IL-25 blockade augments antiviral immunity during respiratory virus infection.

IL-25 is implicated in the pathogenesis of viral asthma exacerbations. However, the effect of IL-25 on antiviral immunity has yet to be elucidated. We observed abundant expression and colocalization of IL-25 and IL-25 receptor at the apical surface of uninfected airway epithelial cells and rhinovirus infection increased IL-25 expression. Analysis of immune transcriptome of rhinovirus-infected differentiated asthmatic bronchial epithelial cells (BECs) treated with an anti-IL-25 monoclonal antibody (LNR125) revealed a re-calibrated response defined by increased type I/III IFN and reduced expression of type-2 immune genes CCL26, IL1RL1 and IL-25 receptor. LNR125 treatment also increased type I/III IFN expression by coronavirus infected BECs. Exogenous IL-25 treatment increased viral load with suppressed innate immunity. In vivo LNR125 treatment reduced IL-25/type 2 cytokine expression and increased IFN-ß expression and reduced lung viral load. We define a new immune-regulatory role for IL-25 that directly inhibits virus induced airway epithelial cell innate anti-viral immunity.

A Biological Insight into the Susceptibility to Influenza Infection in Junior Rats by Comprehensive Analysis of lncRNA Profiles.

Long noncoding RNAs (lncRNAs) have been reported to participate in regulating many biological processes, including immune response to influenza A virus (IAV). However, the association between lncRNA expression profiles and influenza infection susceptibility has not been well elucidated. Here, we analyzed the expression profiles of lncRNAs, miRNAs, and mRNAs among IAV-infected adult rat (IAR), normal adult rat (AR), IAV-infected junior rat (IJR), and normal junior rat (JR) by RNA sequencing. Compared with differently expressed lncRNAs (DElncRNAs) between AR and IAR, 24 specific DElncRNAs were found between IJR and JR. Then, based on the fold changes and P value, the top 5 DElncRNAs, including 3 upregulated and 2 downregulated lncRNAs, were chosen to establish a ceRNA network for further disclosing their regulatory mechanisms. To visualize the differentially expressed genes in the ceRNA network, GO and KEGG pathway analysis was performed to further explore their roles in influenza infection of junior rats. The results showed that the downregulated DElncRNA-target genes were mostly enriched in the IL-17 signaling pathway. It indicated that the downregulated lncRNAs conferred the susceptibility of junior rats to IAV via mediating the IL-17 signaling pathway.

Interleukin-17A (IL-17A): A silent amplifier of COVID-19.

One of the hallmarks of COVID-19 is the cytokine storm that provokes primarily pneumonia followed by systemic inflammation. Emerging evidence has identified a potential link between elevated interleukin-17A (IL-17A) levels and disease severity and progression. Considering that per se, IL-17A can activate several inflammatory pathways, it is plausible to hypothesize an involvement of this cytokine in COVID-19 clinical outcomes. Thus, IL-17A could represent a marker of disease progression and/or a target to develop therapeutic strategies. This hypothesis paper aims to propose this "unique" cytokine as a silent amplifier of the COVID-19 immune response and (potentially) related therapy.

Bioinformatic analyses suggest augmented interleukin-17 signaling as the mechanism of COVID-19-associated herpes zoster.

Herpes zoster results from latent varicella zoster virus reactivation in the dorsal root ganglia, causing blistering rash along the dermatomal distribution and post-herpetic neuralgia. Increasing studies indicated that there may be a correlation between herpes zoster and COVID-19. Nevertheless, the detailed pathophysiological mechanism is still unclear. We used bioinformatic analyses to study the potential genetic crosstalk between herpes zoster and COVID-19. COVID-19 and herpes zoster were associated with a similar subset of genes involved in "cytokine-cytokine receptor interaction," "Jak-STAT signaling pathway," and "IL-17 signaling pathway," including TNF, IL10, ESR1, INFG, HLA-A, CRP, STAT3, IL6, IL7, and IL17A. Protein-protein interaction network assay showed that the combined gene set indicated a raised connectivity as compared to herpes zoster or COVID-19 alone, particularly the potentiated interactions with APOE, ARSA, CCR2, CCR5, CXCL13, EGFR, GAL, GP2, HLA-B, HLA-DRB1, IL5, TECTA, and THBS1, and these genes are related to "cytokine-cytokine receptor interaction". Augmented Th17 cell differentiation and the resulting enhanced IL-17 signaling were identified in both COVID-19 and herpes zoster. Our data suggested aberrant interleukin-17 signaling as one possible mechanism through which COVID-19 could raise the risk of herpes zoster.

Anti-IL-17 monoclonal antibodies in hospitalized patients with severe COVID-19: A pilot study.

BACKGROUND: One of the main pathophysiological mechanisms underlying the severe course of COVID-19 is the hyper-inflammatory syndrome associated with progressive damage of lung tissue and multi-organ dysfunction. IL-17 has been suggested to be involved in hyper-inflammatory syndrome. OBJECTIVE: To evaluate the efficacy and safety of the IL-17 inhibitor netakimab in patients with severe COVID-19. STUDY DESIGN: In our retrospective case-control study we evaluated the efficacy of netakimab in hospitalized patients with severe COVID-19 outside the intensive care unit (ICU). Patients in the experimental group were treated with standard of care therapy and netakimab at a dose of 120 mg subcutaneously. RESULTS: 171 patients with severe COVID-19 were enrolled in our study, and 88 of them received netakimab. On the 3 day of therapy, body temperature, SpO2/FiO2, NEWS2 score, and CRP improved significantly in the netakimab group compared to the control group. Other clinical outcomes such as transfer to ICU (11.4% vs 9.6%), need for mechanical ventilation (10.2% vs 9.6%), 28-day mortality (10.2% vs 8.4%), did not differ between the groups. CONCLUSION: In hospitalized patients with severe COVID-19, anti-IL-17 therapy might mitigate the inflammatory response and improve oxygenation, but do not affect the need for mechanical ventilation and mortality.

Lung Neutrophilic Recruitment and IL-8/IL-17A Tissue Expression in COVID-19.

The new SARS-CoV-2 virus differs from the pandemic Influenza A virus H1N1 subtype (H1N1pmd09) how it induces a pro-inflammatory response in infected patients. This study aims to evaluate the involvement of SNPs and tissue expression of IL-17A and the neutrophils recruitment in post-mortem lung samples from patients who died of severe forms of COVID-19 comparing to those who died by H1N1pdm09. Twenty lung samples from patients SARS-CoV-2 infected (COVID-19 group) and 10 lung samples from adults who died from a severe respiratory H1N1pdm09 infection (H1N1 group) were tested. The tissue expression of IL-8/IL-17A was identified by immunohistochemistry, and hematoxylin and eosin (H&E) stain slides were used for neutrophil scoring. DNA was extracted from paraffin blocks, and genotyping was done in real time-PCR for two IL17A target polymorphisms. Tissue expression increasing of IL-8/IL-17A and a higher number of neutrophils were identified in samples from the H1N1 group compared to the COVID-19 group. The distribution of genotype frequencies in the IL17A gene was not statistically significant between groups. However, the G allele (GG and GA) of rs3819025 was correlated with higher tissue expression of IL-17A in the COVID-19 group. SARS-CoV-2 virus evokes an exacerbated response of the host's immune system but differs from that observed in the H1N1pdm09 infection since the IL-8/IL-17A tissue expression, and lung neutrophilic recruitment may be decreased. In SNP rs3819025 (G/A), the G allele may be considered a risk allele in the patients who died for COVID-19.

Neutrophils mediate Th17 promotion in COVID-19 patients.

From the beginning of 2020, an urgent need to understand the pathophysiology of SARS-CoV-2 disease (COVID-19), much of which is due to dysbalanced immune responses, resonates across the world. COVID-19-associated neutrophilia, increased neutrophil-to-lymphocyte ratio, aberrant neutrophil activation, and infiltration of neutrophils into lungs suggest that neutrophils are important players in the disease immunopathology. The main objective of this study was to assess the phenotypic and functional characteristics of neutrophils in COVID-19 patients, with particular focus on the interaction between neutrophils and T cells. We hypothesize that the altered functional characteristics of COVID-19 patient-derived neutrophils result in skewed Th1/Th17 adaptive immune response, thus contributing to disease pathology. The expansion of G-MDSC and immature forms of neutrophils was shown in the COVID-19 patients. In the COVID-19 neutrophil/T cell cocultures, neutrophils caused a strong polarity shift toward Th17, and, conversely, a reduction of IFNγ-producing Th1 cells. The Th17 promotion was NOS dependent. Neutrophils, the known modulators of adaptive immunity, skew the polarization of T cells toward the Th17 promotion and Th1 suppression in COVID-19 patients, contributing to the discoordinated orchestration of immune response against SARS-CoV-2. As IL-17 and other Th17-related cytokines have previously been shown to correlate with the disease severity, we suggest that targeting neutrophils and/or Th17 represents a potentially beneficial therapeutic strategy for severe COVID-19 patients.

Dynamics of cytokines and lymphocyte subsets associated with the poor prognosis of severe COVID-19.

OBJECTIVE: We aimed to study the dynamics of cytokines and lymphocyte subsets and their correlation with the prognosis of patients with severe COVID-19. PATIENTS AND METHODS: The lymphocyte subsets and cytokines of 31 patients with severe COVID-19 (7 deaths and 24 survivals) were longitudinally analyzed. RESULTS: The mean age of enrolled patients was 64 years, 24 (77.4%) patients were men, and 23 (74.2%) patients had comorbidities. Compared with survival group, the death group showed significant and sustained increases in the levels of IL-6, IL-8, and IL-10 from baseline to 28 days after admission (all p<0.05). No significant differences were observed in the levels of TNF-α, IL-1b, IL-2, IL-4, IL-5, IL-12P70, IL-17, IFN-α, and IFN-γ between the death group and survival group during the follow-up (all p>0.05). The absolute counts of CD3+ T cells, CD4+ T cells, CD8+ T cells, and CD45+ T cells were lower in both survival group and death group patients from hospital admission to 3 days after admission, and gradually recovered in 4 to 35 days in the survival group, but continually stayed at low levels in the death group during the follow-up. CONCLUSIONS: The kinetic changes of cytokines and lymphocyte subsets are related with the prognosis of patients with severe COVID-19.

Safety and Efficacy of Ixekizumab and Antiviral Treatment for Patients with COVID-19: A structured summary of a study protocol for a Pilot Randomized Controlled Trial.

OBJECTIVES: A severe epidemic of COVID-19 has broken out in China and has become a major global public health event. We focus on the Acute Respiratory Distress Syndrome (ARDS)-like changes and overactivation of Th17 cells (these produce cytokines) in patients with COVID-19. We aim to explore the safety and efficacy of ixekizumab (an injectable drug for the treatment of autoimmune diseases) to prevent organ injury caused by the immune response to COVID-19. Ixekizumab is a human monoclonal antibody that binds to interleukin-17A and inhibits the release of pro-inflammatory cytokines and chemokines. TRIAL DESIGN: The experiment is divided into two stages. In the first stage, the open trial, 3 patients with COVID-19 are treated with ixekizumab, and the safety and efficacy are observed for 7 days. In the second stage, 40 patients with COVID-19 are randomly divided into two groups at 1:1 for 14 days. This is a two-center, open-label, randomized controlled pilot trial with 2-arm parallel group design (1:1 ratio). PARTICIPANTS: Patients with COVID-19 aged 18-75 with increased Interleukin (IL)-6 levels will be enrolled, but patients with severe infections requiring intensive care will be excluded. The trial will be undertaken in two centers. The first stage is carried out in Xiangya Hospital of Central South University, and the second stage is carried out simultaneously in the Third Xiangya Hospital of Central South University. INTERVENTION AND COMPARATOR: In the first stage, three subjects are given ixekizumab ("Taltz") (80 mg/ml, 160 mg as a single hypodermic injection) and antiviral therapy (α-interferon (administer 5 million U by aerosol inhalation twice daily), lopinavir/ritonavir (administer 100mg by mouth twice daily, for the course of therapy no more than 10 days), chloroquine (administer 500mg by mouth twice daily, for the course of therapy no more than 10 days), ribavirin (administer 500mg by intravenous injection two to three times a day, for the course of therapy no more than 10 days), or arbidol (administer 200mg by mouth three times a day, for the course of therapy no more than 10 days), but not more than 3 types). The treatment course of the first stage is 7 days. In the second stage, 40 randomized patients will receive the following treatments--Group 1: ixekizumab (80 mg/ml, 160 mg as a single hypodermic injection) with antiviral therapy (the same scheme as in the first stage); Group 2: antiviral therapy alone (the same scheme as in the first stage). The length of the second treatment course is 14 days. MAIN OUTCOMES: The primary outcome is a change in pulmonary CT severity score (an imaging tool for assessing COVID-19, which scores on the basis of all abnormal areas involved). Pulmonary CT severity score is assessed on the 7th day, 14th day, or at discharge. RANDOMISATION: In the second stage, 40 patients with COVID-19 are randomly divided into two groups at 1:1 for 14 days. The eLite random system of Nanjing Medical University is used for randomization. BLINDING (MASKING): The main efficacy indicator, the CT results, will be evaluated by the third-party blinded and independent research team. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): In the second stage, 40 patients with COVID-19 are randomly divided into two groups at 1:1 for 14 days. TRIAL STATUS: Trial registration number is ChiCTR2000030703 (version 1.7 as of March 19, 2020). The recruitment is ongoing, and the date recruitment was initiated in June 2020. The anticipated date of the end of data collection is June 2021. TRIAL REGISTRATION: The name of the trial register is the Chinese Clinical Trial Registry. The trial registration number is ChiCTR2000030703 ( http://www.chictr.org.cn/ ). The date of trial registration is 10 March 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting the dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

Status of a real-life cohort of patients with moderate-to-severe plaque psoriasis treated with secukinumab and considerations on the use of biological agents in the Covid-19 era.

INTRODUCTION: In light of the current Covid-19 pandemic and the ongoing, extensive debate about the use of biological agents in psoriatic patients, we felt compelled to relate our experience in the use of secukinumab in the same cohort before and during the lockdown in Italy. Areas covered: Secukinumab was not discontinued, and there were no cases of confirmed infection with SARS-CoV-2 in this cohort. Expert opinion: In our practice, there is no evidence favoring the discontinuation of secukinumab in these patients. We also present a brief commentary on the use of biological agents in patients with moderate-to-severe plaque psoriasis.

Severe Acute Respiratory Syndrome-Coronavirus-2 Infection and Patients With Lung Cancer: The Potential Role of Interleukin-17 Target Therapy.

The coronavirus disease 2019 outbreak is evolving rapidly worldwide. The lungs are the target of the primary infection and patients with lung cancer seem to have a poor prognosis. To our knowledge, this is the first reported investigation of a possible role of interleukin-17 target therapy in patients with lung cancer and concomitant severe acute respiratory syndrome-coronavirus-2 infection.