[en] Transmission is a matter of life or death for pathogen lineages and can therefore be considered as the main motor of their evolution. Gammaherpesviruses are archetypal pathogenic persistent viruses which have evolved to be transmitted in presence of specific immune response. Identifying their mode of transmission and their mechanisms of immune evasion is therefore essential to develop prophylactic and therapeutic strategies against these infections. As the known human gammaherpesviruses, Epstein-Barr virus and Kaposi's Sarcoma-associated Herpesvirus are host-specific and lack a convenient in vivo infection model; related animal gammaherpesviruses, such as murine gammaherpesvirus-68 (MHV-68), are commonly used as general models of gammaherpesvirus infections in vivo. To date, it has however never been possible to monitor viral excretion or virus transmission of MHV-68 in laboratory mice population. In this study, we have used MHV-68 associated with global luciferase imaging to investigate potential excretion sites of this virus in laboratory mice. This allowed us to identify a genital excretion site of MHV-68 following intranasal infection and latency establishment in female mice. This excretion occurred at the external border of the vagina and was dependent on the presence of estrogens. However, MHV-68 vaginal excretion was not associated with vertical transmission to the litter or with horizontal transmission to female mice. In contrast, we observed efficient virus transmission to naive males after sexual contact. In vivo imaging allowed us to show that MHV-68 firstly replicated in penis epithelium and corpus cavernosum before spreading to draining lymph nodes and spleen. All together, those results revealed the first experimental transmission model for MHV-68 in laboratory mice. In the future, this model could help us to better understand the biology of gammaherpesviruses and could also allow the development of strategies that could prevent the spread of these viruses in natural populations.
Disciplines :
Microbiology
Author, co-author :
François, Sylvie ; Université de Liège - ULiège > Immunologie et vaccinologie
Vidick, Sarah ; Université de Liège - ULiège > Immunologie et vaccinologie
Desmecht, Daniel ; Université de Liège - ULiège > Département de morphologie et pathologie > Pathologie spéciale et autopsies
Drion, Pierre ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > GIGA-R:Méth. expér.des anim. de labo et éth. en expér. anim.
Thorley-Lawson DA, Gross A (2004) Persistence of the Epstein-Barr virus and the origins of associated lymphomas. N Engl J Med 350: 1328-1337.
Verma SC, Robertson ES (2003) Molecular biology and pathogenesis of Kaposi sarcoma-associated herpesvirus. FEMS Microbiol Lett 222: 155-163.
Young LS, Rickinson AB (2004) Epstein-Barr virus: 40 years on. Nat Rev Cancer 4: 757-768.
Mesri EA, Cesarman E, Boshoff C (2010) Kaposi's sarcoma and its associated herpesvirus. Nat Rev Cancer 10: 707-719.
Cesarman E (2011) Gammaherpesvirus and lymphoproliferative disorders in immunocompromised patients. Cancer Lett 305: 163-174.
Niederman JC (1982) Infectious mononucleosis: observations on transmission. Yale J Biol Med 55: 259-264.
Niederman JC, Miller G, Pearson HA, Pagano JS, Dowaliby JM (1976) Infectious mononucleosis. Epstein-Barr-virus shedding in saliva and the oropharynx. N Engl J Med 294: 1355-1359.
Hadinoto V, Shapiro M, Sun CC, Thorley-Lawson DA (2009) The dynamics of EBV shedding implicate a central role for epithelial cells in amplifying viral output. PLoS Pathog 5: e1000496.
Pica F, Volpi A (2007) Transmission of human herpesvirus 8: an update. Curr Opin Infect Dis 20: 152-156.
Sixbey JW, Lemon SM, Pagano JS (1986) A second site for Epstein-Barr virus shedding: the uterine cervix. Lancet 2: 1122-1124.
Silver MI, Paul P, Sowjanya P, Ramakrishna G, Vedantham H, et al. (2011) Shedding of Epstein-Barr virus and cytomegalovirus from the genital tract of women in a periurban community in Andhra Pradesh, India. J Clin Microbiol 49: 2435-2439.
Taylor MM, Chohan B, Lavreys L, Hassan W, Huang ML, et al. (2004) Shedding of human herpesvirus 8 in oral and genital secretions from HIV-1- seropositive and -seronegative Kenyan women. J Infect Dis 190: 484-488.
Whitby D, Smith NA, Matthews S, O'Shea S, Sabin CA, et al. (1999) Human herpesvirus 8: seroepidemiology among women and detection in the genital tract of seropositive women. J Infect Dis 179: 234-236.
Israele V, Shirley P, Sixbey JW (1991) Excretion of the Epstein-Barr virus from the genital tract of men. J Infect Dis 163: 1341-1343.
Naher H, Gissmann L, Freese UK, Petzoldt D, Helfrich S (1992) Subclinical Epstein-Barr virus infection of both the male and female genital tract-indication for sexual transmission. J Invest Dermatol 98: 791-793.
Blaskovic D, Stancekova M, Svobodova J, Mistrikova J (1980) Isolation of five strains of herpesviruses from two species of free living small rodents. Acta Virol 24: 468.
Francois S, Vidick S, Sarlet M, Michaux J, Koteja P, et al. (2010) Comparative study of murid gammaherpesvirus 4 infection in mice and in a natural host, bank voles. J Gen Virol 91: 2553-2563.
Sunil-Chandra NP, Efstathiou S, Arno J, Nash AA (1992) Virological and pathological features of mice infected with murine gamma-herpesvirus 68. J Gen Virol 73 (Pt 9): 2347-2356.
Milho R, Smith CM, Marques S, Alenquer M, May JS, et al. (2009) In vivo imaging of murid herpesvirus-4 infection. J Gen Virol 90: 21-32.
Barton E, Mandal P, Speck SH (2011) Pathogenesis and host control of gammaherpesviruses: lessons from the mouse. Annu Rev Immunol 29: 351-397.
Nash AA, Dutia BM, Stewart JP, Davison AJ (2001) Natural history of murine gamma-herpesvirus infection. Philos Trans R Soc Lond B Biol Sci 356: 569- 579.
Flano E, Kim IJ, Woodland DL, Blackman MA (2002) Gamma-herpesvirus latency is preferentially maintained in splenic germinal center and memory B cells. J Exp Med 196: 1363-1372.
Blaskovic D, Stanekova D, Rajcani J (1984) Experimental pathogenesis of murine herpesvirus in newborn mice. Acta Virol 28: 225-231.
Contag PR, Olomu IN, Stevenson DK, Contag CH (1998) Bioluminescent indicators in living mammals. Nat Med 4: 245-247.
Hwang S, Wu TT, Tong LM, Kim KS, Martinez-Guzman D, et al. (2008) Persistent gammaherpesvirus replication and dynamic interaction with the host in vivo. J Virol 82: 12498-12509.
Gaspar M, May JS, Sukla S, Frederico B, Gill MB, et al. (2011) Murid herpesvirus-4 exploits dendritic cells to infect B cells. PLoS Pathog 7: e1002346.
Gillgrass A, Chege D, Bhavanam S, Kaushic C (2010) Estradiol limits viral replication following intravaginal immunization leading to diminished mucosal IgG response and non-sterile protection against genital herpes challenge. Am J Reprod Immunol 63: 299-309.
Vicetti Miguel RD, Hendricks RL, Aguirre AJ, Melan MA, Harvey SA, et al. (2012) Dendritic cell activation and memory cell development are impaired among mice administered medroxyprogesterone acetate prior to mucosal herpes simplex virus type 1 infection. J Immunol 189: 3449-3461.
Vicetti Miguel RD, Sheridan BS, Harvey SA, Schreiner RS, Hendricks RL, et al. (2010) 17-beta estradiol promotion of herpes simplex virus type 1 reactivation is estrogen receptor dependent. J Virol 84: 565-572.
Alizon S, Luciani F, Regoes RR (2011) Epidemiological and clinical consequences of within-host evolution. Trends Microbiol 19: 24-32.
Keele BF, Derdeyn CA (2009) Genetic and antigenic features of the transmitted virus. Curr Opin HIV AIDS 4: 352-357.
Derdeyn CA, Decker JM, Bibollet-Ruche F, Mokili JL, Muldoon M, et al. (2004) Envelope-constrained neutralization-sensitive HIV-1 after heterosexual transmission. Science 303: 2019-2022.
Lee HR, Lee S, Chaudhary PM, Gill P, Jung JU (2010) Immune evasion by Kaposi's sarcoma-associated herpesvirus. Future Microbiol 5: 1349-1365.
Griffin BD, Verweij MC, Wiertz EJ (2010) Herpesviruses and immunity: the art of evasion. Vet Microbiol 143: 89-100.
Coscoy L (2007) Immune evasion by Kaposi's sarcoma-associated herpesvirus. Nat Rev Immunol 7: 391-401.
White DW, Suzanne Beard R, Barton ES (2012) Immune modulation during latent herpesvirus infection. Immunol Rev 245: 189-208.
Costes B, Raj VS, Michel B, Fournier G, Thirion M, et al. (2009) The major portal of entry of koi herpesvirus in Cyprinus carpio is the skin. J Virol 83: 2819- 2830.
Schoenfisch AL, Dollard SC, Amin M, Gardner LI, Klein RS, et al. (2011) Cytomegalovirus (CMV) shedding is highly correlated with markers of immunosuppression in CMV-seropositive women. J Med Microbiol 60: 768-774.
Mostad SB, Kreiss JK, Ryncarz AJ, Overbaugh J, Mandaliya K, et al. (1999) Cervical shedding of cytomegalovirus in human immunodeficiency virus type 1- infected women. J Med Virol 59: 469-473.
Rinaldo CR, Jr., Kingsley LA, Ho M, Armstrong JA, Zhou SY (1992) Enhanced shedding of cytomegalovirus in semen of human immunodeficiency virusseropositive homosexual men. J Clin Microbiol 30: 1148-1155.
Van de Perre P, Segondy M, Foulongne V, Ouedraogo A, Konate I, et al. (2008) Herpes simplex virus and HIV-1: deciphering viral synergy. Lancet Infect Dis 8: 490-497.
Ma W, Miao Z, Novotny MV (1999) Induction of estrus in grouped female mice (Mus domesticus) by synthetic analogues of preputial gland constituents. Chem Senses 24: 289-293.
Kaushic C (2009) The role of the local microenvironment in regulating susceptibility and immune responses to sexually transmitted viruses in the female genital tract. J Reprod Immunol 83: 168-172.
Kaushic C, Roth KL, Anipindi V, Xiu F (2011) Increased prevalence of sexually transmitted viral infections in women: the role of female sex hormones in regulating susceptibility and immune responses. J Reprod Immunol 88: 204- 209.
Brabin L (2002) Interactions of the female hormonal environment, susceptibility to viral infections, and disease progression. AIDS Patient Care STDS 16: 211-221.
Bhavanam S, Snider DP, Kaushic C (2008) Intranasal and subcutaneous immunization under the effect of estradiol leads to better protection against genital HSV-2 challenge compared to progesterone. Vaccine 26: 6165-6172.
Gillgrass AE, Fernandez SA, Rosenthal KL, Kaushic C (2005) Estradiol regulates susceptibility following primary exposure to genital herpes simplex virus type 2, while progesterone induces inflammation. J Virol 79: 3107-3116.
Gillgrass AE, Tang VA, Towarnicki KM, Rosenthal KL, Kaushic C (2005) Protection against genital herpes infection in mice immunized under different hormonal conditions correlates with induction of vagina-associated lymphoid tissue. J Virol 79: 3117-3126.
Wira CR, Fahey JV, Ghosh M, Patel MV, Hickey DK, et al. (2010) Sex hormone regulation of innate immunity in the female reproductive tract: the role of epithelial cells in balancing reproductive potential with protection against sexually transmitted pathogens. Am J Reprod Immunol 63: 544-565.
Beagley KW, Gockel CM (2003) Regulation of innate and adaptive immunity by the female sex hormones oestradiol and progesterone. FEMS Immunol Med Microbiol 38: 13-22.
Kaushic C, Frauendorf E, Rossoll RM, Richardson JM, Wira CR (1998) Influence of the estrous cycle on the presence and distribution of immune cells in the rat reproductive tract. Am J Reprod Immunol 39: 209-216.
Kutteh WH, Moldoveanu Z, Mestecky J (1998) Mucosal immunity in the female reproductive tract: correlation of immunoglobulins, cytokines, and reproductive hormones in human cervical mucus around the time of ovulation. AIDS Res Hum Retroviruses 14 Suppl 1: 51-55.
Lu FX, Ma Z, Rourke T, Srinivasan S, McChesney M, et al. (1999) Immunoglobulin concentrations and antigen-specific antibody levels in cervicovaginal lavages of rhesus macaques are influenced by the stage of the menstrual cycle. Infect Immun 67: 6321-6328.
Inman M, Lovato L, Doster A, Jones C (2002) A mutation in the latency-related gene of bovine herpesvirus 1 disrupts the latency reactivation cycle in calves. J Virol 76: 6771-6779.
Rock D, Lokensgard J, Lewis T, Kutish G (1992) Characterization of dexamethasone-induced reactivation of latent bovine herpesvirus 1. J Virol 66: 2484-2490.
Workman A, Eudy J, Smith L, da Silva LF, Sinani D, et al. (2012) Cellular transcription factors induced in trigeminal ganglia during dexamethasoneinduced reactivation from latency stimulate bovine herpesvirus 1 productive infection and certain viral promoters. J Virol 86: 2459-2473.
Workman A, Jones C (2010) Productive infection and bICP0 early promoter activity of bovine herpesvirus 1 are stimulated by E2F1. J Virol 84: 6308-6317.
Workman A, Jones C (2011) Analysis of the cell cycle regulatory protein (E2F1) after infection of cultured cells with bovine herpesvirus 1 (BHV-1) or herpes simplex virus type 1 (HSV-1). Virus Res 160: 66-73.
Jones C, da Silva LF, Sinani D (2011) Regulation of the latency-reactivation cycle by products encoded by the bovine herpesvirus 1 (BHV-1) latency-related gene. J Neurovirol 17: 535-545.
Tobian AA, Serwadda D, Quinn TC, Kigozi G, Gravitt PE, et al. (2009) Male circumcision for the prevention of HSV-2 and HPV infections and syphilis. N Engl J Med 360: 1298-1309.
Golden MR, Wasserheit JN (2009) Prevention of viral sexually transmitted infections-foreskin at the forefront. N Engl J Med 360: 1349-1351.
Wald A, Corey L (2007) Persistence in the population: epidemiology, transmission. In: Arvin A, Campadelli-Fiume G, Mocarski E, Moore PS, Roizman B et al., editors. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge: Cambridge University Press.
Telfer S, Bennett M, Carslake D, Helyar S, Begon M (2007) The dynamics of murid gammaherpesvirus 4 within wild, sympatric populations of bank voles and wood mice. J Wildl Dis 43: 32-39.
Thomas R, Macsween KF, McAulay K, Clutterbuck D, Anderson R, et al. (2006) Evidence of shared Epstein-Barr viral isolates between sexual partners, and low level EBV in genital secretions. J Med Virol 78: 1204-1209.
Crawford DH, Swerdlow AJ, Higgins C, McAulay K, Harrison N, et al. (2002) Sexual history and Epstein-Barr virus infection. J Infect Dis 186: 731-736.
Stiglincova V, Chalupkova A, Hrabovska Z, Cipkova J, Wagnerova M, et al. (2011) Vertical transmission of murine gammaherpesvirus 68 in mice. Acta Virol 55: 55-59.
Meyohas MC, Marechal V, Desire N, Bouillie J, Frottier J, et al. (1996) Study of mother-to-child Epstein-Barr virus transmission by means of nested PCRs. J Virol 70: 6816-6819.
Gillet L, May JS, Colaco S, Stevenson PG (2007) The murine gammaherpesvirus- 68 gp150 acts as an immunogenic decoy to limit virion neutralization. PLoS One 2: e705.
Rosa GT, Gillet L, Smith CM, de Lima BD, Stevenson PG (2007) IgG fc receptors provide an alternative infection route for murine gamma-herpesvirus-68. PLoS One 2: e560.
Ehtisham S, Sunil-Chandra NP, Nash AA (1993) Pathogenesis of murine gammaherpesvirus infection in mice deficient in CD4 and CD8 T cells. J Virol 67: 5247-5252.
Gillet L, May JS, Colaco S, Stevenson PG (2007) Glycoprotein L disruption reveals two functional forms of the murine gammaherpesvirus 68 glycoprotein H. J Virol 81: 280-291.
Gillet L, Stevenson PG (2007) Antibody evasion by the N terminus of murid herpesvirus-4 glycoprotein B. EMBO J 26: 5131-5142.
Bennett NJ, May JS, Stevenson PG (2005) Gamma-herpesvirus latency requires T cell evasion during episome maintenance. PLoS Biol 3: e120.