Our lab is interested in understanding the interplay between innate immunity and human pathogenic viruses. 

Key questions are:
•    What is the molecular basis of anti-viralinnate immune responses? 
•    How does an organism return to immune homeostasis after virus elimination? 
•    Why can viruses still replicate in the presence of a functional innate immune system? 
•    What are the weaknesses of viruses?
•    How can we strengthen our innate immune defences against invading viruses?

To understand common principles and differences, we study various viruses, including# HIV, SARS-CoV-2, IAV, MeV, EMCV and ZIKV.

1.    Control of innate immune activation and termination
Rapid activation of innate immune responses upon detection of a pathogen is crucial for effective anti-viral responses. However, prolonged or excessive activation of innate immunity has pathogenic consequences. Thus, precise activation of innate sensors and efficient signal termination is crucial. Recently, we identified that two - not just one – danger signals are required to guarantee specific recognition of RNA viruses (Acharya et al, Cell, 2022). Currently, we are aiming to understand which proteins play a key role in preventing excessive and/or chronic interferon activation using auto-inflammatory diseases as models. In addition, we define consequences of the ‘aftermath’ of a battle between the innate immune system and viruses i.e. how cells return to a pre-activated state.

2.    Viral manipulation of innate immunity
To replicate in the presence of functioning innate immune responses successful viruses have evolved strategies to manipulate and evade anti-viral defence mechanisms. We have recently identified strategies that allow SARS-CoV-2 to counteract (Thoms et al, Science, 2020; Hayn et al, Cell Reports, 2021) or even exploit factors of innate immunity (Prelli Bozzo et al, Nature Communications, 2021). Importantly, these studies also revealed remaining vulnerabilities of viral pathogens against targeted innate immune activation (Hayn et al, Cell Reports, 2021). Currently, we are working to understand how innate immune manipulation evolves in a recent zoonotic virus (SARS-CoV-2) that adapts to the human host and are aiming to identify gaps in the innate immune evasion of other important human pathogens, like HIV and IAV.
 
3.    Modulation of innate immunity as therapeutic approach against viral and inflammatory diseases
Well balanced activation of innate immunity may allow to control viral pathogens without causing harmful inflammation. Thus, we are aiming to identify and characterize novel immunomodulatory peptides from the human peptidome. To this end, we are analysing large libraries derived from various human sources for their impact on innate immune activity. Identified immunomodulatory peptides can be further developed for therapeutic anti-viral and anti-inflammatory approaches. Studying their physiological role will provide new insights into the regulation of innate immune responses.

Recent key publications
Full list: scholar.google.com/citations

1. Acharya D, Reis R, Volcic M, Liu G, Wang MK, Chia BS, Nchioua R, Groß R, Münch J, Kirchhoff F, Sparrer KMJ*, Gack MU*. Actin cytoskeleton remodeling primes RIG-I-like receptor activation. Cell. 2022 Sep 15;185(19):3588-3602.e21. *co-corresponding
2. Hirschenberger M#, Hunszinger V#, Sparrer KMJ. Implications of Innate Immunity in Post-Acute Sequelae of Non-Persistent Viral Infections. Cells. 2021 Aug 19;10(8):2134. # co-first
3. Prelli Bozzo C#, Nchioua R#, Volcic M, Koepke L, Krüger J, Schütz D, Heller S, Stürzel CM, Kmiec D, Conzelmann C, Müller J, Zech F, Braun E, Groß R, Wettstein L, Weil T, Weiß J, Diofano F, Rodríguez Alfonso AA, Wiese S, Sauter D, Münch J, Goffinet C, Catanese A, Schön M, Boeckers TM, Stenger S, Sato K, Just S, Kleger A, Sparrer KMJ*, Kirchhoff F*. IFITM proteins promote SARS-CoV-2 infection and are targets for virus inhibition in vitro. Nat Commun. 2021 Jul 28;12(1):4584. *co-corresponding
4. Koepke L#, Hirschenberger M#, Hayn M#, Kirchhoff F, Sparrer KM. Manipulation of autophagy by SARS-CoV-2 proteins. Autophagy. 2021 Sep;17(9):2659-2661.  # co-first
5. Hayn M#, Hirschenberger M#, Koepke L#, Nchioua R, Straub JH, Klute S, Hunszinger V, Zech F, Prelli Bozzo C, Aftab W, Christensen MH, Conzelmann C, Müller JA, Srinivasachar Badarinarayan S, Stürzel CM, Forne I, Stenger S, Conzelmann KK, Münch J, Schmidt FI, Sauter D, Imhof A, Kirchhoff F, Sparrer KMJ. Systematic functional analysis of SARS-CoV-2 proteins uncovers viral innate immune antagonists and remaining vulnerabilities. Cell Rep. 2021 May 18;35(7):109126. # co-first
6. Thoms M#, Buschauer R#, Ameismeier M#, Koepke L, Denk T, Hirschenberger M, Kratzat H, Hayn M, Mackens-Kiani T, Cheng J, Straub JH, Stürzel CM, Fröhlich T, Berninghausen O, Becker T, Kirchhoff F, Sparrer KMJ*, Beckmann R*. Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2. Science. 2020 Sep 4;369(6508):1249-1255. *co-corresponding. # co-first

Current lab members