRP) as a factor capable of inducing an inflammatory status that may be involved in the severe evolution of the disease, has not been extensively evaluated. A systematic review was performed using the NCBI-PubMed database to find articles related to Covid-19 immunity, inflammatory response, and CRP published from December 2019 to December 2020. High levels of CRP were found in patients with severe evolution of Covid-19 in which several organ systems were affected and in patients who died. CRP activates complement, induces the production of pro-inflammatory cytokines and induces apoptosis which, together with the inflammatory status during the disease, can lead to a severe outcome. Several drugs can decrease the level or block the effect of CRP and might be useful in the treatment of Covid-19. From this review it is reasonable to conclude that CRP is a factor that can contribute to severe evolution of Covid-19 and that the use of drugs able to lower CRP levels or block its activity should be evaluated in randomized controlled clinical trials., (© 2021 John Wiley & Sons Ltd.)

The coronavirus disease (Covid-19) pandemic is the most serious event of the year 2020, causing considerable global morbidity and mortality. The goal of this review is to provide a comprehensive summary of reported associations between inter-individual immunogenic variants and disease susceptibility or symptoms caused by the coronavirus strains severe acute respiratory syndrome-associated coronavirus, severe acute respiratory syndrome-associated coronavirus-2, and two of the main respiratory viruses, respiratory syncytial virus and influenza virus. The results suggest that the genetic background of the host could affect the levels of proinflammatory and anti-inflammatory cytokines and might modulate the progression of Covid-19 in affected patients. Notably, genetic variations in innate immune components such as toll-like receptors and mannose-binding lectin 2 play critical roles in the ability of the immune system to recognize coronavirus and initiate an early immune response to clear the virus and prevent the development of severe symptoms. This review provides promising clues related to the potential benefits of using immunotherapy and immune modulation for respiratory infectious disease treatment in a personalized manner., (© 2021 John Wiley & Sons Ltd.)

We describe the case of a 42 year old, healthy patient with Covid-19 who despite improvement in his respiratory symptoms developed a mild to moderate cytokine release syndrome (CRS) and an associated monoarticular gout flare. Since the patient refused admission to the hospital and had stable vital signs, we chose to treat him with a safe anti-inflammatory and non-immunosuppressive therapy. To hit two birds with one stone, we considered colchicine, as it has systemic anti-inflammatory effects and is also effective in gout flare. Unexpectedly, 48 hours after treatment, not only did his ongoing fever and toe pain disappear, he also had significant improvements in his general state of health and all his inflammatory markers including fibrinogen, ferritin, D-dimer, and IL-6 levels normalized. To our knowledge, the use of colchicine in Covid-19 and CRS has not been reported. This observation merits the consideration of colchicine as a safe, inexpensive and oral medication for the treatment of mild to moderate CRS in Covid-19 patients. More importantly, in Covid-19 patients with early lung involvement colchicine may be an appropriate candidate to prevent CRS in adjunction with routine antiviral agents. Indeed, multicenter, randomized controlled studies are required to evaluate the benefits of this therapy.

Tuberculosis caused by Mycobacterium tuberculosis remains a serious global public health threat. Macrophage polarization is crucial for the innate immunity against M. tuberculosis. However, how M. tuberculosis interferes with macrophage polarization is elusive. We demonstrated here that M. tuberculosis PPE36 (Rv2108) blocked macrophage M1 polarization, preventing the cytokine storm, and alleviating inflammatory damage to mouse immune organs. PPE36 inhibited the polarization of THP-1 cell differentiation to M1 macrophages, reduced mitochondrial dehydrogenase activity, inhibited the expression of CD16, and repressed the expression of pro-inflammatory cytokines IL-6 and TNF-α, as well as chemokines CXCL9, CXCL10, CCL3, and CCL5. Intriguingly, in the mouse infection model, PPE36 significantly alleviated the inflammatory damage of immune organs caused by a cytokine storm. Furthermore, we found that PPE36 inhibited the polarization of macrophages into mature M1 macrophages by suppressing the ERK signaling. The study provided novel insights into the function and mechanism of action of M. tuberculosis effector PPE36 both at the cellular and animal level., (© 2021 Wiley Periodicals LLC.)

Evaluating the effect of convalescent plasma (CP) on some cytokine storm indices in severe COVID-19 patients. Totally, 62 patients were randomly assigned into two groups for this clinical trial. Patients in the intervention group received one unit (500 mL) plasma on the admission day plus standard drugs while the controls merely received standard treatments. Eventually, primary and secondary outcomes were evaluated. In the CP group, compared with controls, the mean levels of lymphocytes and IL-10 significantly increased while the levels of IL-6, TNF-α, and IFN-γ decreased (p < 0.05). The length of in-hospital stay, and mortality rate did not significantly reduce in the CP group compared with controls (p > 0.05) while WHO severity scores remarkably improved (p = 0.01), despite the higher frequency of underlying diseases among the CP group (66.7%) vs. controls (33.3%). Although CP has a remarkable immunomodulatory and antiviral potential to improve the cytokine storm and disease severity in COVID-19 patients, it did not considerably affect the mortality rate., (© 2021. Società Italiana di Medicina Interna (SIMI).)

This review describes the evidence for the potential benefit of vitamin D supplementation in people with respiratory diseases who may have a higher susceptibility to coronavirus disease 2019 (COVID-19) infection and its consequences. Clinical evidence indicates that vitamin D may reduce the risk of both upper and lower respiratory tract infections and offers benefit particularly in people with vitamin D deficiency. Some evidence exists for a higher incidence of active tuberculosis (TB) in patients who are deficient in vitamin D. An association between low levels of 25(OH)D (the active form of vitamin D) and COVID-19 severity of illness and mortality has also been reported. In addition, low 25(OH)D levels are associated with poor outcomes in acute respiratory distress syndrome (ARDS). The cytokine storm experienced in severe COVID-19 infections results from excessive release of pro-inflammatory cytokines. Due to its immunomodulatory effects, adequate vitamin D levels may cause a decrease in the pro-inflammatory cytokines and an increase in the anti-inflammatory cytokines during COVID-19 infections. Vitamin D deficiency was found in 82.2% of hospitalized COVID-19 cases and 47.2% of population-based controls (p < 0.0001). The available evidence warrants an evaluation of vitamin D supplementation in susceptible populations with respiratory diseases, such as TB, and particularly in those who are deficient in vitamin D. This may mitigate against serious complications of COVID-19 infections or reduce the impact of ARDS in those who have been infected., (© 2021 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Competing Interests: Declaration of Competing Interest E. J. Giamarellos-Bourboulis has received honoraria from Abbott CH, bioMérieux, Brahms GmbH, GSK, InflaRx GmbH, Sobi and XBiotech Inc; independent educational grants from Abbott CH, bioMérieux Inc, InflaRx GmbH, Johnson & Johnson, MSD, Novartis, UCB, Sobi and XBiotech Inc.; and funding from the Horizon2020 Marie-Curie Project European Sepsis Academy (granted to the National and Kapodistrian University of Athens), and the Horizon 2020 European Grants ImmunoSep and RISKinCOVID (granted to the Hellenic Institute for the Study of Sepsis).

p65 is one of the important subunits of the inflammation-related transcription factor NF-κB. In the present study, we cloned and identified the p65 from Megalobrama amblycephala (Mnp65) by homologous cloning and RACE technique. The full-length Mnp65 cDNA consisted of 2331 bp, and included one open reading frame encoding a 604-amino acid putative protein. The protein sequence included a DNA binding motif, a well conserved N-terminal Rel-homology domain (RHD), and a C-terminal IG-like plexins transcription (IPT). Mnp65 was closely related with the other p65 proteins of Cypriniformes and clearly distinct from that of Perciformes and Salmoniformes in terms of sequence homology. Mnp65 homodimer may interact with IκBα in the IPT domain based on the predicted 3D structure of IκBα/Mnp65 complex. Mnp65 was ubiquitously expressed in M. amblycephala tissues, and the highest levels were detected in muscle and liver. Intragastric infection with Aeromonas hydrophila caused respiratory burst and cytokine storm from 8 h to 48 h, showing significantly higher level of respiratory burst activities and significantly high cytokines levels, such as TNF-α, IL-1β, IL-6, IL-8 etc., compared to 0 h. In addition, the bacterial challenge downregulated the IkBα, and upregulated Mnp65 and TNF-α in the liver. IkBα-Mnp65 was regulated by the negative feedback of cytokine storm, to increase IkBα and decrease Mnp65. Then cytokine storm was relieved at 96 h. Finally, severe intestinal inflammation was observed from 24 h to 48 h after infection, characterized by extensive villous necrosis, epithelial hyperplasia and lymphocyte infiltration, all of which were relieved at 96 h. Taken together, Mnp65 plays a crucial role in the physiological response of teleost fish to bacterial infection., (Copyright © 2021. Published by Elsevier Inc.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic of respiratory and cardiovascular diseases, known as coronavirus disease 2019 (COVID-19). SARS-CoV-2 encodes the structural proteins spike (S), envelope (E), membrane (M), and nucleocapsid (N). The receptor-binding domain on the surface subunit S1 is responsible for attachment of the virus to angiotensin (Ang)-converting enzyme 2 (ACE2), which is highly expressed in host cells. The cytokine storm observed in patients with COVID-19 contributes to the endothelial vascular dysfunction, which can lead to acute respiratory distress syndrome, multiorgan failure, alteration in iron homeostasis, and death. Growth and differentiation factor 15 (GDF15), which belongs to the transforming growth factor-β (TGF-β) superfamily of proteins, has a pivotal role in the development and progression of diseases because of its role as a metabolic regulator. In COVID-19, GDF15 activity increases in response to tissue damage. GDF15 appears to be a strong predictor of poor outcomes in patients critically ill with COVID-19 and acts as an 'inflammation-induced central mediator of tissue tolerance' via its metabolic properties. In this review, we examine the potential properties of GDF15 as an emerging modulator of immunity in COVID-19 in association with iron metabolism. The virus life cycle in host cell provides potential targets for drug therapy., Competing Interests: Declaration of interests The authors declare that there are no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Tocilizumab is an IL-6 receptor antagonist with the ability to suppress the cytokine storm in critically ill patients infected with severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). We evaluated patients treated with tocilizumab for a SARS-CoV-2 infection who were admitted between March 13, 2020, and April 16, 2020. This was a multicenter study with data collected by chart review both retrospectively and concurrently. Parameters evaluated included age, sex, race, use of mechanical ventilation (MV), usage of steroids and vasopressors, inflammatory markers, and comorbidities. Early dosing was defined as a tocilizumab dose administered prior to or within 1 day of intubation. Late dosing was defined as a dose administered > 1 day after intubation. In the absence of MV, the timing of the dose was related to the patient's date of admission only. We evaluated 145 patients. The average age was 58.1 years, 64% were men, 68.3% had comorbidities, and 60% received steroid therapy. Disposition of patients was 48.3% discharged and 29.3% died, of which 43.9% were African American. MV was required in 55.9%, of which 34.5% died. Avoidance of MV (P = 0.002) and increased survival (P < 0.001) was statistically associated with early dosing. Tocilizumab therapy was effective at decreasing mortality and should be instituted early in the management of critically ill patients with coronavirus disease 2019) COVID-19)., (© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

During COVID-19 infection, reduced function of natural killer (NK) cells can lead to both compromised viral clearance and dysregulation of the immune response. Such dysregulation leads to overproduction of cytokines, a raised neutrophil/lymphocyte ratio and monocytosis. This in turn increases IL-6 expression, which promotes scar and thrombus formation. Excess IL-6 also leads to a further reduction in NK function through downregulation of perforin expression, therefore forming a pathogenic auto-inflammatory feedback loop. The perforin/granzyme system of cytotoxicity is the main mechanism through which NK cells and cytotoxic T lymphocytes eliminate virally infected host cells, as well as being central to their role in regulating immune responses to microbial infection. Here, we present epidemiological evidence suggesting an association between perforin expression and resistance to COVID-19. In addition, we outline the manner in which a pathogenic auto-inflammatory feedback loop could operate and the relationship of this loop to genes associated with severe COVID-19. Such an auto-inflammatory loop may be amenable to synergistic multimodal therapy., (© 2021 The Scandinavian Foundation for Immunology.)

Coronavirus disease 2019 (COVID-19), an acute and highly transmissible infectious disease, has reached a pandemic level since 11 March 2020 and continues to challenge the healthcare system worldwide. The pathogenesis of COVID-19 is a complex process involving mechanisms that suppress the host antiviral and innate immune response, while triggering marked activation of coagulation and hyperinflammation leading to cytokine storm in severe COVID-19. This review summarizes current evidence related to COVID-19-associated cardiovascular severe illness and mortality, which encompasses life-threatening clinical manifestations, including myocardial injury, fulminant myocarditis, cardiac arrhythmia, and ischemic stroke. The onset of hypercoagulable state is consistent with increased venous thromboembolism including deep vein thrombosis and pulmonary embolism. Thromboembolic manifestations include arterial thrombotic events such as stroke, myocardial infarction, and limb ischemia. Several treatment strategies have been investigated to mitigate COVID-19-associated cardiovascular clinical manifestations. The prevalence of thrombo-inflammatory syndrome and subsequent cardiovascular dysfunction prompted the implementation of antithrombotic therapy and strategies targeting major pro-inflammatory cytokines involved in COVID-19 cytokine storm. The development of new guidelines for effective treatment strategies requires concerted efforts to refine our understanding of the mechanisms underlying cardiovascular disease and large-scale clinical trials to reduce the burden of COVID-19 hospitalization and mortality.

The global outbreak of the SARS-Cov-2 virus in 2020 has killed millions of people worldwide and forced large parts of the world into lockdowns. While multiple vaccine programs are starting to immunize the global population, there is no direct cure for COVID-19, the disease caused by the SARS-Cov-2 infection. A common symptom in patients is a decrease in T cells, called lymphopenia. It is as of yet unclear what the exact role of T cells are in the immune response to COVID-19. The research so far has mainly focused on the involvement of classical αβ T cells. However, another subset of T cells called γδ T cells could have an important role to play. As part of the innate immune system, γδ T cells respond to inflammation and stressed or infected cells. The γδ T cell subset appears to be particularly affected by lymphopenia in COVID-19 patients and commonly express activation and exhaustion markers. Particularly in children, this subset of T cells seems to be most affected. This is interesting and relevant because γδ T cells are more prominent and active in early life. Their specific involvement in this group of patients could indicate a significant role for γδ T cells in this disease. Furthermore, they seem to be involved in other viral infections and were able to kill SARS infected cells in vitro . γδ T cells can take up, process and present antigens from microbes and human cells. As e.g. tumour-associated antigens are presented by MHC on γδ T cells to classical T-cells, we argue here that it stands to reason that also viral antigens, such as SARS-Cov-2-derived peptides, can be presented in the same way. γδ T cells are already used for medical purposes in oncology and have potential in cancer therapy. As γδ T cells are not necessarily able to distinguish between a transformed and a virally infected cell it could therefore be of great interest to investigate further the relationship between COVID-19 and γδ T cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 von Massow, Oh, Lam and Gustafsson.)

As the number of confirmed cases and deaths occurring from Coronavirus disease 2019 (COVID-19) surges worldwide, health experts are striving hard to fully comprehend the extent of damage caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although COVID-19 primarily manifests itself in the form of severe respiratory distress, it is also known to cause systemic damage to almost all major organs and organ systems within the body. In this review, we discuss the molecular mechanisms leading to multi-organ failure seen in COVID-19 patients. We also examine the potential of stem cell therapy in treating COVID-19 multi-organ failure cases.

Cytokine release syndrome (CRS) embodies a mixture of clinical manifestations, including elevated circulating cytokine levels, acute systemic inflammatory symptoms and secondary organ dysfunction, which was first described in the context of acute graft-versus-host disease after allogeneic hematopoietic stem-cell transplantation and was later observed in pandemics of influenza, SARS-CoV and COVID-19, immunotherapy of tumor, after chimeric antigen receptor T (CAR-T) therapy, and in monogenic disorders and autoimmune diseases. Particularly, severe CRS is a very significant and life-threatening complication, which is clinically characterized by persistent high fever, hyperinflammation, and severe organ dysfunction. However, CRS is a double-edged sword, which may be both helpful in controlling tumors/viruses/infections and harmful to the host. Although a high incidence and high levels of cytokines are features of CRS, the detailed kinetics and specific mechanisms of CRS in human diseases and intervention therapy remain unclear. In the present review, we have summarized the most recent advances related to the clinical features and management of CRS as well as cutting-edge technologies to elucidate the mechanisms of CRS. Considering that CRS is the major adverse event in human diseases and intervention therapy, our review delineates the characteristics, kinetics, signaling pathways, and potential mechanisms of CRS, which shows its clinical relevance for achieving both favorable efficacy and low toxicity., (© 2021. The Author(s).)

Provoked by sterile/nonsterile insults, prolonged monocyte mobilization and uncontrolled monocyte/macrophage activation can pose imminent or impending harm to the affected organs. Curiously, folate receptor beta (FRβ), with subnanomolar affinity for the vitamin folic acid (FA), is upregulated during immune activation in hematopoietic cells of the myeloid lineage. This phenomenon has inspired a strong interest in exploring FRβ-directed diagnostics/therapeutics. Previously, we have reported that FA-targeted aminopterin (AMT) therapy can modulate macrophage function and effectively treat animal models of inflammation. Our current investigation of a lead compound (EC2319) leads to discovery of a highly FR-specific mechanism of action independent of the root causes against inflammatory monocytes. We further show that EC2319 suppresses interleukin-6/interleukin-1β release by FRβ + monocytes in a triple co-culture leukemic model of cytokine release syndrome with anti-CD19 chimeric antigen receptor T cells. Because of its chemical stability and metabolically activated linker, EC2319 demonstrates favorable pharmacokinetic characteristics and cross-species translatability to support future pre-clinical and clinical development., Competing Interests: I.R.V., C.P.L., F.Y., P.J.K., and Y.J.L. hold a patent in Japan (JP 6772186) for the design and synthesis of EC2319. There is a patent pending in the United States., (© 2021 Novartis Pharmaceuticals.)

Innate and adaptive immune responses have a well-known link and represent the distinctive origins of several diseases, many of which may be the consequence of the loss of balance between these two responses. Indeed, autoinflammation and autoimmunity represent the two extremes of a continuous spectrum of pathologic conditions with numerous overlaps in different pathologies. A common characteristic of these dysregulations is represented by hyperinflammation, which is an exaggerated response of the immune system, especially involving white blood cells, macrophages, and inflammasome activation with the hyperproduction of cytokines in response to various triggering stimuli. Moreover, hyperinflammation is of great interest, as it is one of the main manifestations of COVID-19 infection, and the cytokine storm and its most important components are the targets of the pharmacological treatments used to combat COVID-19 damage. In this context, the purpose of our review is to provide a focus on the pathogenesis of autoinflammation and, in particular, of hyperinflammation in order to generate insights for the identification of new therapeutic targets and strategies.

Ocular HSV-1 infection is a major cause of eye disease and innate and adaptive immunity both play a role in protection and pathology associated with ocular infection. Previously we have shown that M1-type macrophages are the major and earliest infiltrates into the cornea of infected mice. We also showed that HSV-1 infectivity in the presence and absence of M2-macrophages was similar to wild-type (WT) control mice. However, it is not clear whether the absence of M1 macrophages plays a role in protection and disease in HSV-1 infected mice. To explore the role of M1 macrophages in HSV-1 infection, we used mice lacking M1 activation (M1-/- mice). Our results showed that macrophages from M1-/- mice were more susceptible to HSV-1 infection in vitro than were macrophages from WT mice. M1-/- mice were highly susceptible to ocular infection with virulent HSV-1 strain McKrae, while WT mice were refractory to infection. In addition, M1-/- mice had higher virus titers in the eyes than did WT mice. Adoptive transfer of M1 macrophages from WT mice to M1-/- mice reduced death and rescued virus replication in the eyes of infected mice. Infection of M1-/- mice with avirulent HSV-1 strain KOS also increased ocular virus replication and eye disease but did not affect latency-reactivation seen in WT control mice. Severity of virus replication and eye disease correlated with significantly higher inflammatory responses leading to a cytokine storm in the eyes of M1-/- infected mice that was not seen in WT mice. Thus, for the first time, our study illustrates the importance of M1 macrophages specifically in primary HSV-1 infection, eye disease, and survival but not in latency-reactivation., Competing Interests: The authors have declared that no competing interests exist.

Multisystem inflammatory syndrome in children (MIS-C) manifests as a severe and uncontrolled inflammatory response with multiorgan involvement, occurring weeks after SARS-CoV-2 infection. Here, we utilized proteomics, RNA sequencing, autoantibody arrays, and B cell receptor (BCR) repertoire analysis to characterize MIS-C immunopathogenesis and identify factors contributing to severe manifestations and intensive care unit admission. Inflammation markers, humoral immune responses, neutrophil activation, and complement and coagulation pathways were highly enriched in MIS-C patient serum, with a more hyperinflammatory profile in severe than in mild MIS-C cases. We identified a strong autoimmune signature in MIS-C, with autoantibodies targeted to both ubiquitously expressed and tissue-specific antigens, suggesting autoantigen release and excessive antigenic drive may result from systemic tissue damage. We further identified a cluster of patients with enhanced neutrophil responses as well as high anti-Spike IgG and autoantibody titers. BCR sequencing of these patients identified a strong imprint of antigenic drive with substantial BCR sequence connectivity and usage of autoimmunity-associated immunoglobulin heavy chain variable region (IGHV) genes. This cluster was linked to a TRBV11-2 expanded T cell receptor (TCR) repertoire, consistent with previous studies indicating a superantigen-driven pathogenic process. Overall, we identify a combination of pathogenic pathways that culminate in MIS-C and may inform treatment.

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), resulted in an unprecedented global crisis. Although primarily a respiratory illness, dysregulated immune responses may lead to multi-organ dysfunction. Prior data showed that the resident microbial communities of gastrointestinal and respiratory tracts act as modulators of local and systemic inflammatory activity (the gut-lung axis). Evolving evidence now signals an alteration in the gut microbiome, brought upon either by cytokines from the infected respiratory tract or from direct infection of the gut, or both. Dysbiosis leads to a "leaky gut". The intestinal permeability then allows access to bacterial products and toxins into the circulatory system and further exacerbates the systemic inflammatory response. In this review, we discuss the available data related to the role of the gut microbiome in the development and progression of COVID-19. We provide mechanistic insights into early data with a focus on immunological crosstalk and the microbiome's potential as a biomarker and therapeutic target., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hussain, Cher, Abid and Abid.)

Chimeric antigen receptor (CAR) T cell therapy has shown unprecedented success in treating advanced hematological malignancies. Its effectiveness in solid tumors has been limited due to heterogeneous antigen expression, a suppressive tumor microenvironment, suboptimal trafficking to the tumor site and poor CAR T cell persistence. Several approaches have been developed to overcome these obstacles through various strategies including the genetic engineering of CAR T cells to blunt the signaling of immune inhibitory receptors as well as to modulate signaling of cytokine/chemokine molecules and their receptors. In this review we offer our perspective on how genetically modifying cytokine/chemokine molecules and their receptors can improve CAR T cell qualities such as functionality, persistence (e.g. resistance to pro-apoptotic signals) and infiltration into tumor sites. Understanding how such modifications can overcome barriers to CAR T cell effectiveness will undoubtedly enhance the potential of CAR T cells against solid tumors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ghahri-Saremi, Akbari, Soltantoyeh, Hadjati, Ghassemi and Mirzaei.)

Cancer therapy reduces tumor burden via tumor cell death ("debris"), which can accelerate tumor progression via the failure of inflammation resolution. Thus, there is an urgent need to develop treatment modalities that stimulate the clearance or resolution of inflammation-associated debris. Here, we demonstrate that chemotherapy-generated debris stimulates metastasis by up-regulating soluble epoxide hydrolase (sEH) and the prostaglandin E 2 receptor 4 (EP4). Therapy-induced tumor cell debris triggers a storm of proinflammatory and proangiogenic eicosanoid-driven cytokines. Thus, targeting a single eicosanoid or cytokine is unlikely to prevent chemotherapy-induced metastasis. Pharmacological abrogation of both sEH and EP4 eicosanoid pathways prevents hepato-pancreatic tumor growth and liver metastasis by promoting macrophage phagocytosis of debris and counterregulating a protumorigenic eicosanoid and cytokine storm. Therefore, stimulating the clearance of tumor cell debris via combined sEH and EP4 inhibition is an approach to prevent debris-stimulated metastasis and tumor growth., Competing Interests: Competing interest statement: Y.S., K.-K.H., X.Y., and B.D.H. work with Ionova and EicOsis, respectively, on the development of EP4 and epoxide hydrolase inhibitors for clinical use. D.P., A.G., and B.D.H., and colleagues C. N. Serhan and P. Sime were coauthors on an earlier commentary suggesting modulating the eicosanoid and cytokine storms with a soluble epoxide hydrolase inhibitor to modulate severity of COVID infections, introducing the same mechanism as is suggested here for reduction of the cytokine storm following cancer therapy., (Copyright © 2021 the Author(s). Published by PNAS.)

Tumor progression locus 2 (Tpl2) is a serine-threonine kinase known to promote inflammation in response to various pathogen-associated molecular patterns (PAMPs), inflammatory cytokines and G-protein-coupled receptors and consequently aids in host resistance to pathogens. We have recently shown that Tpl2 -/- mice succumb to infection with a low-pathogenicity strain of influenza (x31, H3N2) by an unknown mechanism. In this study, we sought to characterize the cytokine and immune cell profile of influenza-infected Tpl2 -/- mice to gain insight into its host protective effects. Although Tpl2 -/- mice display modestly impaired viral control, no virus was observed in the lungs of Tpl2 -/- mice on the day of peak morbidity and mortality suggesting that morbidity is not due to virus cytopathic effects but rather to an overactive antiviral immune response. Indeed, increased levels of interferon-β (IFN-β), the IFN-inducible monocyte chemoattractant protein-1 (MCP-1, CCL2), Macrophage inflammatory protein 1 alpha (MIP-1α; CCL3), MIP-1β (CCL4), RANTES (CCL5), IP-10 (CXCL10) and Interferon-γ (IFN-γ) was observed in the lungs of influenza-infected Tpl2 -/- mice at 7 days post infection (dpi). Elevated cytokine and chemokines were accompanied by increased infiltration of the lungs with inflammatory monocytes and neutrophils. Additionally, we noted that increased IFN-β correlated with increased CCL2, CXCL1 and nitric oxide synthase (NOS2) expression in the lungs, which has been associated with severe influenza infections. Bone marrow chimeras with Tpl2 ablation localized to radioresistant cells confirmed that Tpl2 functions, at least in part, within radioresistant cells to limit pro-inflammatory response to viral infection. Collectively, this study suggests that Tpl2 tempers inflammation during influenza infection by constraining the production of interferons and chemokines which are known to promote the recruitment of detrimental inflammatory monocytes and neutrophils., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Latha, Jamison and Watford.)

The mortality risk of coronavirus disease 2019 (COVID-19) patients has been linked to the cytokine storm caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Understanding the inflammatory responses shared between COVID-19 and other infectious diseases that feature cytokine storms may therefore help in developing improved therapeutic strategies. Here, we use integrative analysis of single-cell transcriptomes to characterize the inflammatory signatures of peripheral blood mononuclear cells from patients with COVID-19, sepsis, and HIV infection. We identify ten hyperinflammatory cell subtypes in which monocytes are the main contributors to the transcriptional differences in these infections. Monocytes from COVID-19 patients share hyperinflammatory signatures with HIV infection and immunosuppressive signatures with sepsis. Finally, we construct a "three-stage" model of heterogeneity among COVID-19 patients, related to the hyperinflammatory and immunosuppressive signatures in monocytes. Our study thus reveals cellular and molecular insights about inflammatory responses to SARS-CoV-2 infection and provides therapeutic guidance to improve treatments for subsets of COVID-19 patients., Competing Interests: Declaration of interests Jingwen Fang is the chief executive officer of HanGen Biotech. The other authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

The coronavirus disease 2019 (COVID-19) pandemic is an ongoing global health crisis causing major challenges for clinical care in patients with gastrointestinal diseases. Although triggering of anti-viral immune responses is essential for clearance of infection, some patients have severe lung inflammation and multiorgan failure due to marked immune cell dysregulation and cytokine storm syndrome. Importantly, the activation of cytotoxic follicular helper T cells and a reduction of regulatory T cells have a crucial, negative prognostic role. These findings lead to the question of whether immunosuppressive and biologic therapies for gastrointestinal diseases affect the incidence or prognosis of COVID-19 and, thus, whether they should be adjusted to prevent or affect the course of the disease. In this Review, data on the use of such therapies are discussed with a primary focus on inflammatory bowel disease, autoimmune hepatitis and liver transplantation. In particular, the roles of corticosteroids, classic immunosuppressive agents (such as thiopurines and mycophenolate mofetil), small molecules (such as Janus kinase (JAK) inhibitors), and biologic agents (such as tumour necrosis factor (TNF) blockers, vedolizumab and ustekinumab) are reviewed. Finally, the use of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines for the prevention of infection in patients with gastrointestinal diseases and concomitant immunosuppressive or biologic therapy will be discussed., (© 2021. Springer Nature Limited.)

Serious bacterial infections (SBI) can lead to devastating complications with CD19 CAR T cells and cytokine release syndrome (CRS). Little is known about consequences of and risk factors for SBI with novel CAR T-cell constructs or with CRS complicated by HLH-like toxicities. We report on three patients with B-cell acute lymphoblastic leukemia treated with CD22 CAR T cells who developed SBI and CRS-associated HLH. Serum cytokine profiling revealed sustained elevations well beyond CRS resolution, suggesting ongoing systemic inflammation. Heightened inflammatory states converging with SBI contribute to poor outcomes, and recognition and prevention of extended inflammation may be needed to improve outcomes., (© 2021 Wiley Periodicals LLC.)