Eosinophil-mediated lung inflammation associated with elevated natural killer T cell response in COVID-19 patients

Background/Aims@#Coronavirus disease 2019 (COVID-19) is associated with acute respiratory syndrome. The mechanisms underlying the different degrees of pneumonia severity in patients with COVID-19 remain elusive. This study provides evidence that COVID-19 is associated with eosinophil-mediated inflammation. @*Methods@#We performed a retrospective case series of three patients with laboratory and radiologically confirmed COVID-19 pneumonia admitted to Chosun University Hospital. Demographic and clinical data on inflammatory cell lung infiltration and cytokine levels in patients with COVID-19 were collected. @*Results@#Cytological analysis of sputum, tracheal aspirates, and bronchoalveolar lavage fluid (BALF) samples from all three patients revealed massive infiltration of polymorphonuclear cells (PMNs), such as eosinophils and neutrophils. All sputum and BALF specimens contained high levels of eosinophil cationic proteins. The infiltration of PMNs into the lungs, together with elevated levels of natural killer T (NKT) cells in BALF and peripheral blood samples from patients with severe pneumonia in the acute phase was confirmed by flow cytometry. @*Conclusions@#These results suggest that the lungs of COVID-19 patients can exhibit eosinophil-mediated inflammation, together with an elevated NKT cell response, which is associated with COVID-19 pneumonia.

Kinetics of Neutralizing Antibody Responses Against SARS-CoV-2 Delta Variant in Patients Infected at the Beginning of the Pandemic

We investigated the kinetics of the neutralizing antibody responses to the severe acute respiratory syndrome-coronavirus-2 delta variant over the course of 1 year in 16 patients infected at the beginning of the pandemic. In patients with severe disease, neutralizing responses to the delta variant were detectable, albeit at lower levels than responses to the wild type. Neutralizing responses to the delta variant were undetectable, however, in asymptomatic persons. This finding implies that the vaccination strategy for persons with past natural infection should depend on the severity of the previous infection.

Outbreaks of Middle East Respiratory Syndrome in Two Hospitals Initiated by a Single Patient in Daejeon, South Korea / 감염과화학요법

BACKGROUND: A Middle East Respiratory Syndrome coronavirus (MERS-CoV) outbreak in South Korea in 2015 started by a single imported case and was amplified by intra- and inter-hospital transmission. We describe two hospital outbreaks of MERS-CoV infection in Daejeon caused by a single patient who was infected by the first Korean case of MERS. MATERIALS AND METHODS: Demographic and clinical information involving MERS cases in the Daejeon cluster were retrospectively collected and potential contacts and exposures were assessed. The incubation periods and serial intervals were estimated. Viral RNAs were extracted from respiratory tract samples obtained from the index case, four secondary cases and one tertiary case from each hospital. The partial S2 domain of the MERS-CoV spike was sequenced. RESULTS: In Daejeon, a MERS patient (the index case) was hospitalized at Hospital A in the first week of illness and was transferred to Hospital B because of pneumonia progression in the second week of illness, where he received a bronchoscopic examination and nebulizer therapy. A total of 23 secondary cases (10 in Hospital A and 13 in Hospital B) were detected among patients and caregivers who stayed on the same ward with the index case. There were no secondary cases among healthcare workers. Among close hospital contacts, the secondary attack rate was 15.8% (12/76) in Hospital A and 14.3% (10/70) in Hospital B. However, considering the exposure duration, the incidence rate was higher in Hospital B (7.7/100 exposure-days) than Hospital A (3.4/100 exposure-days). In Hospital B, the median incubation period was shorter (4.6 days vs. 10.8 days), the median time to pneumonia development was faster (3 days vs. 6 days) and mortality was higher (70% vs. 30.8%) than in Hospital A. MERS-CoV isolates from 11 cases formed a single monophyletic clade, with the closest similarity to strains from Riyadh. CONCLUSION: Exposure to the MERS case in the late stage (2nd week) of diseases appeared to increase the risk of transmission and was associated with shorter incubation periods and rapid disease progression among those infected. Early detection and isolation of cases is critical in preventing the spread of MERS in the hospital and decreasing the disease severity among those infected.

Role of Th17 and Treg during the Chronic Infection of Hepatitis C Virus

Hepatitis C virus (HCV) is one of the main causes of liver disease. 1~2% of the Korean people has been reported to be infected by HCV. Although HCV is less infectious than hepatitis B virus (HBV), it is more prone to develop chronic infection (~ 80%) which may link to cirrhosis and hepatocellular carcinogenesis. In addition, prevalence of hepatitis caused by HCV infection is gradually increased every year in Korea. Recently, a large number of clinical trials using direct-acting antiviral (DAA) drugs have been shown efficient therapeutic results for chronic HCV infections and some of them are on the market. However, there is still a concern on viral evasion to the DAAs and the effective mechanisms of immunological clearance of HCV remains to be elucidated. Here, we introduce the recent findings on the role of Th17-Treg axis which may play a critical role of the viral pathogenesis and/or immunological defense against HCV infection. The underlying regulatory mechanisms of Th17-Treg axis might be a potential candidate for the better control of HCV chronic infections.

Role of Type I Interferon during Bacterial Infection

Type 1 Interferons (T1 IFN) play a pivotal role in innate immune responses against viral infection. Recently, this anti-viral cytokines are shown to be induced during bacterial infections via activation of various pattern recognition receptors (PRRs) including Toll-like receptors, RIG-I-like receptors, or NOD-like receptors. Signaling mediators such as MyD88, TRIF, MAVS, STING, or RIP2 of the receptor signaling pathways are also involved in T1 IFN responses depending on the bacterial species and their ligands. However, role of T1 IFN in anti-bacterial immunity is still obscure and its effect on immunological pathogenesis during bacterial infection has been controversial. It has been reported that T1 IFN could provide protective effect on several bacterial infections but it also aggravates pathogenic situation during some intracellular pathogens or secondary bacterial infection after respiratory viral infection. Here, we summarize recent findings how T1 IFN is induced by various bacterial pathogens and discuss the potential effect of T1 IFN responses on immune responses against bacterial infection.

Molecular Characterization of sca Genes Found in Orientia tsutsugamushi Genome

Scrub typhus is an acute, febrile illness caused by Orientia tsutsugamushi infection and it is one of the main causes of acute febrile illness in the Asian-Pacific region. The incidence of scrub typhus has been significantly increased in Korea during last 10 years. Although early diagnosis and proper antibiotic treatment are important to prevent severe complications, the clinical discrimination of scrub typhus from other undifferentiated fevers, such as leptospirosis or dengue fever, is often very difficult. In addition, an effective vaccine has not yet been developed. As a novel diagnostic and vaccine target for scrub typhus, we described surface cell antigen (sca) family genes encoding autotransporter proteins found in the genome of O. tsutsugamushi. The molecular characteristics and recent findings on the bacterial genes were introduced in this letter.

Cellular and Systemic Interactions of Orientia tsutsugamushi with Mammalian Host

Scrub typhus is an acute febrile illness caused by Orientia tsutsugamushi infection and one of main causes of febrile illness in the Asia-Pacific region. It has been estimated that one billion people are at risk and one million new cases arise each year in the endemic region. Despite of aggressive attempts to develop a prophylactic vaccine against scrub typhus during last several decades, all approaches have failed to generate long lasting immunity. In addition, little is known about the immunological pathogenesis of scrub typhus. In this review, we summarized recent findings of cellular and systemic interaction of O. tsutsugamushi with mammalian host, especially focusing on the molecular basis of intracellular invasion and immunological changes observed during the bacterial infection.

Multi-transmembrane protein K15 of Kaposi's sarcoma-associated herpesvirus targets Lyn kinase in the membrane raft and induces NFAT/AP1 activities

Viral proteins of gamma-2 herpesviruses, such as LMP2A of Epstein Barr virus (EBV) and Tip of herpesvirus saimiri (HVS) dysregulate lymphocyte signaling by interacting with Src family kinases. K15 open reading frame of Kaposi's sarcoma associated herpesvirus (KSHV), located at the right end of the viral genome, encodes several splicing variants differing in numbers of transmembrane domains. Previously, we demonstrated that the cytoplasmic tail of the K15 protein interfered with B cell receptor signal transduction to cellular tyrosine phosphorylation and calcium mobilization. However, the detailed mechanism underlying this phenomenon was not understood. In the C-terminal cytoplasmic region of K15, putative binding domains for Src-SH2 and -SH3 were identified. In this study, we attempted to characterize these modular elements and cellular binding protein(s) by GST pull down and co-immunoprecipitation assays. These studies revealed that K15 interacted with the major B cell tyrosine kinase Lyn. In vitro kinase and transient co-expression assays showed that the expression of K15 protein resulted in activation of Lyn kinase activity. In addition, GST pull down assay suggested that the SH2 domain of Lyn alone was necessary for interaction with the C-terminal SH2B (YEEV) of K15, but the addition of Lyn SH3 to the SH2 domain increases the binding affinity to K15 protein. The data from luciferase assays indicate that K15 expression in BJAB cells induced NFAT and AP1 activities. The tyrosine residue in the C-terminal end of K15 required for the Lyn interaction appeared to be essential for NFAT/AP1 activation, highlighting the significance of the C-terminal SH2B of K15 as a modular element in interfering with B lymphocyte signaling through interaction with Lyn kinase.

The Profiles of Plasma Chemokines Following Unrelated Allogeneic Bone Marrow Transplantation and Their Relationship to Transplant-Related Complications

Chemokines are a family of closely related chemotactic cytokines known to be potent attractors for various leukocyte subsets such as neutrophils, monocytes, or lymphocytes. We investigated the chemokine profiles in 26 patients who received unrelated allogeneic bone marrow transplantation (BMT) and evaluated the relationship of chemokines to transplant-related complications. We measured plasma levels of regulated upon activation normal T-cell expressed and secreted (RANTES), macrophage inflammatory protein-1alpha (MIP-1alpha), macrophage inflammatory protein-1beta (MIP-1beta), and interleukin-8 (IL-8) at BMT day -7, day 0, and day 21. When compared with preBMT levels, the mean level of RANTES was significantly decreased at day 21, and the mean level of IL-8 was significantly elevated at day 21. Methotrexate given for graft-versus-host disease (GVHD) prophylaxis and postBMT infectious complication respectively may have contributed to these plasma chemokine level changes. The mean level of IL-8 was significantly higher in patients with infectious complications at day 21 (p=0.009). However, plasma chemokine levels were not associated with the development of acute GVHD and veno-occlusive disease (VOD). Since chemokine production acts in a local manner, plasma levels may not reflect the actual activity of chemokines in target tissue. Further experimental and clinical studies, including chemokine expression in target tissue, are warranted to define the roles of chemokines following allogeneic BMT.