Principal Investigator:

The role of FXR signaling during infection with
persistent prone virus

Suppression of viral replication after a primary infection is one important factor of the immune response to defend disease. In recent publications we and others showed that liver-resident macrophages (Kupffer cells) and red pulp macrophages play an essential role in the early virus control. Both cell types take up virus inoculum minutes after inoculation and suppress its propagation. Molecular mechanisms exerted by these cell types remain to be defined. In the second funding period, we will use different screening approaches to identify new genes that are involved in the process of virus uptake and suppression. With the help of gene-targeted mice we will confirm the importance of the newly identified candidates. Molecular and cellular mechanisms will be defined. Ultimately, our project aims to identify the importance of new genes in the antiviral immune defense.

Publications

Duhan V, Khairnar V, Friedrich SK, Zhou F, Gassa A, Honke N, Shaabani N, Gailus N, Botezatu L, Khandanpour C, Dittmer U, Häussinger D, Recher M, Hardt C, Lang PA, Lang KS. Virus-specific antibodies allow viral replication in the marginal zone, thereby promoting CD8(+) T-cell priming and viral control. Sci Rep. 2016 Jan 25;6:19191.

Honke N, Shaabani N, Cadeddu G, Sorg UR, Zhang DE, Trilling M, Klingel K, Sauter M, Kandolf R, Gailus N, van Rooijen N, Burkart C, Baldus SE, Grusdat M, Lohning M, Hengel H, Pfeffer K, Tanaka M, Haussinger D, Recher M, Lang PA, Lang KS. Enforced viral replication activates adaptive immunity and is essential for the control of a cytopathic virus. Nat Immunol 2012; 13:51-57.

Honke N, Shaabani N, Zhang DE, Iliakis G, Xu HC, Häussinger D, Recher M, Löhning M, Lang PA, Lang KS. Usp18 driven enforced viral replication in dendritic cells contributes to break of immunological tolerance in autoimmune diabetes. PLoS Pathog. 2013; 9(10):e1003650.

Honke N, Shaabani N, Merches K, Gassa A, Kraft A, Ehrhardt K, Häussinger D, Löhning M, Dittmer U, Hengel H, Recher M, Lang PA, Lang KS. Immunoactivation induced by chronic viral infection inhibits viral replication and drives immunosuppression through sustained IFN-I responses. Eur J Immunol. 2015; 10.1002/eji.201545765.

Honke N, Shaabani N, Hardt C, Krings C, Häussinger D, Lang PA, Keitel V, Lang KS. Farnesoid X receptor in mice prevents severe liver immunopathology during lymphocytic choriomeningitis virus infection. Cell Physiol Biochem. 2017;41(1):323-338. doi: 10.1159/000456168.

Khairnar V, Duhan V, Maney S, Honke N, Shaabani N, Pandyra A, Pozdeev V, Xu HC, Seifert M, Sharma P, Baldin F, Marquardsen F, Kirschning C, Merches K, Westendorf AM, Häussinger D, Dittmer U, Küppers R, Recher M, Hardt C, Scheffrahn I, Beauchemin N, Göthert JR, Singer BB, Lang PA, Lang KS. CEACAM1 induces B-cell survival and is essential for protective antiviral antibody production. Nature communications 2015; 6:6217.

Lang PA, Recher M, Honke N, Scheu S, Borkens S, Gailus N, Krings C, Meryk A, Kulawik A, Cervantes-Barragan L, Van Rooijen N, Kalinke U, Ludewig B, Hengartner H, Harris N, Haussinger D, Ohashi PS, Zinkernagel RM, Lang KS. Tissue macrophages suppress viral replication and prevent severe immunopathology in an interferon-I-dependent manner in mice. Hepatology 2010; 52:25-32.

Shaabani N, Duhan V, Khairnar V, Gassa A, Ferrer-Tur R, Häussinger D, Recher M, Zelinskyy G, Liu J, Dittmer U, Trilling M, Scheu S, Hardt C, Lang PA, Honke N, Lang KS. CD169+ macrophages regulate PD-L1 expression via type I interferon and thereby prevent severe immunopathology after LCMV infection. Cell Death Dis. 2016 Nov 3;7(11):e2446.

Shaabani N, Khairnar V, Duhan V, Zhou F, Tur RF, Häussinger D, Recher M, Tumanov AV, Hardt C, Pinschewer D, Christen U, Lang PA, Honke N, Lang KS. Two separate mechanisms of enforced viral replication balance innate and adaptive immune activation. J Autoimmun. 2015; S0896-8411(15)30049-4.

Xu HC, Grusdat M, Pandyra AA, Polz R, Huang J, Sharma P, Deenen R, Köhrer K, Rhabar R, Diefenbach A, Gibbert K, Löhning M, Höcker L, Waibler Z, Häussinger D, Mak TW, Ohashi PS, Lang KS, Lang PA. Type I interferon protects anti-viral CD8+ T cells from NK cell cytotoxicity. Immunity 2014; 40(6):949-60.