Lambda interferons (IFN-λs) are a major component of the innate immune defense to viruses, bacteria, and fungi. In human liver, IFN-λ not only drives antiviral responses, but also promotes inflammation and fibrosis in viral and non-viral diseases. Here we demonstrate that macrophages are primary responders to IFN-λ, uniquely positioned to bridge the gap between IFN-λ producing cells and lymphocyte populations that are not intrinsically responsive to IFN-λ. While CD14+ monocytes do not express the IFN-λ receptor, IFNLR1, sensitivity is quickly gained upon differentiation to macrophages in vitro. IFN-λ stimulates macrophage cytotoxicity and phagocytosis as well as the secretion of pro-inflammatory cytokines and interferon stimulated genes that mediate immune cell chemotaxis and effector functions. In particular, IFN-λ induced CCR5 and CXCR3 chemokines, stimulating T and NK cell migration, as well as subsequent NK cell cytotoxicity. Using immunofluorescence and cell sorting techniques, we confirmed that human liver macrophages expressing CD14 and CD68 are highly responsive to IFN-λ ex vivo. Together, these data highlight a novel role for macrophages in shaping IFN-λ dependent immune responses both directly through pro-inflammatory activity and indirectly by recruiting and activating IFN-λ unresponsive lymphocytes.

ObjectiveVaccination against hepatitis B virus (HBV) confers protection from subsequent infection through immunological memory that is traditionally considered the domain of the adaptive immune system. This view has been challenged following the identification of antigen-specific memory natural killer cells (mNKs) in mice and non-human primates. While the presence of mNKs has been suggested in humans based on the expansion of NK cells following pathogen exposure, evidence regarding antigen-specificity is lacking. Here, we demonstrate the existence of HBV-specific mNKs in humans after vaccination and in chronic HBV infection.DesignNK cell responses were evaluated by flow cytometry and ELISA following challenge with HBV antigens in HBV vaccinated, non-vaccinated and chronic HBV-infected individuals.ResultsNK cells from vaccinated subjects demonstrated higher cytotoxic and proliferative responses against autologous hepatitis B surface antigen (HBsAg)-pulsed monocyte-derived dendritic cells (moDCs) compared with unvaccinated subjects. Moreover, NK cell lysis of HBsAg-pulsed moDCs was significantly higher than that of hepatitis B core antigen (HBcAg)-pulsed moDCs (non-vaccine antigen) or tumour necrosis factor α-activated moDCs in a NKG2D-dependent manner. The mNKs response was mediated by CD56dim NK cells coexpressing CD57, CD69 and KLRG1. Further, mNKs from chronic hepatitis B patients exhibited greater degranulation against HBcAg-pulsed moDCs compared with unvaccinated or vaccinated patients. Notably, mNK activity was negatively correlated with HBV DNA levels.ConclusionsOur data support the presence of a mature mNKs following HBV antigen exposure either through vaccination or infection. Harnessing these antigen specific, functionally active mNKs provides an opportunity to develop novel treatments targeting HBV in chronic infection.

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Background & aims Coronavirus disease 2019 (COVID-19) has a wide clinical spectrum, ranging from asymptomatic infection to severe diseases with high mortality rate. Early identification of high-risk COVID-19 patients may be beneficial to reduce morbidity and in-hospital mortality. This study aimed to investigate whether baseline levels of inflammatory markers such as C-reactive protein (CRP) and immune-cell-based inflammatory indices, neutrophil to lymphocyte ratio (NLR), derived-NLR (d-NLR), and platelet to lymphocyte ratio (PLR) at hospital admission are associated with adverse disease outcomes in COVID-19 patients. Methods Clinical data from 391 hospitalized COVID-19 patients in three Siloam Hospitals in Indonesia were retrospectively collected and analysed from March 20 to October 30, 2020. Results Fifty-four (13.8%) hospitalized patients had clinical deterioration and required ICU treatment, categorizing them as severe COVID-19 cases. Older age, presence of underlying diseases, and increased inflammatory markers values at admission were significantly associated with severe cases. After adjustment of sociodemographic and comorbidities factors, CRP, NLR, and d-NLR values, but not PLRs, were identified as independent risk factors for disease severity and death in COVID-19 patients. The area under curve (AUC) of CRP, NLR, and d-NLR were 0.854, 0.848, and 0.854, respectively. The optimal cut-off points for CRP, NLR, and d-NLR for identification of COVID-19 patients with potential worse disease outcomes were 47 mg/L, 6, and 4, respectively. Conclusion Initial assessment of CRP, NLR, and d-NLR values at hospital admission may be important predictors for adverse disease outcomes in COVID-19 patients.

Background Healthcare workers (HCWs) compared to the general population are at an increased risk of exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease-19 (COVID-19). Therefore, they are given priority for the COVID-19 vaccine in the national COVID-19 vaccination campaign in Indonesia. However, when the daily new COVID-19 cases are still high, and the data regarding the vaccine’s efficacy in healthcare settings remains unavailable, the vaccinated HCWs still likely to get COVID-19 infection and at risk for further transmission. Objective To identify COVID-19 cases among vaccinated HCWs at Siloam Teaching Hospital, Indonesia, via active and passive surveillance conducted by the hospital’s COVID-19 infection prevention and control unit Results Among 1,040 HCWs who have received the first and second vaccination, 13 (1.25%) HCWs were positive for SARS-CoV-2 RNA detection by reverse-transcriptase polymerase chain reaction (RT-PCR) from 2-11 days (median five days) after the second vaccination. Conclusion The early laboratory-confirmed COVID-19 among post-vaccinated HCWs indicates that HCWs are still at risk to acquire COVID-19 disease during the vaccination campaign. Therefore, the presence of symptoms after vaccination cannot be considered as vaccine-related symptoms, and regular COVID-19 testing should be conducted among HCWs.

Background As healthcare workers (HCWs) are at high risk for SARS-CoV-2 infection, they have prioritized the COVID-19 vaccine. Inactivated SARS-CoV-2 vaccine has been mainly used in Indonesia to induce HCWs antibody response against SARS-CoV-2 infection. However, information regarding the kinetics of antibody-induced by this vaccine remains scarce. Objective To investigate the magnitude and durability of antibodies against spike (S) protein (anti-S) after complete dose of vaccination among HCWs by using the electrochemiluminescence immunoassay. Results Seroconversion of anti-S antibodies was observed among 159 (99.4%) of 160 HCWs after 14 days of full-dose vaccination. The levels of anti-S antibodies significantly decreased after day 42 compared to day 14 post-vaccination, but it persisted up to 98 days following vaccination. In contrast, the vaccinated HCWs with prior SARS-CoV-2 infection had significantly higher and stably elevated anti-S antibodies concentrations than vaccinated HCWs without SARS-CoV-2 infection history. Conclusion The remarkable decline and lower anti-S antibodies concentration among infection-naïve HCWs potentially indicate the additional booster dose of SARS-CoV-2 vaccination may be required to ascertain COVID-19 protection among HCWs by this vaccine. This early study of antibody response induced by inactivated SARS-CoV-2 vaccine among HCWs potentially contributes to the future policy decision regarding vaccination.

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Direct acting antiviral therapies rapidly clear chronic hepatitis C virus (HCV) infection and restore natural killer (NK) cell function. We investigated NK cell memory formation following HCV clearance by examining NK cell phenotype and responses from control and chronic HCV patients before and after therapy following sustained virologic response at 12 weeks post-therapy (SVR12). NK cell phenotype at SVR12 differed significantly from paired pre-treatment samples, with an increase in maturation markers CD16, CD57 and KLRG1. HCV patients possessed stronger cytotoxic responses against HCV infected cells as compared to healthy controls; a response that further increased following SVR12. The antigen-specific response was mediated by KLRG1+ NK cells, as demonstrated by increased degranulation and proliferation in response to HCV antigen only. Our data suggest that KLRG1+ HCV-specific memory NK cells develop following viral infection, providing insight into their role in HCV clearance and relevance with regard to vaccine design.