Inborn errors of TLR3-dependent IFN-α/β- and -λ-mediated immunity in the central nervous system (CNS) can underlie herpes simplex virus 1 (HSV-1) encephalitis (HSE). The respective contributions of IFN-α/β and -λ are unknown. We report a child homozygous for a genomic deletion of the entire coding sequence and part of the 3’UTR of the last exon of IFNAR1, who died from HSE at the age of two years. An older cousin died following vaccination against measles, mumps and rubella at 12 months of age, and another 17-year-old cousin homozygous for the same variant has had other, less severe viral illnesses. The encoded IFNAR1 protein is expressed on the cell surface but is truncated and cannot interact with the tyrosine kinase TYK2. The patient’s fibroblasts and EBV-B cells did not respond to IFN-α2b or IFN-β, in terms of STAT1, STAT2 and STAT3 phosphorylation, or the genome-wide induction of IFN-stimulated genes. The patient’s fibroblasts were susceptible to viruses, including HSV-1, even in the presence of exogenous IFN-α2b or IFN-β. HSE is therefore a consequence of inherited complete IFNAR1 deficiency. This viral disease occurred in natural conditions, unlike those previously reported in other patients with IFNAR1 or IFNAR2 deficiency. This experiment of Nature indicates that IFN-α/β are essential for anti-HSV-1 immunity in the CNS.
Paul Bastard, Jeremy Manry, Jie Chen, Jérémie Rosain, Yoann Seeleuthner, Omar AbuZaitun, Lazaro Lorenzo, Taushif Khan, Mary Hasek, Nicholas Hernandez, Benedetta Bigio, Peng Zhang, Romain Lévy, Shai Shrot, Eduardo J. Garcia Reino, Yoon Seung Lee, Soraya Boucherit, Mélodie Aubart, Rik Gijsbers, Vivien Béziat, Zhi Li, Sandra Pellegrini, Isabelle Meyts, Flore Rozenberg, Nico Marr, Bertrand Boisson, Aurélie Cobat, Jacinta Bustamante, Qian Zhang, Emmanuelle Jouanguy, Laurent Abel, Raz Somech, Jean-Laurent Casanova, Shen-Ying Zhang
Macrophages are main effectors of heme metabolism, increasing transiently in the liver during heightened disposal of damaged or senescent red blood cells (sRBC). Macrophages are also essential in defense against microbial threats, but pathologic states of heme excess may be immunosuppressive. Herein, we uncovered a mechanism whereby an acute rise in sRBC disposal by macrophages led to an immunosuppressive phenotype following intrapulmonary Klebsiella pneumoniae infection characterized by increased extrapulmonary bacterial proliferation and reduced survival from sepsis in mice. The impaired immunity to K. pneumoniae during heightened sRBC disposal was independent of iron acquisition by bacterial siderophores, as K. pneumoniae mutant lacking siderophore function recapitulated findings observed with wildtype strain. Rather, sRBC disposal induced a liver transcriptomic profile notable for suppression of Stat1 and interferon-related responses during K. pneumoniae sepsis. Excess heme handling by macrophages recapitulated STAT1 suppression during infection that required synergistic NRF1 and NRF2 activation but was independent of heme oxygenase-1 induction. Whereas iron was dispensable, the porphyrin moiety of heme was sufficient to mediate suppression of STAT1-dependent responses in human and mouse macrophages and promoted liver dissemination of K. pneumoniae in vivo. Thus, cellular heme metabolism dysfunction negatively regulates the STAT1 pathway with implications in severe infection.
Tolani F. Olonisakin, Tomeka L. Suber, Shekina Gonzalez-Ferrer, Zeyu Xiong, Hernán F. Peñaloza, Rick van der Geest, Yuting Xiong, David O. Osei-Hwedieh, Jesus Tejero, Matthew R. Rosengart, Wendy M. Mars, Daria Van Tyne, Andreas Perlegas, Samuel Brashears, Daniel B. Kim-Shapiro, Mark T. Gladwin, Michael A. Bachman, Eldad A. Hod, Claudette St. Croix, Yulia Y. Tyurina, Valerian E. Kagan, Rama K. Mallampalli, Anuradha Ray, Prabir Ray, Janet S. Lee
The newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlights the urgent need for assays that detect protective levels of neutralizing antibodies. We studied the relationship between anti-spike ectodomain (ECD), anti-receptor binding domain (RBD) IgG titers, and SARS-CoV-2 virus neutralization (VN) titers generated by two in vitro assays using convalescent plasma samples from 68 COVID-19 patients. We report a strong positive correlation between both plasma anti-RBD and anti-ECD IgG titers and in vitro VN titer. The probability of a VN titer ≥160, the FDA-recommended level for convalescent plasma used for COVID-19 treatment, was ≥80% when anti-RBD or anti-ECD titers were ≥1:1350. Of all donors, 37% lacked VN titers ≥160. Dyspnea, hospitalization, and disease severity were significantly associated with higher VN titer. Frequent donation of convalescent plasma did not significantly decrease VN or IgG titers. Analysis of 2,814 asymptomatic adults found 73 individuals with anti-ECD IgG titers of ≥1:50 and strong positive correlation with anti-RBD and VN titers. Fourteen of these individuals had VN titers ≥1:160, all of which had anti-RBD titer ≥1:1350. We conclude that anti-RBD or anti-ECD IgG titers can serve as a surrogate for VN titers to identify suitable plasma donors. Plasma anti-RBD or anti-ECD titers of ≥1:1350 may provide critical information about protection against COVID-19 disease.
Eric Salazar, Suresh V. Kuchipudi, Paul A. Christensen, Todd Eagar, Xin Yi, Picheng Zhao, Zhicheng Jin, S. Wesley Long, Randall J. Olsen, Jian Chen, Brian Castillo, Christopher Leveque, Dalton Towers, Jason J. Lavinder, Jimmy Gollihar, Jose A. Cardona, Gregory C. Ippolito, Ruth H. Nissly, Ian Bird, Denver Greenawalt, Randall M. Rossi, Abhinay Gontu, Sreenidhi Srinivasan, Indira Poojary, Isabella M. Cattadori, Peter Hudson, Nicole M. Josleyn, Laura Prugar, Kathleen E. Huie, Andrew S. Herbert, David W. Bernard, John M. Dye, Vivek Kapur, James M. Musser
Although broadly protective, stem-targeted Abs against the influenza A virus hemagglutinin (HA) have been well studied, very limited information is available on Abs that broadly recognize the head domain. We determined the crystal structure of the HA protein of the avian H7N9 influenza virus in complex with a pan-H7, non-neutralizing, protective human Ab. The structure revealed a B cell epitope in the HA head domain trimer interface (TI). This discovery of a second major protective TI epitope supports a model in which uncleaved HA trimers exist on the surface of infected cells in a highly dynamic state that exposes hidden HA head domain features.
Jinhui Dong, Iuliia Gilchuk, Sheng Li, Ryan Irving, Matthew T. Goff, Hannah L. Turner, Andrew B. Ward, Robert H. Carnahan, James E. Crowe Jr.
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.
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
Dengue virus (DENV) infection requires cholesterol as a pro-viral factor although statin treatment did not show antiviral efficacy in dengue patients. Here, we show that DENV infection manipulates cholesterol metabolism in cells residing in low oxygen microenvironments (hypoxia) such as the liver, spleen and lymph nodes. DENV infection induced proprotein convertase subtilisin/kexin type 9 (PCSK9), which reduces low-density lipoprotein receptor (LDLR) recycling and hence cholesterol uptake. We found that, whereas LDLR uptake would have distributed cholesterol throughout the various cell compartments, de novo cholesterol synthesis enriched this lipid in the endoplasmic reticulum (ER). With cholesterol enrichment in the ER, ER-resident STING and type-I interferon (IFN) activation were repressed during DENV infection. Our in vitro findings were further supported by the finding of elevated plasma PCSK9 levels in dengue patients with high viremia and increased severity of plasma leakage. Our findings thus suggest PCSK9 plays a hitherto unrecognized role in dengue pathogenesis and therefore PCSK9 inhibitors could be a suitable host-directed treatment for dengue patients.
Esther S. Gan, Hwee Cheng Tan, Huynh Le Thi Duyen, Huynh Trung Trieu, Bridget Wills, Nabil G. Seidah, Eng Eong Ooi, Sophie Yacoub
The SARS-CoV-2 is the causative agent for COVID-19 pneumonia. Little is known about the kinetics, tissue distribution, cross-reactivity and neutralization antibody response in COVID-19 patients. Two groups of RT-PCR confirmed COVID-19 patients were enrolled in this study, including 12 severe patients in ICUs who needed mechanical ventilation and 11 mild patients in isolation wards. Serial clinical samples were collected for laboratory detection. Results showed that most of the severe patients had viral shedding in a variety of tissues for 20~40 days post onset of disease (8/12, 66.7%); while the majority of mild patients had viral shedding restricted to the respiratory tract and had no detectable virus RNA after 10 days post-onset (9/11, 81.8%). Mild patients showed significantly lower IgM response compared with that of the severe group. IgG responses were detected in most patients in both severe and mild groups at 9 days post onset and remained high level throughout the study. Antibodies cross-reactive to SARS-CoV and SARS-CoV-2 were detected in COVID-19 patients but not in MERS patients. High-levels of neutralizing antibodies were induced after about 10 days post onset in both severe and mild patients which were higher in the severe group. SARS-CoV-2 pseudotype neutralization test and focus reduction neutralization test with authentic virus showed consistent results. Sera from COVID-19 patients, but not convalescent SARS and MERS patients inhibited SARS-CoV-2 entry. Anti-SARS-CoV-2 S and N IgG level exhibited moderate correlation with neutralization titers in patients’ plasma. This study improves our understanding of immune response in human after SARS-CoV-2 infection.
Yanqun Wang, Lu Zhang, Ling Sang, Feng Ye, Shicong Ruan, Bei Zhong, Tie Song, Abeer N. Alshukairi, Rongchang Chen, Zhaoyong Zhang, Mian Gan, Airu Zhu, Yongbo Huang, Ling Luo, Chris KP Mok, Manal M. Al Gethamy, Haitao Tan, Zhengtu Li, Xiaofang Huang, Fang Li, Jing Sun, Yanjun Zhang, Liyan Wen, Yuming Li, Zhao Chen, Zhen Zhuang, Jianfen Zhuo, Chunke Chen, Lijun Kuang, Junxiang Wang, Huibin Lv, Yongliang Jiang, Min Li, Yimin Lin, Ying Deng, Lan Tang, Jieling Liang, Jicheng Huang, Stanley Perlman, Nanshan Zhong, Jingxian Zhao, J.S. Malik Peiris, Yimin Li, Jincun Zhao
While the advent of combination antiretroviral therapy (ART) has significantly improved survival, tuberculosis (TB) remains the leading cause of death in the HIV-infected population. We employed Mtb/Simian Immunodeficiency Virus (SIV) co-infected macaques to model Mtb/HIV co-infection and study the impact of ART on TB reactivation due to HIV-infection. While ART significantly reduced viral loads and increased CD4+ T cell counts in whole blood and BAL samples, it did not reduce the relative risk of SIV- induced TB reactivation in ART treated macaques in the early phase of treatment. CD4+ T cells were poorly restored specifically in the lung interstitium, despite their significant restoration in the alveolar compartment of the lung as well as in the periphery. IDO1 induction on myeloid cells in the iBALT likely contributed to dysregulated T cell homing and impaired lung immunity. Thus, while ART is indispensable in controlling viral replication, CD4+ T cells restoration and preventing opportunistic infection, it appears inadequate in reversing clinical signs of TB reactivation during the relatively short duration of ART and follow-up during this study. This warrants modeling concurrent treatment of TB and HIV to potentially reduce the risk of reactivation of TB due to HIV. The current and future studies like this have the potential to inform treatment strategies in patients with Mtb/HIV co-infection.
Shashank R. Ganatra, Allison N. Bucsan, Xavier Alvarez, Shyamesh Kumar, Ayan Chatterjee, Melanie Quezada, Abigail I. Fish, Dhiraj K. Singh, Bindu Singh, Riti Sharan, Tae-Hyung Lee, Uma Shanmugasundaram, Vijayakumar Velu, Shabaana A. Khader, Smriti Mehra, Jyothi Rengarajan, Deepak Kaushal
Posttranslational modifications are a common feature of proteins associated with neurodegenerative diseases including prion protein (PrPC), tau and α-synuclein. Alternative self-propagating protein states or strains give rise to different disease phenotypes and display strain-specific subsets of posttranslational modifications. The relationships between strain-specific structure, posttranslational modifications and disease phenotype are poorly understood. We previously reported that among hundreds of PrPC sialoglycoforms expressed by a cell, individual prion strains recruited PrPC molecules selectively, according to the sialylation status of their N-linked glycans. Here we report that transmission of a prion strain to a new host is accompanied by a dramatic shift in the selectivity of recruitment of PrPC sialoglycoforms giving rise to PrPSc with a unique sialoglycoform signature and disease phenotype. The newly emerged strain has the shortest incubation time to disease, is characterized by a colocalization of PrPSc with microglia and a very profound proinflammatory response, features that are linked to a unique sialoglycoform composition of PrPSc. The current work provides experimental support for a hypothesis that strain-specific patterns of PrPSc sialoglycoforms formed as a result of selective recruitment dictate strain-specific disease phenotypes. This work suggests a causative relationship between a strain-specific structure, posttranslational modifications and disease phenotype.
Natallia Makarava, Jennifer Chen-Yu Chang, Kara Molesworth, Ilia V. Baskakov
FTY720 (Gilenya, Novartis), is a treatment for relapsing remitting multiple sclerosis (MS). It is an analog of sphingosine-1-phosphate (S1P) and targets S1P receptors 1,3,4, and 5. Recent reports indicate an association between long term exposure to FTY720 and cases of cryptococcal infection. Here, we studied the effect of FTY720 and its derivative, BAF312 (Mayzent, Novartis), which only target S1P receptors 1 and 5, in a mouse model of cryptococcal infection. We found that treatment with FTY720, but not with BAF312, lead to decreased survival and increased organ burden in mouse cryptococcal granulomas. Both FTY720 and BAF312 caused a profound CD4+ and CD8+ T cell depletion in blood and lungs but only treatment with FTY720 lead to cryptococcal reactivation. Treatment with FTY720, but not with BAF312, was associated with disorganization of macrophages and with a M2 polarization at the granuloma site. In a cell system, FTY720 decreased phagocytosis and production of reactive oxygen species by macrophages, a phenotype recapitulated in the S1pr3-/- knockout macrophages. Our results suggest that FTY720 reactivates cryptococcosis from the granuloma through a S1P receptor 3-mediated mechanism and support the rationale for development of more specific receptor modulators for therapeutic use of MS.
Arielle M. Bryan, Jeehyun Karen You, Travis McQuiston, Cristina Lazzarini, Zhijuan Qiu, Brian S. Sheridan, Barbara Nuesslein-Hildesheim, Maurizio Del Poeta
No posts were found with this tag.