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Immunopathology of Virus Infections

A systematic survey of P2Y receptors

Line’s PhD research is now published in EMBO! In this study, we systematically investigated the responses of human macrophages to extracellular nucleotides and revealed that adenine- and uridine-based nucleotides induce a specific and transient cytokine response through activating MAPK signaling pathway. We further categorized the nucleotide sensing P2Ys into two subgroups: P2Y1/2/6/11 that govern inflammatory responses via cytokine induction, and P2Y4/11/12/13/14 that directly induce antiviral responses.

Congratulations to Line, Yiqi, Chris, Lila, and all the collaborators involved in this study!

Read more in the EMBO paper:
Systematic P2Y receptor survey identifies P2Y11 as modulator of immune responses and virus replication in macrophages

Text by Yiqi, illustration by Line.

Identification of MDM2 as a regulator for SARS-CoV-2 uptake

We are excited to present our latest research publication! Building on our previous work (Stukalov et al., 2020, Nature), we investigated the impact of the genetic depletion of 21 host proteins on five different viruses. Our findings showed an increased SARS-CoV-2 replication in MDM2 knockout cells, which was virus-specific. This phenomenon can be attributed to the notable elevation of ACE2 levels in the absence of MDM2, thereby triggering an augmented SARS-CoV-2 uptake. Furthermore, our study highlights the crucial role of the MDM2 ubiquitination site Lysine 788 in stabilizing ACE2 and its significance in the context of SARS-CoV-2 particle uptake.

Congratulations to all the authors involved in this exciting research!

Read more here: MDM2 Influences ACE2 Stability and SARS-CoV-2 Uptake

Text and illustration by Quirin.

Targeting host 2’O-methyltransferases to suppress Influenza virus

We are proud to be part of the massive effort, spearheaded by Hiroki Kato and his team from Bonn, that revealed the critical role of the host RNA 2’O-methyltransferase MTr1 in influenza A/B cap-snatching! The activity of MTr1 is pivotal for Influenza A and B but not for other cap-snatching viruses and can be inhibited by a host-directed small molecule to achieve an antiviral effect through a novel mechanism.

Congratulations to Hiroki Kato in Bonn and collaborators for the fabulous manuscript published in Science!

Read more here: Inhibition of cellular RNA methyltransferase abrogates influenza virus capping and replication

Text by Valter and illustration by Andreas.

New host factors mediating SARS-CoV-2 entry and pathogenesis

This amazing study also reports repurposed ADAM inhibitors exerting antiviral activity against SARS-CoV-2 and its related variants of concern both in vitro and ex vivo. Such knowledge will help to develop new therapies to fight against COVID-19 as ADAM17 and ADAM10 expression correlates with disease severity in patients.

Congratulations to Vincent and Sabri, our collaborators from the Lichtenthaler’s lab and all authors!

Read more here: ADAM10 and ADAM17 promote SARS-CoV-2 cell entry and spike protein-mediated lung cell fusion

Text and illustration by Vincent.

Defining highly functional SARS-CoV-2-specific CD8+ T cells

We are finishing the year with an amazing collaborative work performed with Dirk Busch’s lab! In this study, we uncovered that SARS-CoV-2-specific CD8+ T cells are detectable up to 12 months post-infection. Moreover, by scRNA sequencing, we were able to develop cytotoxic engineered T cells allowing us to define cell signature for highly functional SARS-CoV-2-specific CD8+ T cells.

Congratulation to all the people involved in this great study!

Read more in the Cell Reports paper: Recruitment of highly cytotoxic CD8+ T cell receptors in mild SARS-CoV-2 infection

Discovery of a cellular degradation mechanism for viral PPP-RNA

We are excited to share that our manuscript was recently published in Nature Communications. You can now read about our work on the evolutionarily conserved class of Nudix hydrolases in the context of innate immunity.

We identified Nudix hydrolase 2 (NUDT2) as one key player to clear cells from viral triphosphorylated RNA (PPP-RNA). NUDT2 trims those RNAs into monophosphorylated RNA (P-RNA), which then serve as a substrate for the canonical XRN-1 degradation pathway.

This was a great collaborative effort, and we thank all our collaborators for their contributions. Congratulations to Bea, Karsten, Quirin, Line, Pietro, Sarah, and Andreas.

Read the whole story here: NUDT2 initiates viral RNA degradation by removal of 5′-phosphates

Analysis of evolutionary conserved viral nucleic acid binding proteins

We are very happy that our manuscript on evolutionary conserved viral nucleic acid binding proteins was published in Nature Communications.

It describes the most comprehensive evaluation of viral nucleic acid interactions in human, mouse and flies. We used conservation of binding properties over evolution to identify proteins that are relevant for innate immunity.

This was a great collaborative effort particularly between our laboratory and the laboratories of Jean-Luc Imler and Carine Meignin. Congratulations to Rike, Chris, Alexey, Line, Vincent, Teresa, Cathleen, Lila, Matthias & Andreas!    

Read more in the Nature Communications paper: Cross-species analysis of viral nucleic acid interacting proteins identifies TAOKs as innate immune regulators

Therapeutic potential of ACE2-IgG4-Fc fusion protein against SARS coronaviruses

In collaboration with Ulla Protzer’s and Johannes Buchner’s lab, without forgetting the engineering skills of Formycon AG, we set up and characterized how ACE2-IgG4-Fc fusion protein could provide us new therapeutic tools in our non-stopping fight against COVID-19. While this construct can neutralize all SARS coronaviruses, including its variants of concern, it also has an activity at the picomolar range.

Congratulation to all the people involved in this great study!

Read more in the Antiviral Research paper: Picomolar inhibition of SARS-CoV-2 variants of concern by an engineered ACE2-IgG4-Fc fusion protein

Mechanism of transcriptional modulation by NS1 of Respiratory Syncytial Virus (RSV)

In a joint collaborative battle, Daisy Leung published a mechanism employed by NS1 of Respiratory Syncytial Virus (RSV) to modulate gene transcription: We (Valter/Philipp/Andreas) identified that NS1 binds to the mediator complex, an essential component of inducible gene expression. Jingjing and Daisy could show that NS1 thereby blunts the expression of genes associated with innate immunity.

Congratulations particularly to Jingjing, Nina, Jacqueline and Daisy, well done!

Read more in the Cell Reports paper: Nuclear-localized human respiratory syncytial virus NS1 protein modulates host gene transcription

HCMV infection induces citrullination to evade the antiviral defence

Gloria Griffante and colleagues (Santo Landolfo laboratory, University of Turin, Italy) discovered that HCMV infection induced protein citrullination, a post-translational modification catalyzed by PADs. In particular, the host defense protein IFIT1 was citrullinated by PAD2 and treatment with the enzyme impaired its ability to bind 5’PPP-RNA, thus constituting a novel immune evasion strategy. We contributed with mass-spectrometry and RNA-protein binding assays to characterize IFIT1 citrullination sites and PAD2-dependant modulation of its interaction with RNA.

Congratulations for this great work!

Read more in the Nature paper: Human cytomegalovirus-induced host protein citrullination is crucial for viral replication