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Dr Anne L’Hernault

Dr Anne L’Hernault

Research Associate

Infectious Disease

microRNAs

Innate immunity


Office Phone: 01223 336853

Research Interests

Millions of years of co-evolution have resulted in a complex interaction network between natural killer (NK) cells and murine cytomegalovirus (MCMV). This has driven the expansion of activating and inhibitory NK cell receptors as well as viral inhibitors/activators thereof. Differences in the Ly49 receptor repertoire play a major role in the susceptibility of different mouse strains to acute MCMV infection. As such, direct recognition of the MCMV m157 protein on the cell surface results in robust NK cell activation and elimination of MCMV infected cells. This interaction is responsible for the increased resistance of C57BL/6 mice to acute MCMV infection. In MAMy/J mice, resistance to MCMV is mediated via the activating NK cell receptor Ly49P. This has been shown to recognize a complex of MHC-I molecules (H2-Dk) and the viral m04 protein. During lytic MCMV infection, the m06 and m152 proteins inhibit MHC-I antigen presentation by disrupting transport of MHC-I molecules to the plasma membrane. In order to evade NK cell activation via the missing-self-recognition mechanism, the m04 protein binds to MHC-I molecules and rescues surface expression. Thus, m04 appears to balance viral evasion of NK missing-self-recognition and CD8 T cell priming. Interestingly, expression of m04 in the right MHC-I context (H2-Dk) is not sufficient to activate NK cells via Ly49P. Here, we show that this activation is also dependent on the most abundant MCMV transcript, m169, which we recently found to mediate degradation of two cellular miRNAs (miR-27a/b) by a mechanism involving their 3’-tailing and -trimming. Nevertheless, activation of Ly49P was neither dependent on miR-27a/b degradation nor on the 17 kD protein encoded by m169. In contrast, deletion or mutation of the m169 5’ UTR completely abolished NK cell activation. To our knowledge, m169 is the first viral transcript that contains both coding and non-coding functions. We are currently investigating the mechanisms by which the m169 5’ UTR mediates activating Ly49 recognition.

Keywords

NK ; microRNA ; non-coding RNA ; MHC class I ; MHC ; viral evasion ; CD8+ ; natural killer cells ; natural killer receptors ; RNA viruses

Topics

  • cytomegalovirus
  • infectious diseases

Key Publications

Bell N, L’Hernault A, Murat P, Richards JE, Lever AM, Balasubramanian S. Targeting RNA-protein interactions within the HIV Type 1 lifecycle. Biochemistry 2013; 52(51): 9269-9274

Windhager L, Bonfert T, Burger K, Ruzsics Z, Krebs S, Kaufmann S, Malterer G, L'Hernault A, Schilhabel M, Schreiber S, Rosenstiel P, Zimmer R, Eick D, Friedel CC, Dölken L. Ultrashort and progressive 4sU-tagging reveals key characteristics of RNA processing at nucleotide resolution. Genome Res. 2012 Oct;22(10):2031-42.

L'Hernault A, Weiss EU, Greatorex JS, Lever AM. HIV-2 genome dimerization is required for the correct processing of Gag: a second-site reversion in matrix can restore both processes in dimerization-impaired mutant viruses. J Virol. 2012 May;86(10):5867-76.

L'Hernault A, Greatorex JS, Crowther RA, Lever AM. Dimerisation of HIV-2 genomic RNA is linked to efficient RNA packaging, normal particle maturation and viral infectivity. Retrovirology. 2007 Dec 13;4:90.