University of Virginia Health System

Email Address: mgb4n@virginia.edu

A central objective of current research in the laboratory is aimed to examine, identify and characterize molecular and cellular mechanisms of innate immunity and antiviral host defenses.  Classical genetics strategies are a mainstay for the research program as genetic diversity in common laboratory strains of mice clearly affects innate immune responses toward viruses and consequently may also contribute to variation in host disease resistance or susceptibility traits.  Identification of major alleles, sculpted through natural selection (genetic diversity), that affect innate immune control (resistance alleles), a lack of immune control (susceptibility alleles), or altered or even dysfunctional immune control (potential autoimmune disease alleles), will undoubtedly foster our understanding of the immune system and should also lead to new potential targets for therapeutic interventions. Two major research project areas established in the lab are detailed below.

Virus Immunity Research ­ Microbiology, Immunology and Infectious Disease

Natural killer cells are well known for efficient recognition and killing of virus infected cells.  Their intrinsic value is highlighted because they contribute in innate immunity against a wide range of pathogens, including RNA and DNA viruses. In fact, NK cells in humans and mice have a major role in controlling herpesvirus infections.  Previous work from our lab and others has shown that NK cells in C57BL/6 mice require Ly49H activation receptors to control murine cytomegalovirus (MCMV) infection.  Ly49H is now known to recognize MHC class I-related ligands on infected cells that are encoded and expressed by MCMV’s m157 gene.  Further study of NK cell-mediated virus immunity in the lab now focuses on MHC-dependent (H-2k) MCMV resistance since a mechanistic understanding for this mode of innate virus protection is still vague.  Genetic mapping strategies and later identification of candidate virus resistance or susceptibility alleles is a major research objective that should enhance our understanding of MHC-dependent innate virus immunity, NK cell recognition of virus infected cells, and also viral immune evasion mechanisms.  Because human NK cells also display NK cell KIR receptors for MHC class I molecules and some KIR / MHC I allele combinations correlate with disease progression rates in HCV or HIV virus infected patients, these studies might also yield important insights into the role of human NK cells in virus infections.

Viral Pathogenesis Research ­ Immunity and Inflammation

We have shown that immune competent systemic lupus erythematosus (SLE-) prone NZM2328 mice display marked sialadenitis during acute MCMV infection when virus levels are elevated (d.14-28) in the salivary glands.  Later, when viral latency is established in most MCMV-infected NZM2328 females (typically by d. 56 after infection), a qualitative shift from diffuse to focal inflammation in salivary and lacrimal glands occurs that is marked by lymphocyte aggregation in periductal foci, some with lymphocytes segregated into lymphoid-like structures.  Additionally, we have shown that salivary gland function is also significantly compromised in NZM2328 mice at discrete times after infection.  Interestingly, these features are similar to those observed in Sjögren’s Syndrome (SS) patients who display exocrine gland dysfunction.  Thus, virus-induced sialadenitis in NZM2328 mice might prove useful in modeling SS or SS secondary to HCV infection.  To extend our work and to investigate a potential role for genetic factors in virus-induced exocrinopathy, similar studies are underway in genetically-related inbred strains of mice.  Future research is therefore aimed to investigate the genetic and cellular basis for virus-induced inflammation and exocrine gland dysfunction in this model system.