The primary interest of Dr. Xiang’s laboratory is host-pathogen interactions, with poxviruses as the model systems. Poxviruses include some dangerous emerging or re-emerging pathogens as well as some promising vaccine vectors for infectious diseases and cancers.
The main research projects are:
1. Mechanisms of antiviral immunity and viral strategies of immune evasion.
Viruses have evolved ingenious strategies to evade host antiviral immunity. Uncovering these strategies will not only provide insights on viral pathogenesis but also could reveal important aspects of host immunity. Poxviruses are unique among viruses in that they encode a large number of proteins that are dedicated to evading host immune responses. These proteins include secreted inhibitors of cytokines as well as intracellular inhibitors of immune signaling or antiviral factors.
Xiang lab has studied extensively a secreted interleukin-18 binding protein (IL-18BP) from poxviruses and their mammalian hosts. Interleukin-18 (IL-18) is a proinflammatory cytokine that can enhance both the innate and acquired immunity. IL-18 protects against microbial infection and tumors. Excessive IL-18 activities, however, are associated with autoimmune and inflammatory diseases. The work from Xiang lab has elucidated the mechanism by which IL-18BPs bind and inhibit IL-18. The detailed structural knowledge has also been used in developing small molecule inhibitors of IL-18, which could potentially be useful for treating inflammatory diseases.
Xiang lab has also studied extensively viral host-range determinants and their specific antagonism of host restriction factors. The interferon (IFN) system is the first line of host defense against intracellular pathogens, particularly viruses. IFNs induce the expression of hundreds of interferon-stimulated genes (ISGs), some of which are antiviral factors that restrict viral replication. To successfully replicate in the cells, viruses have to overcome the formidable barriers posed by the IFN system, particularly the restriction factors. Research from Xiang lab recently showed that a paralogous pair of ISGs, SAMD9 and SAMD9L, form a critical host barrier against poxvirus Infection. Poxviruses, in turn, employ two structurally distinct classes of inhibitors to antagonize SAMD9 and SAMD9L. The outcome of this genetic conflict between poxviruses and their hosts is a major determinant for poxvirus host range. SAMD9 and SAMD9L are tumor suppressors, and their mutations are associated with cancers or developmental disorders.
2. Viral assembly mechanism.
Viruses, as obligate intracellular parasites, have evolved strategies to manipulate the cellular membranes for entry, genome replication, virion production, and exit. Enveloped viruses typically acquire their outer lipid bilayer by budding from cellular membranes. Poxviruses, however, are unusual in that their primary envelope is not acquired by budding but through extending of open-ended crescent membranes. The origin and biogenesis of the crescent membranes have puzzled virologists for over half a century, albeit recent studies suggest that the crescents may derive from the endoplasmic reticulum (ER). Five viral proteins, conserved in all vertebrate poxviruses and collectively termed viral membrane assembly proteins (VMAPs), have been found to be essential for the biogenesis of crescent membranes.The A6 protein of vaccinia virus (VACV) is the largest VMAP, which Xiang lab discovered and have continued to study its mechanism of action. Uncovering the mechanism by which poxviruses acquire the envelope not only reveal key viral replication steps for developing antivirals but also provide mechanistic insights on fundamental cellular processes.
3. Antibody response to vaccination.
Vaccinia virus, the live vaccine for smallpox, is one of the most successful vaccines in human history but presents a level of risk that has become unacceptable for the current population. Studying the immune protection mechanism of smallpox vaccine is important for understanding the basic principle of successful vaccines and the development of next generation, safer vaccines. Xiang lab has studied antibody targets in smallpox vaccine by comprehensively characterizing monoclonal antibodies against vaccinia antigens. The knowledge has also been used to optimize vaccinia-based vaccines against other infectious diseases.
Complete List of Publications
Mechanisms of antiviral immunity and viral strategies of immune evasion.
Krumm B, Meng X, Li Y, Xiang Y, Deng J. 2008. Structural basis for antagonism of human interleukin 18 by poxvirus interleukin 18-binding protein. Proc Natl Acad Sci U S A. 105(52):20711-5.
Meng X, Krumm B, Li Y, Deng J, Xiang Y. 2015. Structural basis for antagonizing a host restriction factor by C7 family of poxvirus host-range proteins. Proc Natl Acad Sci U S A. 112(48):14858-63.
Meng X, Zhang F, Yan B, Si C, Honda H, Nagamachi A, Sun L, and Xiang Y. 2018. A Paralogous Pair of Mammalian Host Restriction Factors Form a Critical Host Barrier against Poxvirus Infection. Plos Pathogens. Accepted.
Viral assembly mechanism.
Meng X, Embry A, Rose L, Yan B, Xu C, Xiang Y. 2012. Vaccinia virus A6 is essential for virion membrane biogenesis and localization of virion membrane proteins to sites of virion assembly. Journal of virology. 86(10):5603-13.
Meng X, Rose L, Han Y, Deng J, Xiang Y. 2017. Vaccinia Virus A6 Is a Two-Domain Protein Requiring a Cognate N-Terminal Domain for Full Viral Membrane Assembly Activity. Journal of virology. 91(10).
Weisberg AS, Maruri-Avidal L, Bisht H, Hansen BT, Schwartz CL, Fischer ER, Meng X, Xiang Y, Moss B. 2017. Enigmatic origin of the poxvirus membrane from the endoplasmic reticulum shown by 3D imaging of vaccinia virus assembly mutants.Proc Natl Acad Sci U S A.114(51):E11001-E11009.
Antibody response to vaccination.
Meng X, Zhong Y, Embry A, Yan B, Lu S, Zhong G, Xiang Y. 2011. Generation and characterization of a large panel of murine monoclonal antibodies against vaccinia virus. Virology. 409(2):271-9.
Embry A, Meng X, Cantwell A, Dube PH, Xiang Y. 2011. Enhancement of immune response to an antigen delivered by vaccinia virus by displaying the antigen on the surface of intracellular mature virion. Vaccine. 29(33):5331-9.
Kaever T, Meng X, Matho MH, Schlossman A, Li S, Sela-Culang I, Ofran Y, Buller M, Crump RW, Parker S, Frazier A, Crotty S, Zajonc DM, Peters B, Xiang Y. 2014. Potent neutralization of vaccinia virus by divergent murine antibodies targeting a common site of vulnerability in L1 protein. Journal of virology. 88(19):11339-55.