Group Leader

Dr. Alexan­der Lercher

Depart­ment of Infec­tious Dis­eases, Inte­gra­tive Virology

alexander.lercher@med.uni-heidelberg.de

Phone: +49 6221 56–318452

Inflammatory signal integration and epigenetic memory in viral disease.

Group Mem­bers

Humans encounter a pletho­ra of microbes dai­ly. Immune cells are the first respon­ders to fend off pathogens, but can also cause life-threat­en­ing hyper­in­flam­ma­to­ry dys­reg­u­la­tion. We focus on viral infec­tion, where this bal­ance is par­tic­u­lar­ly pre­car­i­ous. Virus­es and cytokines are prime induc­ers of inflam­ma­tion, but cell-intrin­sic and extrin­sic fac­tors, includ­ing cell iden­ti­ty, tis­sue envi­ron­ment and even diet, influ­ence immune respons­es. Anoth­er reg­u­la­to­ry lay­er comes from past inflam­ma­to­ry encoun­ters, which result in durable epi­ge­net­ic mem­o­ry that alters sec­ondary immune responses.

There is a gap in our under­stand­ing of how cells inte­grate this myr­i­ad of immuno­log­i­cal and envi­ron­men­tal cues to mount ade­quate acute respons­es and estab­lish epi­ge­net­ic mem­o­ry. In the Lercher lab, we take a holis­tic approach to map the under­ly­ing mol­e­c­u­lar net­works and deci­pher the black box of inflam­ma­to­ry sig­nal inte­gra­tion and mem­o­ry for­ma­tion. We com­bine tractable pri­ma­ry cell cul­ture sys­tems with mouse mod­els of viral infec­tion to reca­pit­u­late real-world pathogen encoun­ters. Using next-gen­er­a­tion sequenc­ing, real-time imag­ing, genet­ic engi­neer­ing and immune pro­fil­ing, we aim to build a frame­work of sig­nal inte­gra­tion and cell-cell com­mu­ni­ca­tion across tis­sues in health and dis­ease. Our over­ar­ch­ing goal is to uncov­er fun­da­men­tal prin­ci­ples of immu­ni­ty that under­lie dis­ease devel­op­ment, pro­gres­sion and res­o­lu­tion, to enable new ther­a­peu­tic approach­es and boost pan­dem­ic preparedness.

Research Questions

+ How do cells inte­grate inflam­ma­to­ry cues to mount ade­quate immune responses?

+ What are the deter­mi­nants of cell-type or tis­sue-spe­cif­ic immune responses?

+ How do innate immune respons­es lead to durable epi­ge­net­ic memory?

+ Which cel­lu­lar and cross-organ com­mu­ni­ca­tion net­works shape innate immu­ni­ty and memory?

+ Can we use syn­thet­ic immunol­o­gy to build cir­cuits that con­trol com­plex immune responses?

Full pub­li­ca­tion list:

https://www.ncbi.nlm.nih.gov/myncbi/alexander.lercher.2/bibliography/public/

Lewy T, Sier­ra MA, Pour­sha­di N, Hoff­mann HH, Din­non KH 3rd, Gola A, Wang W, Chen HA, Quirk C, Zhang H, Doyle MP, Mason CE, Diehl GE, Hohl TM, Fuchs E, Mac­Don­ald MR, Wu Z, Crowe JE Jr, Rice CM*, Lercher A*. Brain endothe­lial cells orches­trate a neu­ro­pro­tec­tive antivi­ral state in the CNS in response to periph­er­al viral pat­tern sens­ing. Immu­ni­ty. 2026

Link: https://www.cell.com/immunity/fulltext/S1074-7613(26)00260–8

Lercher A, Cheong JG, Bale MJ, Jiang C, Hoff­mann HH, Ash­brook AW, Lewy T, Yin YS, Quirk C, DeGrace EJ, Chiri­bo­ga L, Rosen­berg BR, Jose­fow­icz SZ, Rice CM. Antivi­ral innate immune mem­o­ry in alve­o­lar macrophages fol­low­ing SARS-CoV­‑2 infec­tion ame­lio­rates sec­ondary influen­za A virus dis­ease. Immu­ni­ty. 2024

Link: https://www.cell.com/immunity/fulltext/S1074-7613(24)00417–5

Lercher A, Popa AM, Viczenc­zo­va C, Kosack L, Klavins K, Ager­er B, Opitz CA, Lanz TV, Plat­ten M, Bergth­aler A. Hepa­to­cyte-intrin­sic type I inter­fer­on sig­nal­ing repro­grams metab­o­lism and reveals a nov­el com­pen­sato­ry mech­a­nism of the tryp­to­phan-kynure­nine path­way in viral hepati­tis. PLoS Pathogens. 2020

Link: https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1008973

Lercher A, Baaz­im H, Bergth­aler A. Sys­temic Immunome­tab­o­lism: Chal­lenges and Oppor­tu­ni­ties. Immu­ni­ty. 2020

Link: https://www.cell.com/immunity/fulltext/S1074-7613(20)30369–1

Lercher A, Bhat­tacharya A, Popa AM, Caldera M, Schla­pan­sky MF, Baaz­im H, Ager­er B, Gürtl B, Kosack L, Májek P, Brun­ner JS, Vitko D, Pin­ter T, Genger JW, Orlo­va A, Pikor N, Reil D, Ozsvár-Koz­ma M, Kalinke U, Ludewig B, Morig­gl R, Ben­nett KL, Menche J, Cheng PN, Sch­ab­bauer G, Trauner M, Klavins K, Bergth­aler A. Type I Inter­fer­on Sig­nal­ing Dis­rupts the Hepat­ic Urea Cycle and Alters Sys­temic Metab­o­lism to Sup­press T Cell Func­tion. Immu­ni­ty. 2019

Link: https://www.cell.com/immunity/fulltext/S1074-7613(19)30458–3