Prof. Dr. Math­ias Munschauer

mathias.munschauer
(at)med.uni-heidelberg.de
Phone: +49 6221 56–4225
Fax: +49 6221 56–4570

RNA Biology of Viral Infections

Projects

We aim to achieve a high­ly resolved spa­tial and tem­po­ral under­standin­gof RNA reg­u­la­to­ry events that deter­mine the suc­cess or fail­ure of viral infection.Particularly, we are inter­est­ed in learn­ing how viral RNA mol­e­cules inter­face with­the host cell, and how RNA-bind­ing pro­teins shape the fate of viral RNA to con­trol­repli­ca­tion, immune eva­sion, and infec­tion out­come. To dis­sect these processes,we apply a sys­tems-lev­el, RNA-cen­tric strat­e­gy that inte­grates quan­ti­ta­tive massspec­trom­e­try, func­tion­al genomics, and sin­gle-cell tran­scrip­tomics data.

Fig­ure 1. Graph­i­cal sum­ma­ry of key research areas in the Mun­schauer lab.

1 | RNA Interactomics: A New Perspective on RNA Viruses

The sys­tem­at­ic analy­sis of RNA inter­ac­tomes can uncov­er mol­e­c­u­lar sig­na­turesthat detail the func­tion­al and reg­u­la­to­ry depen­den­cies of spe­cif­ic RNA molecules.Our lab exam­ines these inter­ac­tion sig­na­tures for dif­fer­ent RNA virus­es at var­i­ousstages of the infec­tion cycle to gain insights into the viral RNA repli­ca­tion pro­gra­mand its depen­dence on spe­cif­ic virus and host cell factors.

We are pio­neer­ing a new gen­er­a­tion of RNA-cen­tric tools that provide­un­prece­dent­ed insights into the mol­e­c­u­lar inter­ac­tions between virus­es and theirhosts. One such tool, SHIFTR (https://doi.org/10.1093/nar/gkae038),promis­es to rev­o­lu­tion­ize our under­stand­ing of viral RNA genomes, their design­prin­ci­ples, and mol­e­c­u­lar build­ing blocks. SHIFTR allows us to ana­lyze inter­ac­tions­for any cis-reg­u­la­to­ry RNA ele­ment encod­ed by any virus, in its native state, and­through­out the viral repli­ca­tion cycle (see Fig­ure 2). In doing so, we are unrav­el­ingthe mol­e­c­u­lar blue­print that dic­tates the mol­e­c­u­lar work­ings of an RNA virus andits reliance on spe­cif­ic inter­ac­tions the pro­teomes of virus and host. Cur­rent projects in this area aim at devel­op­ing tech­nolo­gies to assess RNA-pro­tein­in­ter­ac­tions and their func­tion­al roles at the sin­gle-cell and sin­gle-mol­e­cule level.

Fig­ure 2. RNA inter­ac­tomics for defined RNA regions in their native con­text. a, Graph­i­cal out­line of the SHIFTR method­ol­o­gy. b, Quan­ti­ta­tive mass spec­trom­e­try­da­ta for SHIFTR exper­i­ments tar­get­ing dif­fer­ent SARS-CoV­‑2 RNA regions.

2 | CRISPR meets Single Cells: From Interaction to Function

Com­ple­ment­ing the area of RNA inter­ac­tomics, we com­bine CRISPR screen­ingtech­nolo­gies with sin­gle-cell tran­scrip­tomics (named aka Per­turb-seq) tosys­tem­at­i­cal­ly elu­ci­date the impact of a large num­ber of host fac­tors on the gene­ex­pres­sion pro­grams of viral pathogens and their hosts. Lever­ag­ing AI and machine­learn­ing, these sin­gle-cell read­outs help iden­ti­fy path­ways and pro­grams rel­e­vant­to viral infec­tions and devise strate­gies to inter­fere with viral repli­ca­tion. Beyonds­in­gle-cell sequenc­ing, we employ advanced imag­ing tech­niques to obtain aspa­tio-tem­po­ral­ly resolved view on the com­plex mol­e­c­u­lar biol­o­gy of viralinfections.

3 | Molecular Mechanisms: a Path to New Antivirals

Our ulti­mate goal is to char­ac­ter­ize the mol­e­c­u­lar mech­a­nisms under­ly­ing (i) the­suc­cess­ful exe­cu­tion of viral repli­ca­tion pro­grams in human cells, and (ii) the abil­i­ty­of a host cell to restrict viral pathogens. Using our unique RNA-cen­tric approach,we pro­file inter­ac­tions at unprece­dent­ed res­o­lu­tion and resolve func­tion­alde­pen­den­cies for each viral RNA type, includ­ing incom­ing and repli­cat­ed viralgenomes, viral mRNAs, as well as viral repli­ca­tion inter­me­di­ates. This approach hasun­cov­ered fun­da­men­tal aspects of viral RNA biol­o­gy, includ­ing a pre­vi­ous­ly­over­looked pro­tein-prim­ing mech­a­nism uti­lized by SARS-CoV­‑2 (https://doi.org/10.1016/j.cell.2023.09.002), which is unex­pect­ed­ly con­trolled by ahost-encod­ed RNA-bind­ing protein.

4 | RNA Therapeutics

RNA-based ther­a­peu­tics hold tremen­dous poten­tial to rev­o­lu­tion­ize the treat­mentof human dis­eases, includ­ing infec­tious dis­eases. To improve the design anden­hance the bio­log­i­cal activ­i­ty of future RNA-based ther­a­peu­tics, we inves­ti­gate­how ther­a­peu­tic RNAs inter­act with and are sub­ject to reg­u­la­tion by the RNAreg­u­la­to­ry machin­ery of a tar­get cell. We focus on under­stand­ing the sequence­fea­tures of ther­a­peu­tic RNAs that deter­mine their sta­bil­i­ty and activ­i­ty in the tar­get­cell type, as well as their inter­ac­tion with the innate immune system.

For addi­tion­al infor­ma­tion on our research projects, please fol­low the link below:
https://www.klinikum.uni-heidelberg.de/zentrum-fuer-infektiologie/molecular-virology/about-us/research-teams/ag-munschauer

  • Aydin J, Gabel A, Zielin­s­ki S, Gan­skih S, Schmidt N, Har­ti­gan CR, Schenone M,Carr SA, Mun­schauer M. SHIFTR enables the unbi­ased iden­ti­fi­ca­tion of pro­teins­bound to spe­cif­ic RNA regions in live cells. Nucle­ic Acids Research (2024) gkae038. https://doi.org/10.1093/nar/gkae038
  • Schmidt N, Gan­skih S, Wei Y, Gabel A, Zielin­s­ki S, Keshishi­an H, Lareau CA,Zimmermann L, Makroczy­o­va J, Pearce C, Krey K, Hen­nig T, Stegmaier S, Moy­on L,Horlacher M, Wern­er S, Aydin J, Olguin-Nava M, Pota­bat­tula R, Kibe A, Dölken L,Smyth RP, Caliskan N, Mar­si­co A, Krem­pl C, Bodem J, Pichlmair A, Carr SA, ChlandaP, Erhard F, Mun­schauer M. SND1 binds SARS-CoV­‑2 neg­a­tive-sense RNA and­pro­motes viral RNA syn­the­sis through NSP9. Cell (2023) 186(22):4834–4850.e23. https://doi.org/10.1016/j.cell.2023.09.002
  • Schmidt N, Lareau C, Keshishi­an H, Gan­skih S, Schnei­der C, Hen­nig T, Melan­son R,Werner S, Wei Y, Zim­mer M, Ade J, Kirschn­er L, Zielin­s­ki S, Dölken L, Lan­der ES,Caliskan N, Fis­ch­er U, Vogel J, Carr SA, Bodem J, Mun­schauer M. The SARS-CoV-2RNA-pro­tein inter­ac­tome in infect­ed human cells. Nature Micro­bi­ol­o­gy (2021) 6, 339–353. https://doi.org/10.1038/s41564-020–00846‑z
  • Mun­schauer M# (# co-cor­re­spond­ing author), Nguyen CT, Sirokman K, Har­ti­gan CR, Hogstrom L, Engre­itz JM, Ful­co CP, Sub­ra­man­ian V, Chen J, Ulirch JC,Schenone M, Guttman M, Carr SA, Lan­der ES#. The NORAD lncR­NA assem­bles atopoi­so­merase com­plex crit­i­cal for genome sta­bil­i­ty. Nature (2018) 561(7721):132–136. https://doi.org/10.1038/s41586-018‑0453‑z
  • Baltz AG*, Mun­schauer M* (* co-first author), Schwan­haeuss­er B, Vasile A,Murakawa Y, Schuel­er M, Youngs N, Pen­fold-Brown D, Drew K, Milek M, Wyler E,Bonneau R, Sel­bach M, Dieterich C, and Landthaler M. The mRNA-bound pro­teome and its glob­al occu­pan­cy pro­file on pro­tein-cod­ing­tran­scripts. Mol­e­c­u­lar Cell (2012) 46(5):674–90. https://doi.org/10.1016/j.molcel.2012.05.021