Research Article: Genomic Modifiers of Natural Killer Cells, Immune Responsiveness and Lymphoid Tissue Remodeling Together Increase Host Resistance to Viral Infection

Date Published: February 4, 2016

Publisher: Public Library of Science

Author(s): Alyssa Lundgren Gillespie, Jeffrey Teoh, Heather Lee, Jessica Prince, Michael D. Stadnisky, Monique Anderson, William Nash, Claudia Rival, Hairong Wei, Awndre Gamache, Charles R. Farber, Kenneth Tung, Michael G. Brown, Chris A. Benedict.


The MHC class I Dk molecule supplies vital host resistance during murine cytomegalovirus (MCMV) infection. Natural killer (NK) cells expressing the Ly49G2 inhibitory receptor, which specifically binds Dk, are required to control viral spread. The extent of Dk-dependent host resistance, however, differs significantly amongst related strains of mice, C57L and MA/My. As a result, we predicted that relatively small-effect modifier genetic loci might together shape immune cell features, NK cell reactivity, and the host immune response to MCMV. A robust Dk-dependent genetic effect, however, has so far hindered attempts to identify additional host resistance factors. Thus, we applied genomic mapping strategies and multicolor flow cytometric analysis of immune cells in naive and virus-infected hosts to identify genetic modifiers of the host immune response to MCMV. We discovered and validated many quantitative trait loci (QTL); these were mapped to at least 19 positions on 16 chromosomes. Intriguingly, one newly discovered non-MHC locus (Cmv5) controlled splenic NK cell accrual, secondary lymphoid organ structure, and lymphoid follicle development during MCMV infection. We infer that Cmv5 aids host resistance to MCMV infection by expanding NK cells needed to preserve and protect essential tissue structural elements, to enhance lymphoid remodeling and to increase viral clearance in spleen.

Partial Text

Yellow fever virus (YFV), once a major scourge of humanity, was one of the first viruses studied experimentally in mammalian hosts [1]. In pioneering studies, Nobel Laureate Max Theiler developed an inactivated YFV vaccine [2], and laid the groundwork for investigations into the genetic basis of host resistance to virus infection. Sawyer and Lloyd later observed that different strains of white mice are differently susceptible to YFV [3], and Lynch and Hughes solidified the point that YFV susceptibility is a heritable trait [4]. Many years later, the underlying cause of disease and effect of genetic variance on host resistance to viral infection and pathogenesis is still of vital interest [5], as it promises to reveal yet unknown molecular targets, signaling pathways and cellular networks with relevance to human health and disease.

Although small-effect QTL were thought to increase the extent of Dk-dependent resistance to MCMV in C57L, compared to MA/My background mice [26], until now they have eluded detection likely due to the robust effect of Dk. A genome-driven integrated approach with multiparametric flow cytometry revealed 56 novel immune and MCMV responsive QTL. Though improbable that any two separately measured traits (e.g. splenic MCMV level and percentage G2+ NK cells postinfection) would map similarly, unless controlled by the same, or another closely linked gene, the combined approach helped to distinguish significant genomic linkages. Importantly, the combined genome scanning approach resulted in the discovery and mapping of multiple QTL, which together shape strain-specific variances associated with MCMV infection.




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