Browsing by Author "Lorenzo, Lazaro"

Now showing 1 - 4 of 4

Open Access
A common form of dominant human IFNAR1 deficiency impairs IFN-α and -ω but not IFN-β-dependent immunity
(Rockefeller University Press, 2024-12-16) Qureshah, Fahd Al; Pen, Jérémie Le; Weerd, Nicole A. de; Moncada-Velez, Marcela; Materna, Marie; Lin, Daniel C.; Milisavljevic, Baptiste; Vianna, Fernanda; Bizien, Lucy; Lorenzo, Lazaro; Lecuit, Marc; Pommier, Jean-David; Keles, Sevgi; Özçelik, Tayfun; Pedraza-Sanchez, Sigifredo; Prost, Nicolas de; Zein, Loubna El; Hammoud, Hassan; Ng, Lisa F.P.; Halwani, Rabih; Sharif-Askari, Narjes Saheb; Lau, Yu Lung; Tam, Anthony R.; Singh, Neha; Bhattad, Sagar; Berkun, Yackov; Chantratita, Wasun; Aguilar-López, Raúl; Shahrooei, Mohammad; Abel, Laurent; Bastard, Paul; Jouanguy, Emmanuelle; Béziat, Vivien; Zhang, Peng; Rice, Charles M.; Cobat, Aurélie; Zhang, Shen-Ying; Hertzog, Paul J.; Casanova, Jean-Laurent; Zhang, Qian
Autosomal recessive deficiency of the IFNAR1 or IFNAR2 chain of the human type I IFN receptor abolishes cellular responses to IFN-α, -β, and -ω, underlies severe viral diseases, and is globally very rare, except for IFNAR1 and IFNAR2 deficiency in Western Polynesia and the Arctic, respectively. We report 11 human IFNAR1 alleles, the products of which impair but do not abolish responses to IFN-α and -ω without affecting responses to IFN-β. Ten of these alleles are rare in all populations studied, but the remaining allele (P335del) is common in Southern China (minor allele frequency ≈2%). Cells heterozygous for these variants display a dominant phenotype in vitro with impaired responses to IFN-α and -ω, but not -β, and viral susceptibility. Negative dominance, rather than haploinsufficiency, accounts for this dominance. Patients heterozygous for these variants are prone to viral diseases, attesting to both the dominance of these variants clinically and the importance of IFN-α and -ω for protective immunity against some viruses.
Open Access
Fulminant viral hepatitis in two siblings with inherited IL-10RB deficiency
(Springer, 2022-10-29) Korol, Cecilia B.; Belkaya, Serkan; Alsohime, Fahad; Lorenzo, Lazaro; Boisson-Dupuis, Stéphanie; Brancale, Joseph; Neehus, Anna-Lena; Vilarinho, Silvia; Zobaida, Alsum; Halwani, Rabih; Al-Muhsen, Saleh; Casanova, Jean-Laurent; Jouanguy, Emmanuelle
Fulminant viral hepatitis (FVH) caused by hepatitis A virus (HAV) is a life-threatening disease that typically strikes otherwise healthy individuals. The only known genetic etiology of FVH is inherited IL-18BP deficiency, which unleashes IL-18-dependent lymphocyte cytotoxicity and IFN-γ production. We studied two siblings who died from a combination of early-onset inflammatory bowel disease (EOIBD) and FVH due to HAV. The sibling tested was homozygous for the W100G variant of IL10RB previously described in an unrelated patient with EOIBD. We show here that the out-of-frame IL10RB variants seen in other EOIBD patients disrupt cellular responses to IL-10, IL-22, IL-26, and IFN-λs in overexpression conditions and in homozygous cells. By contrast, the impact of in-frame disease-causing variants varies between cases. When overexpressed, the W100G variant impairs cellular responses to IL-10, but not to IL-22, IL-26, or IFN-λ1, whereas cells homozygous for W100G do not respond to IL-10, IL-22, IL-26, or IFN-λ1. As IL-10 is a potent antagonist of IFN-γ in phagocytes, these findings suggest that the molecular basis of FVH in patients with IL-18BP or IL-10RB deficiency may involve excessive IFN-γ activity during HAV infections of the liver. Inherited IL-10RB deficiency, and possibly inherited IL-10 and IL-10RA deficiencies, confer a predisposition to FVH, and patients with these deficiencies should be vaccinated against HAV and other liver-tropic viruses. © 2022, The Author(s).
Open Access
Human genetic and immunological determinants of critical COVID-19 pneumonia
(Springer Nature, 2022-03-24) Zhang, Qian; Bastard, Paul; Karbuz, Adem; Gervais, Adrian; Tayoun, Ahmad Abou; Aiuti, Alessandro; Belot, Alexandre; Bolze, Alexandre; Gaudet, Alexandre; Bondarenko, Anastasiia; Liu, Zhiyong; Spaan, András N.; Guennoun, Andrea; Arias, Andres Augusto; Planas, Anna M.; Sediva, Anna; Shcherbina, Anna; Neehus, Anna-Lena; Puel, Anne; Froidure, Antoine; Novelli, Antonio; Parlakay, Aslınur Özkaya; Pujol, Aurora; Yahşi, Aysun; Gülhan, Belgin; Bigio, Benedetta; Boisson, Bertrand; Drolet, Beth A.; Franco, Carlos Andres Arango; Flores, Carlos; Rodríguez-Gallego, Carlos; Prando, Carolina; Biggs, Catherine M.; Luyt, Charles-Edouard; Dalgard, Clifton L.; O’Farrelly, Cliona; Matuozzo, Daniela; Dalmau, David; Perlin, David S.; Mansouri, Davood; van de Beek, Diederik; Vinh, Donald C.; Dominguez-Garrido, Elena; Hsieh, Elena W. Y.; Erdeniz, Emine Hafize; Jouanguy, Emmanuelle; Şevketoglu, Esra; Talouarn, Estelle; Quiros-Roldan, Eugenia; Andreakos, Evangelos; Husebye, Eystein; Alsohime, Fahad; Haerynck, Filomeen; Casari, Giorgio; Novelli, Giuseppe; Aytekin, Gökhan; Morelle, Guillaume; Alkan, Gulsum; Bayhan, Gulsum Iclal; Feldman, Hagit Baris; Su, Helen C.; von Bernuth, Horst; Resnick, Igor; Bustos, Ingrid; Meyts, Isabelle; Migeotte, Isabelle; Tancevski, Ivan; Bustamante, Jacinta; Fellay, Jacques; El Baghdadi, Jamila; Martinez-Picado, Javier; Casanova, Jean-Laurent; Rosain, Jeremie; Manry, Jeremy; Chen, Jie; Christodoulou, John; Bohlen, Jonathan; Franco, José Luis; Li, Juan; Anaya, Juan Manuel; Rojas, Julian; Ye, Junqiang; Uddin, K. M. Furkan; Yasar, Kadriye Kart; Kisand, Kai; Okamoto, Keisuke; Chaïbi, Khalil; Mironska, Kristina; Maródi, László; Abel, Laurent; Renia, Laurent; Lorenzo, Lazaro; Hammarström, Lennart; Ng, Lisa F. P.; Quintana-Murci, Lluis; Erazo, Lucia Victoria; Notarangelo, Luigi D.; Reyes, Luis Felipe; Allende, Luis M.; Imberti, Luisa; Renkilaraj, Majistor Raj Luxman Maglorius; Moncada-Velez, Marcela; Materna, Marie; Anderson, Mark S.; Gut, Marta; Chbihi, Marwa; Ogishi, Masato; Emiroglu, Melike; Seppänen, Mikko R. J.; Uddin, Mohammed J.; Shahrooei, Mohammed; Alexander, Natalie; Hatipoglu, Nevin; Marr, Nico; Akçay, Nihal; Boyarchuk, Oksana; Slaby, Ondrej; Akcan, Ozge Metin; Zhang, Peng; Soler-Palacín, Pere; Gregersen, Peter K.; Brodin, Petter; Garçon, Pierre; Morange, Pierre-Emmanuel; Pan-Hammarström, Qiang; Zhou, Qinhua; Philippot, Quentin; Halwani, Rabih; de Diego, Rebeca Perez; Levy, Romain; Yang, Rui; Öz, Şadiye Kübra Tüter; Muhsen, Saleh Al; Kanık-Yüksek, Saliha; Espinosa-Padilla, Sara; Ramaswamy, Sathishkumar; Okada, Satoshi; Bozdemir, Sefika Elmas; Aytekin, Selma Erol; Karabela, Şemsi Nur; Keles, Sevgi; Senoglu, Sevtap; Zhang, Shen-Ying; Duvlis, Sotirija; Constantinescu, Stefan N.; Boisson-Dupuis, Stephanie; Turvey, Stuart E.; Tangye, Stuart G.; Asano, Takaki; Özcelik, Tayfun; Le Voyer, Tom; Maniatis, Tom; Morio, Tomohiro; Mogensen, Trine H.; Sancho-Shimizu, Vanessa; Beziat, Vivien; Solanich, Xavier; Bryceson, Yenan; Lau, Yu-Lung; Itan, Yuval; Cobat, Aurélie; Casanova, Jean-Laurent
SARS-CoV-2 infection is benign in most individuals but, in around 10% of cases, it triggers hypoxaemic COVID-19 pneumonia, which leads to critical illness in around 3% of cases. The ensuing risk of death (approximately 1% across age and gender) doubles every five years from childhood onwards and is around 1.5 times greater in men than in women. Here we review the molecular and cellular determinants of critical COVID-19 pneumonia. Inborn errors of type I interferons (IFNs), including autosomal TLR3 and X-chromosome-linked TLR7 deficiencies, are found in around 1–5% of patients with critical pneumonia under 60 years old, and a lower proportion in older patients. Pre-existing auto-antibodies neutralizing IFNα, IFNβ and/or IFNω, which are more common in men than in women, are found in approximately 15–20% of patients with critical pneumonia over 70 years old, and a lower proportion in younger patients. Thus, at least 15% of cases of critical COVID-19 pneumonia can be explained. The TLR3- and TLR7-dependent production of type I IFNs by respiratory epithelial cells and plasmacytoid dendritic cells, respectively, is essential for host defence against SARS-CoV-2. In ways that can depend on age and sex, insufficient type I IFN immunity in the respiratory tract during the first few days of infection may account for the spread of the virus, leading to pulmonary and systemic inflammation. © 2022, Springer Nature Limited.
Open Access
Human TMEFF1 is a restriction factor for herpes simplex virus in the brain
(NATURE PORTFOLIO, 2024-07) Chan, Yi-Hao; Liu, Zhiyong; Bastard, Paul; Khobrekar, Noopur; Hutchison, Kennen M.; Yamazaki, Yasuhiro; Fan, Qing; Matuozzo, Daniela; Harschnitz, Oliver; Kerrouche, Nacim; Nakajima, Koji; Amin, Param; Yatim, Ahmad; Rinchai, Darawan; Chen, Jie; Zhang, Peng; Ciceri, Gabriele; Chen, Jia; Dobbs, Kerry; Belkaya, Serkan; Lee, Danyel; Gervais, Adrian; Aydin, Kuersad; Kartal, Ayse; Hasek, Mary L.; Zhao, Shuxiang; Reino, Eduardo Garcia; Lee, Yoon Seung; Seeleuthner, Yoann; Chaldebas, Matthieu; Bailey, Rasheed; Vanhulle, Catherine; Lorenzo, Lazaro; Boucherit, Soraya; Rozenberg, Flore; Marr, Nico; Mogensen, Trine H.; Aubart, Melodie; Cobat, Aurelie; Dulac, Olivier; Emiroglu, Melike; Paludan, Soren R.; Abel, Laurent; Notarangelo, Luigi; Longnecker, Richard; Smith, Greg; Studer, Lorenz; Casanova, Jean-Laurent; Zhang, Shen-Ying
Most cases of herpes simplex virus 1 (HSV-1) encephalitis (HSE) remain unexplained1,2. Here, we report on two unrelated people who had HSE as children and are homozygous for rare deleterious variants of TMEFF1, which encodes a cell membrane protein that is preferentially expressed by brain cortical neurons. TMEFF1 interacts with the cell-surface HSV-1 receptor NECTIN-1, impairing HSV-1 glycoprotein D- and NECTIN-1-mediated fusion of the virus and the cell membrane, blocking viral entry. Genetic TMEFF1 deficiency allows HSV-1 to rapidly enter cortical neurons that are either patient specific or derived from CRISPR-Cas9-engineered human pluripotent stem cells, thereby enhancing HSV-1 translocation to the nucleus and subsequent replication. This cellular phenotype can be rescued by pretreatment with type I interferon (IFN) or the expression of exogenous wild-type TMEFF1. Moreover, ectopic expression of full-length TMEFF1 or its amino-terminal extracellular domain, but not its carboxy-terminal intracellular domain, impairs HSV-1 entry into NECTIN-1-expressing cells other than neurons, increasing their resistance to HSV-1 infection. Human TMEFF1 is therefore a host restriction factor for HSV-1 entry into cortical neurons. Its constitutively high abundance in cortical neurons protects these cells from HSV-1 infection, whereas inherited TMEFF1 deficiency renders them susceptible to this virus and can therefore underlie HSE. A study of two childhood cases of herpes simplex encephalitis shows that TMEFF1 interacts with the HSV-1 cell-surface receptor NECTIN-1, preventing HSV-1 from fusing with the cell membrane and entering cortical neurons.