Circadian rhythm influences induction of trained immunity by BCG vaccination

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Abstract

BACKGROUND. The anti-tuberculosis vaccine Bacillus Calmette-Guérin (BCG) reduces overall infant mortality. Induction of innate immune memory, also termed trained immunity, contributes towards protection against heterologous infections. Since immune cells display oscillations in numbers and function throughout the day, we investigated the effect of BCG administration time on the induction of trained immunity. METHODS. 18 volunteers were vaccinated with BCG at 6pm and compared with 36 age- and sex-matched volunteers vaccinated between 8-9 am. Peripheral blood mononuclear cells were stimulated with Staphylococcus aureus and Mycobacterium tuberculosis before, as well as two weeks and three months after BCG vaccination. Cytokine production was measured to assess the induction of trained immunity and adaptive responses, respectively. Additionally, the influence of vaccination time on induction of trained immunity was studied in an independent cohort of 302 individuals vaccinated between 8am-12pm with BCG. RESULTS. Compared to evening vaccination, morning vaccination elicited both a stronger trained immunity and adaptive immune phenotype. In a large cohort of 302 volunteers, early morning vaccination resulted in a superior cytokine production capacity compared with later morning. A cellular, rather than soluble, substrate of the circadian effect of BCG vaccination was demonstrated by the enhanced capacity to induce trained immunity in vitro in morning compared to evening isolated monocytes. CONCLUSIONS. BCG vaccination in the morning induces stronger trained immunity and adaptive responses compared to evening vaccination. Future studies should take vaccine administration time into account when studying specific and non-specific effects of vaccines: early morning should be the preferred moment of BCG administration. FUNDING Spinoza grant of the Netherlands Organization for Scientific Research, ERC Advanced Grant (TRAIN-OLD nr. 833247), Danish National Research Foundation (DNRF108).

Authors

L. Charlotte J. de Bree, Vera P. Mourits, Valerie A.C.M. Koeken, Simone J.C.F.M. Moorlag, Robine Janssen, Lukas Folkman, Daniele Barreca, Thomas Krausgruber, Victoria Fife-Gernedl, Boris Novakovic, Rob J.W. Arts, Helga Dijkstra, Heidi Lemmers, Christoph Bock, Leo A.B. Joosten, Reinout van Crevel, Christine S. Benn, Mihai G. Netea

Diagnostic accuracy of three urine lipoarabinomannan tuberculosis assays in HIV-negative outpatients

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Abstract

Background: Inadequate tuberculosis (TB) diagnostics are a major hurdle in the reduction of disease burden and accurate point-of-care tests (POCT) are urgently needed. We assessed the diagnostic accuracy of Fujifilm SILVAMP TB LAM (FujiLAM) for TB diagnosis in HIV-negative outpatients compared to Alere Determine TB LAM Ag (AlereLAM) and a laboratory-based ultrasensitive electrochemiluminescence LAM research assay (EclLAM). Methods: In this multicentre diagnostic test accuracy study, we recruited HIV-negative adults with symptoms suggestive of pulmonary TB presenting to outpatient healthcare centres in Peru and South Africa. Urine samples were tested using FujiLAM, AlereLAM and EclLAM and the diagnostic accuracy was assessed against microbiological (MRS) and composite reference standards. Results: 372 HIV-negative participants were included and the prevalence of microbiologically confirmed TB was 30%. Compared to the MRS, the sensitivities of AlereLAM, FujiLAM and EclLAM were 10.8% (95% CI 6.3to18.0), 53.2% (43.9to62.1), and 66.7% (57.5to74.7) respectively. The specificities of AlereLAM, FujiLAM and EclLAM were 92.3% (88.5to95.0), 98.9% (96.7to99.6), and 98.1% (95.6to99.2) respectively. Positive Likelihood Ratio of AlereLAM, FujiLAM and EclLAM were 1.4, 46.2, and 34.8 and positive predictive values 37.5%, 95.2%, and 93.7% respectively. Conclusion: Compared to AlereLAM, FujiLAM detected five times more TB patients in HIV-negative participants, has a high positive predictive value and has the potential to improve rapid diagnosis of TB at the point-of-care. EclLAM demonstrated that additional sensitivity gains are possible, which highlights LAMs potential as a biomarker. Additional research is required to assess FujiLAMs performance in prospective cohorts, its cost-effectiveness, and its impact in real-world clinical settings.

Authors

Tobias Broger, Mark Nicol, George Sigal, Eduardo Gotuzzo, Alexandra J. Zimmer, Shireen Surtie, Tatiana Caceres-Nakiche, Anna Mantsoki, Elena Ivanova Reipold, Rita Székely, Michael Tsionsky, Judith van Heerden, Tatiana Plisova, Kinuyo Chikamatsu, Todd L. Lowary, Abraham Pinter, Satoshi Mitarai, Emmanuel Moreau, Samuel G Schumacher, Claudia M. Denkinger

BCG vaccination in humans inhibits systemic inflammation in a sex-dependent manner

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Abstract

Background. Induction of innate immune memory, also termed trained immunity, by the anti-tuberculosis vaccine Bacillus Calmette-Guérin (BCG) contributes to protection against heterologous infections. However, the overall impact of BCG vaccination on the inflammatory status of an individual is not known: while induction of trained immunity may suggest increased inflammation, BCG vaccination has been epidemiologically associated with a reduced incidence of inflammatory and allergic diseases. Methods. We investigated the impact of BCG (BCG-Bulgaria, InterVax) vaccination on systemic inflammation in a cohort of 303 healthy volunteers, as well as the effect of the inflammatory status on the response to vaccination. A targeted proteome platform was used to measure circulating inflammatory proteins before and after BCG vaccination, while ex vivo Mycobacterium tuberculosis and Staphylococcus aureus induced cytokine responses in peripheral blood mononuclear cells were used to assess trained immunity. Results. While BCG vaccination enhanced cytokine responses to restimulation, it reduced systemic inflammation. This effect was validated in three smaller cohorts, and was much stronger in men than in women. In addition, baseline circulating inflammatory markers were associated with ex vivo cytokine responses (trained immunity) after BCG vaccination. Conclusion. The capacity of BCG to enhance microbial responsiveness while dampening systemic inflammation should be further explored for potential therapeutic applications. Funding. This study was funded by a Spinoza grant of the Netherlands Organization for Scientific Research and an ERC Advanced Grant (TRAIN-OLD nr. 833247).

Authors

Valerie A. C. M. Koeken, L. Charlotte J. de Bree, Vera P. Mourits, Simone J.C.F.M. Moorlag, Jona Walk, Branko Cirovic, Rob J.W. Arts, Martin Jaeger, Helga Dijkstra, Heidi Lemmers, Leo A.B. Joosten, Christine Stabell Benn, Reinout van Crevel, Mihai Netea

Prevalence and pathogenicity of autoantibodies in patients with idiopathic CD4 lymphopenia

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BACKGROUND. Idiopathic CD4 lymphopenia (ICL) is defined by persistent low CD4 counts (<300 cells/µL) in the absence of a causal infection or immune deficiency and can manifest with opportunistic infections. Approximately 30% of ICL patients develop autoimmune disease. The prevalence and breadth of their autoantibodies, however, and their potential contribution to pathogenesis of ICL remain unclear. METHODS. We hybridized 35 and 51 ICL patients’ sera to a 9,000 human proteome array and to a 128 known autoantigens array, respectively. Using a flow-based method, we characterized the presence of anti-lymphocyte Ab in the whole cohort of 72 patients, as well as the Ab functional capability of inducing antibody-dependent cell-mediated cytotoxicity (ADCC), complement deposition, and complement dependent cytotoxicity (CDC). We tested ex vivo the activation of the classical complement pathway on ICL CD4 T cells. RESULTS. All ICL patients had multitude of autoantibodies mostly directed against private (not shared) targets and unrelated quantitatively or qualitatively to the patients’ autoimmune disease status. The targets included lymphocyte intracellular and membrane antigens, confirmed by the detection by flow of IgM and IgG (mostly IgG1 and IgG4) anti-CD4 cell Ab in 50% of the patients with half of these cases triggering lysis of CD4 T cells. We also detected in vivo classical complement activation on CD4 T cells in 14% of the whole cohort. CONCLUSION. Our data demonstrate a high prevalence of autoantibodies in ICL, some of which are specific against CD4 T cells, may contribute to pathogenesis and may represent a potential novel therapeutic target.

Authors

Ainhoa Perez-Diez, Chun-Shu Wong, Xiangdong Liu, Harry A. Mystakelis, Jian song, Yong Lu, Virginia Sheikh, Jeffrey S. Bourgeois, Andrea Lisco, Elizabeth Laidlaw, Cornelia D. Cudrici, Chengsong Zhu, Quan-Zhen Li, Alexandra F. Freeman, Peter R. Williamson, Megan V. Anderson, Gregg Roby, John S. Tsang, Richard M. Siegel, Irini Sereti

SARS-CoV-2 infection of the placenta

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Background. The effects of Covid-19 in pregnancy remain relatively unknown. We present a case of second trimester pregnancy with symptomatic Covid-19 complicated by severe preeclampsia and placental abruption. Methods. We analyzed placenta for the presence of SARS-CoV-2 through molecular and immunohistochemical assays and by and electron microscopy, and we measured the maternal antibody response in blood to this infection. Results. SARS-CoV-2 localized predominantly to syncytiotrophoblast cells at the maternal-fetal interface of the placenta. Histological examination of the placenta revealed a dense macrophage infiltrate, but no evidence for vasculopathy typically associated with preeclampsia. Conclusion. This case demonstrates SARS-CoV-2 invasion of the placenta, highlighting the potential for severe morbidity among pregnant women with Covid-19.

Authors

Hillary Hosier, Shelli F. Farhadian, Raffaella A. Morotti, Uma Deshmukh, Alice Lu-Culligan, Katherine H. Campbell, Yuki Yasumoto, Chantal B.F. Vogels, Arnau Casanovas-Massana, Pavithra Vijayakumar, Bertie Geng, Camila D. Odio, John Fournier, Anderson F. Brito, Joseph R. Fauver, Feimei Liu, Tara Alpert, Reshef Tal, Klara Szigeti-Buck, Sudhir Perincheri, Christopher P. Larsen, Aileen M. Gariepy, Gabriela Aguilar, Kristen L. Fardelmann, Malini Harigopal, Hugh S. Taylor, Christian M. Pettker, Anne L. Wyllie, Charles S. Dela Cruz, Aaron M. Ring, Nathan D. Grubaugh, Albert I. Ko, Tamas L. Horvath, Akiko Iwasaki, Uma M. Reddy, Heather S. Lipkind

Early safety indicators of COVID-19 convalescent plasma in 5,000 patients

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BACKGROUND. Convalescent plasma is the only antibody based therapy currently available for COVID 19 patients. It has robust historical precedence and sound biological plausibility. Although promising, convalescent plasma has not yet been shown to be safe as a treatment for COVID-19. METHODS. Thus, we analyzed key safety metrics after transfusion of ABO compatible human COVID-19 convalescent plasma in 5,000 hospitalized adults with severe or life threatening COVID-19, with 66% in the intensive care unit, as part of the US FDA Expanded Access Program for COVID-19 convalescent plasma. RESULTS. The incidence of all serious adverse events (SAEs) in the first four hours after transfusion was <1%, including mortality rate (0.3%). Of the 36 reported SAEs, there were 25 reported incidences of related SAEs, including mortality (n = 4), transfusion-associated circulatory overload (TACO; n = 7), transfusion-related acute lung injury (TRALI; n = 11), and severe allergic transfusion reactions (n = 3). However, only 2 (of 36) SAEs were judged as definitely related to the convalescent plasma transfusion by the treating physician. The seven-day mortality rate was 14.9%. CONCLUSION. Given the deadly nature of COVID 19 and the large population of critically-ill patients included in these analyses, the mortality rate does not appear excessive. These early indicators suggest that transfusion of convalescent plasma is safe in hospitalized patients with COVID-19.

Authors

Michael J. Joyner, R. Scott Wright, DeLisa Fairweather, Jonathon W. Senefeld, Katelyn A. Bruno, Stephen A. Klassen, Rickey E. Carter, Allan M. Klompas, Chad C. Wiggins, John R.A. Shepherd, Robert F. Rea, Emily R. Whelan, Andrew J. Clayburn, Matthew R. Spiegel, Patrick W. Johnson, Elizabeth R. Lesser, Sarah E. Baker, Kathryn F. Larson, Juan G. Ripoll, Kylie J. Andersen, David O. Hodge, Katie L. Kunze, Matthew R. Buras, Matthew N.P. Vogt, Vitaly Herasevich, Joshua J. Dennis, Riley J. Regimbal, Philippe R. Bauer, Janis E. Blair, Camille M. van Buskirk, Jeffrey L. Winters, James R. Stubbs, Nigel S. Paneth, Nicole C. Verdun, Peter Marks, Arturo Casadevall

Myeloid signature reveals immune contexture and predicts the prognosis of hepatocellular carcinoma

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BACKGROUND. Despite an increasing appreciation of the roles that myeloid cells play in tumor progression and therapy, challenges remain in interpreting the tumor-associated myeloid response balance and its translational value. We aimed to construct a simple and reliable myeloid signature for hepatocellular carcinoma (HCC). METHODS. Using in situ immunohistochemistry, we assessed the distribution of major myeloid subtypes in both peri- and intratumoral regions of HCC. A 2-feature-based, myeloid-specific prognostic signature, named the myeloid response score (MRS), was constructed using an L1-penalized Cox regression model based on data from a training subset (n=244) and in a test subset (n=244), an independent internal (n=341), and two external (n= 94; n=254) cohorts. RESULTS. The MRS and the MRS-based nomograms displayed remarkable discriminatory power, accuracy, and clinical usefulness for predicting recurrence and patient survival, superior to current staging algorithms. Moreover, an increase in MRS was associated with a shift in the myeloid response balance from antitumor to protumor activities, accompanied with enhanced CD8+ T cell exhaustion patterns. Additionally, we provide evidence that the MRS was associated with the efficacy of sorafenib treatment for recurrent HCC. CONCLUSION. We identified and validated a simple myeloid signature for HCC which showed remarkable prognostic potential and may serve as a basis for the stratification of HCC immune subtypes. FUNDING. This work was supported by the National Science and Technology Major Project of China, the National Natural Science Foundation of China, the Science and Information Technology of Guangzhou, the Fundamental Research Funds for the Central Universities, and the China Postdoctoral Science Foundation.

Authors

Chong Wu, Jie Lin, Yulan Weng, Dan-Ni Zeng, Jing Xu, Shufeng Luo, Li Xu, Mingyu Liu, Qiaomin Hua, Chao-Qun Liu, Jin-Qing Li, Jing Liao, Cheng Sun, Jian Zhou, Min-Shan Chen, Chao Liu, Zhenhong Guo, Shi-Mei Zhuang, Jin-Hua Huang, Limin Zheng

Impaired immune cell cytotoxicity in severe COVID-19 is IL-6 dependent

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Background: Coronavirus disease 19 (COVID-19) is an emerging infectious disease caused by SARS-CoV-2. Anti-viral immune response is crucial to achieve pathogen clearance, however in some patients an excessive and aberrant host immune response can lead to an acute respiratory distress syndrome. The comprehension of the mechanisms that regulate pathogen elimination, immunity, and pathology is essential to better characterize disease progression and widen the spectrum of therapeutic options. Methods: We performed a flow cytometric characterization of immune cells subsets from 30 COVID-19 patients and correlated these data with clinical outcomes. Results: COVID-19 patients showed decreased numbers of circulating T, B and NK cells, and exhibited a skewing of CD8+ T cells towards a terminally differentiated/senescent phenotype. In agreement, T CD4+, T CD8+ but also NK cells displayed reduced anti-viral cytokine production capability. Moreover, a reduced cytotoxic potential was identified in COVID-19 patients, particularly in those that required intensive care. The latter group of patients showed also increased serum IL-6 levels, that correlated to the frequency of granzyme-expressing NK cells. Off-label treatment with tocilizumab restored the cytotoxic potential of NK cells. Conclusion: In conclusion, the association between IL-6 serum levels and the impairment of cytotoxic activity suggests the possibility that targeting this cytokine may restore anti-viral mechanisms. Funding: This study was supported by funds of Dept. of Experimental and Clinical Medicine of University of Florence (ex-60%) derived from Ministero dell’Istruzione, dell’Università e della Ricerca (Italy).

Authors

Alessio Mazzoni, Lorenzo Salvati, Laura Maggi, Manuela Capone, Anna Vanni, Michele Spinicci, Jessica Mencarini, Roberto Caporale, Benedetta Peruzzi, Alberto Antonelli, Michele Trotta, Lorenzo Zammarchi, Luca Ciani, Leonardo Gori, Chiara Lazzeri, Andrea Matucci, Alessandra Vultaggio, Oliviero Rossi, Fabio Almerigogna, Paola Parronchi, Paolo Fontanari, Federico Lavorini, Adriano Peris, Gian Maria Rossolini, Alessandro Bartoloni, Sergio Romagnani, Francesco Liotta, Francesco Annunziato, Lorenzo Cosmi

New York City COVID-19 resident physician exposure during exponential phase of pandemic

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Background From March 2-April 12, 2020, New York City (NYC) experienced exponential growth of the COVID-19 pandemic due to novel coronavirus (SARS-CoV-2). Little is known regarding how physicians have been affected. We aimed to characterize COVID-19 impact on NYC resident physicians. Methods IRB-exempt and expedited cross-sectional analysis through survey to NYC residency program directors (PDs) April 3–12, 2020, encompassing events from March 2–April 12, 2020. Results From an estimated 340 residency programs around NYC, recruitment yielded 91 responses, representing 24 specialties and 2,306 residents. 45.1% of programs reported at least one resident with confirmed COVID-19: 101 resident physicians were confirmed COVID-19-positive, with an additional 163 residents presumed positive for COVID-19 based on symptoms but awaiting or unable to obtain testing. Two COVID-19-positive residents were hospitalized, with one in intensive care. Among specialties with >100 residents represented, negative binomial regression indicated that infection risk differed by specialty (p=0.039). 80% of programs reported quarantining a resident. 90/91 programs reported reuse or extended mask use, and 43 programs reported that personal protective equipment (PPE) was suboptimal. 65 programs (74.7%) have redeployed residents elsewhere to support COVID-19 efforts. Conclusion Many resident physicians around NYC have been affected by COVID-19 through direct infection, quarantine, or redeployment. Lack of access to testing and concern regarding suboptimal PPE are common among residency programs. Infection risk may differ by specialty. Funding AHA, MPB, RWSC, CGM, LRDG, JDH: NEI Core Grant P30EY019007, RPB Unrestricted Grant. ACP and JS: Parker Family Chair. SXX: University of Pennsylvania.

Authors

Mark P. Breazzano, Junchao Shen, Aliaa H. Abdelhakim, Lora Dagi Glass, Jason Horowitz, Sharon X. Xie, C. Gustavo De Moraes, Alice Chen-Plotkin, Royce W.S. Chen

Taste-related reward is associated with weight loss following bariatric surgery

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Background: Bariatric surgeries are the most effective treatments for successful and sustained weight loss but individuals vary in treatment response. Understanding the neurobiological and behavioral mechanisms accounting for this variation could lead to the development of personalized therapeutic approaches and improve treatment outcomes. The primary objectives were to investigate changes in taste preferences and taste-induced brain responses after Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) and to identify potential taste-related predictors of weight loss. Methods: Women, ages 18 to 55, with a body mass index ≥ 35 kg/m2 and approved for bariatric surgery at the Johns Hopkins Center for Bariatric Surgery were recruited for participation. Demographics, anthropometrics, liking ratings, and neural responses to varying concentrations of sucrose+fat mixtures were assessed pre- and post-surgery via visual analogue scales and functional magnetic resonance imaging. Results: Bariatric surgery produced decreases in liking for sucrose-sweetened mixtures. Greater preference for sucrose-sweetened mixtures prior to surgery was associated with greater weight loss in RYGB but not VSG. In the RYGB group only, individuals who showed lower taste-induced activation in the ventral tegmental area (VTA) prior to surgery and greater changes in taste-induced VTA activation two weeks following surgery experienced better weight loss. Conclusions: The anatomical and/or metabolic changes associated with RYGB may more effectively “reset” the neural processing of reward stimuli, thereby rescuing the blunted activation in the mesolimbic pathway found in patients with obesity. Further, these findings suggest that RYGB may be particularly effective in patients with a preference for sweet foods. Trial Registration: Not Applicable.Funding: K23DK100559 and The Dalio Philanthropies. Funding: K23DK100559 and The Dalio Philanthropies.

Authors

Kimberly R. Smith, Afroditi Papantoni, Maria G. Veldhuizen, Vidyulata Kamath, Civonnia Harris, Timothy H. Moran, Susan Carnell, Kimberley E. Steele