Dr. Jia Zhu is affiliate member in VIDD and research assistant professor in the Department of Laboratory Medicine, University of Washington.
For the past several years, Zhu has studied the human immune response to genital HSV-2 reactivation and its impact on increased HIV acquisition in HSV-2 infected individuals. She has developed several tools, including a novel methodology for detecting antigen-specific T cells in situ using Quantum dots nanoparticles conjugated peptide-MHC multimers to characterize the spatiotemporal dynamics of various immune cells, especially HSV-2 specific CD8 T cells in human genital tissue during herpes lesion evolution. These studies have shown for the first time that virus-specific CD8 T cells persist at the healed lesion site and accumulated near sensory nerve endings in the genital skin and mucosa during subclinical HSV-2 reactivation.
“Battlefield” between human host and viral pathogen
The human pathogen herpes simplex virus type 2 (HSV-2) is a leading cause of genital ulcer disease and a risk factor for HIV acquisition and transmission. Recent studies have shown that over 80% of HSV-2 reactivations are subclinical and of short duration, typically lasting only 6 to 12 hours. This indicates that a rapid host immune response in the genital skin and mucosa (i.e., the periphery) can contain viral reactivation thus preventing symptoms. The lab’s work has shown that HSV-specific CD8 T cells persist in the periphery at the dermal-epidermal junction (DEJ) contiguous to the sensory nerve endings where HSV virion particles are released, and that HSV-2 specific CD8 T cells frequently encounter viral antigens. These resident, persistent CD8 T cells at the DEJ exert antiviral effector functions upon re-encountering viral antigen and rapidly eliminate infected cells before the virus can cause clinically symptomatic disease. The lab has a platform to understand this “battleground:” HSV pathobiology and the peripheral immunity required for effective protection and control of viral infection.
Zhu has developed novel technologies to define, in situ, the mechanisms by which these CD8 T cells contain virus at the DEJ. The lab uses in situ immunofluorescence staining and cell type specific laser capture microdissection (LCM) on patient biopsies to define immune control mechanisms and proliferation for T cells at their original anatomic site and native physiological state. They also use high-throughput sequencing of the T-cell receptor (TCR) to determine the breadth and clonality of the TCR repertoire in locally affected skin/mucosa tissue and in blood.
Tissue resident memory CD8 T cells in HSV-2 disease severity
As a newly identified lymphoid linage, tissue resident memory (TRM) T cell provides effective, localized protection against pathogen re-encountering at barrier surfaces. The TRM cells persist in local tissues without recirculation and have little representation in the blood lymphocytes. Resident CD8+ T cells exhibit effective protection superior to their circulating counterparts and provide global immunity in skin and mucosa against local challenge. In human HSV-2 infection, the disease spectrum varies widely from completely asymptomatic to infrequent and short-lasting recurrences to frequent and severe genital ulcerations. TRM CD8+ T cells localize at the dermal-epidermal junction interacting with basal keratinocytes, the periphery target of reactivating HSV viruses. Zhu and her team currently are studying whether the quantity, quality or diversity of TRM CD8+ T cells affects the antiviral function of barrier tissue, and therefore influences disease outcomes in HSV-2 infected people.
Protective Role of CD8αα T cells in the Human Female Reproductive Tract
Recently published work (Zhu, et al. 2013, Nature) indicates that these resident and persisting CD8 T cells express the CD8αα homodimer as a co-receptor instead of the heterodimeric CD8αβ which dominates blood circulating CD8 T cells. CD8αα has been proposed to preserve high-affinity effector T cells for long-lived mucosal memory. Whether CD8αα expression is a general mechanism for tissue resident memory in the human periphery is currently unclear.
The mucosal surface of the vagina and ectocervix serves as both the point of entry as well as a barrier against sexually transmitted pathogens. The lab investigates the immunological relevance of CD8αα T cells in the human female reproductive tract (FRT) using biopsies of vulva, vagina and ectocervical tissue, as well as the residency status of CD4 T cells. These studies can then directly inform design of future vaccines and immunotherapeutic approaches that elicit a tissue resident immune response with the hope of effectively protecting against STIs.
Modeling inflammation in HIV transmission
Epidemiologic studies suggest that the risk of acquiring HIV-1 infection is increased in women with cervicovaginal inflammation induced by STIs, especially HSV-2. However, despite the epidemiologic associations and supporting circumstantial evidence, it is not possible to directly determine the effects of genital inflammation on HIV transmission in humans. Zhu and colleagues are using a non-human primate (NHP) model to study the role HSV-2-induced genital inflammation plays in HIV transmission and dissemination after vaginal exposure, and whether HIV transmission can be mitigated by combining antimicrobial therapy and topical anti-inflammatory agents that reduce genital inflammation.
Zhu received a Bachelor of Sciences in the Department of Biochemical Engineering, East China University of Chemical Technology, Shanghai, P.R. China and her PhD from the Chinese Academy of Sciences, Shanghai Institute of Materia Medica, Shanghai, P.R. China. She did her post graduate training at University of Maryland School of Medicine, the Wistar Institute in Philadelphia, and Harvard Medical School. Zhu joined the Department of Laboratory Medicine, University of Washington in 2003 and the Hutchinson Center in 2006. In her spare time, Zhu enjoys cooking, reading, hiking and traveling.
Peng T, Chanthaphavong RS, Sun S, Trigilio JA, Phasouk K, Jin L, Layton ED, Li AZ, Correnti CE, De van der Schueren W, Vazquez J, O'Day DR, Glass IA, Knipe DM, Wald A, Corey L, Zhu J. Keratinocytes produce IL-17c to protect peripheral nervous systems during human HSV-2 reactivation. J Exp Med. 2017 Jun 29.
Posavad CM, Zhao L, Dong L, Jin L, Stevens CE, Magaret AS, Johnston C, Wald A, Zhu J, Corey L, Koelle DM. Enrichment of herpes simplex virus type 2 (HSV-2) reactive mucosal T cells in the human female genital tract. Mucosal Immunol. 2017 Jan 4.
Milman N, Zhu J, Johnston C, Cheng A, Magaret A, Koelle DM, Huang ML, Jin L, Klock A, Layton ED, Corey L. In situ detection of regulatory T cells in human genital HSV-2 reactivation and their influence on spontaneous HSV-2 reactivation. J Infect Dis. 2016 Jul 1;214(1):23-31.
Johnston C, Zhu J, Jing L, Laing KJ, McClurkan CM, Klock A, Diem K, Jin L, Stanaway J, Tronstein E, Kwok WW, Huang ML, Selke S, Fong Y, Magaret A, Koelle DM, Wald A, Corey L. Virologic and immunologic evidence of multifocal genital herpes simplex virus 2 infection. J Virol. 2014 May;88(9):4921-31.
Zhu J, Peng T, Johnston C, Phasouk K, Kask Angela, Klock A, Jin L, Diem K, Koelle DM, Wald A, Robins H and Corey L. Immune Surveillance by CD8αα+ Skin Resident T Cells in Human Herpesvirus Infection. Nature. 2013 May 23;497(7450):494-7.
Zhu J*, Peng T*, Phasouk K, Koelle DM, Wald A and Corey L. An Effector phenotype of CD8+ T cells at the junction epithelium during clinical quiescence of HSV-2 infection. J Virol. 2012;86(19):10587-96. *Co-first authors. PMC3457322
Chapuis AG, Casper C, Kuntz S, Zhu J, Tjernlund A, Diem K, Turtle CJ, Cigal ML, Velez R, Riddell SR, Corey L, Greenberg P. HIV-specific CD8+ T cells from HIV+ individuals receiving HAART can be expanded ex-vivo to augment systemic and mucosal immunity in vivo. Blood. 2011 May 19;117(20):5391-402. PMC3109713
Schiffer JT, Abu-Raddad L, Mark KE, Zhu J, Selke S, Koelle DM, Wald A, Corey L. Mucosal host immune response predicts the severity and duration of herpes simplex virus-2 genital tract shedding episodes. Proc Natl Acad Sci U S A. 2010;107(44):18973-8. PMC2973882
Schiffer JT, Abu-Raddad L, Mark KE, Zhu J, Selke S, Magaret A, Wald A, Corey L. Frequent release of low amounts of herpes simplex virus from neurons: results of a mathematical model. Sci Transl Med. 2009;1(7):7ra16. PMC2818652
Zhu J, Hladik F, Woodward A, Klock A, Peng T, Johnson C, Remington M, Magaret A, Koelle D, Wald A and Corey L. Persistence of HIV-1 receptor-positive cells after HSV-2 reactivation is a potential mechanism for increased HIV-1 acquisition. Nat Med. 2009;15(8):886-92. PMC2723183
Peng T, Zhu J, Klock A, Phasouk K, Huang ML, Koelle DM, Wald A and Corey L. Evasion of mucosal innate immune system by HSV-2. J Virol. 2009;83(23):12559-68. PMC2786730
Zhu J*, Peng T*, Hwangbo Yon, Corey L and Bumgarner RE. Independent and cooperative antiviral actions of beta interferon and gamma interferon against herpes simplex virus replication in primary human fibroblasts. J Virol. 2008;82(4):1934-45. *Co-first authors. PMC2258722
Zhu J, Koelle DM, Cao J, Vazquez J, Huang ML, Hladik F, Wald A, and Corey L. Virus-specific CD8+ T cells accumulate near sensory nerve endings in genital skin during subclinical HSV-2 reactivation. J Exp Med. 2007;204(3):595-603. PMC2137910