All Title Author
Keywords Abstract

PLOS ONE  2012 

Characterization of Omental Immune Aggregates during Establishment of a Latent Gammaherpesvirus Infection

DOI: 10.1371/journal.pone.0043196

Full-Text   Cite this paper   Add to My Lib


Herpesviruses are characterized by their ability to establish lifelong latent infection. The gammaherpesvirus subfamily is distinguished by lymphotropism, establishing and maintaining latent infection predominantly in B lymphocytes. Consequently, gammaherpesvirus pathogenesis is closely linked to normal B cell physiology. Murine gammaherpesvirus 68 (MHV68) pathogenesis in laboratory mice has been extensively studied as a model system to gain insights into the nature of gammaherpesvirus infection in B cells and their associated lymphoid compartments. In addition to B cells, MHV68 infection of macrophages contributes significantly to the frequency of viral genome-positive cells in the peritoneal cavity throughout latency. The omentum, a sheet of richly-vascularized adipose tissue, resides in the peritoneal cavity and contains clusters of immune cell aggregates termed milky spots. Although the value of the omentum in surgical wound-healing has long been appreciated, the unique properties of this tissue and its contribution to both innate and adaptive immunity have only recently been recognized. To determine whether the omentum plays a role in gammaherpesvirus pathogenesis we examined this site during early MHV68 infection and long-term latency. Following intraperitoneal infection, immune aggregates within the omentum expanded in size and number and contained virus-infected cells. Notably, a germinal-center B cell population appeared in the omentum of infected animals with earlier kinetics and greater magnitude than that observed in the spleen. Furthermore, the omentum harbored a stable frequency of viral genome-positive cells through early and into long-term latency, while removal of the omentum prior to infection resulted in a slight decrease in the establishment of splenic latency following intraperitoneal infection. These data provide the first evidence that the omentum is a site of chronic MHV68 infection that may contribute to the maintenance of chronic infection.


[1]  Barton E, Mandal P, Speck SH (2011) Pathogenesis and host control of gammaherpesviruses: lessons from the mouse. Annu Rev Immunol 29: 351–397.
[2]  Speck SH, Ganem D (2010) Viral latency and its regulation: lessons from the gamma-herpesviruses. Cell Host Microbe 8: 100–115.
[3]  Willer DO, Speck SH (2003) Long-term latent murine Gammaherpesvirus 68 infection is preferentially found within the surface immunoglobulin D-negative subset of splenic B cells in vivo. J Virol 77: 8310–8321.
[4]  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.
[5]  Peacock JW, Bost KL (2000) Infection of intestinal epithelial cells and development of systemic disease following gastric instillation of murine gammaherpesvirus-68. J Gen Virol 81: 421–429.
[6]  Krug LT, Collins CM, Gargano LM, Speck SH (2009) NF-kappaB p50 plays distinct roles in the establishment and control of murine gammaherpesvirus 68 latency. J Virol 83: 4732–4748.
[7]  Moser JM, Farrell ML, Krug LT, Upton JW, Speck SH (2006) A gammaherpesvirus 68 gene 50 null mutant establishes long-term latency in the lung but fails to vaccinate against a wild-type virus challenge. J Virol 80: 1592–1598.
[8]  Kearney JF, Bartels J, Hamilton AM, Lehuen A, Solvason N, et al. (1992) Development and function of the early B cell repertoire. Int Rev Immunol 8: 247–257.
[9]  Solvason N, Chen X, Shu F, Kearney JF (1992) The fetal omentum in mice and humans. A site enriched for precursors of CD5 B cells early in development. Ann N Y Acad Sci 651: 10–20.
[10]  Solvason N, Kearney JF (1992) The human fetal omentum: a site of B cell generation. J Exp Med 175: 397–404.
[11]  Ansel KM, Harris RB, Cyster JG (2002) CXCL13 is required for B1 cell homing, natural antibody production, and body cavity immunity. Immunity 16: 67–76.
[12]  Rangel-Moreno J, Moyron-Quiroz JE, Carragher DM, Kusser K, Hartson L, et al. (2009) Omental milky spots develop in the absence of lymphoid tissue-inducer cells and support B and T cell responses to peritoneal antigens. Immunity 30: 731–743.
[13]  Gerber SA, Rybalko VY, Bigelow CE, Lugade AA, Foster TH, et al. (2006) Preferential attachment of peritoneal tumor metastases to omental immune aggregates and possible role of a unique vascular microenvironment in metastatic survival and growth. Am J Pathol 169: 1739–1752.
[14]  Sorensen EW, Gerber SA, Sedlacek AL, Rybalko VY, Chan WM, et al. (2009) Omental immune aggregates and tumor metastasis within the peritoneal cavity. Immunol Res
[15]  Collins CM, Speck SH (2012) Tracking murine gammaherpesvirus 68 infection of germinal center B cells in vivo. PLoS One 7: e33230.
[16]  Weck KE, Barkon ML, Yoo LI, Speck SH, Virgin HI (1996) Mature B cells are required for acute splenic infection, but not for establishment of latency, by murine gammaherpesvirus 68. J Virol 70: 6775–6780.
[17]  Weck KE, Kim SS, Virgin HI, Speck SH (1999) B cells regulate murine gammaherpesvirus 68 latency. J Virol 73: 4651–4661.
[18]  Weck KE, Kim SS, Virgin HI, Speck SH (1999) Macrophages are the major reservoir of latent murine gammaherpesvirus 68 in peritoneal cells. J Virol 73: 3273–3283.
[19]  Coleman CB, Nealy MS, Tibbetts SA (2010) Immature and transitional B cells are latency reservoirs for a gammaherpesvirus. J Virol 84: 13045–13052.
[20]  Moon H, Lee JG, Shin SH, Kim TJ (2012) LPS-induced migration of peritoneal B-1 cells is associated with upregulation of CXCR4 and increased migratory sensitivity to CXCL12. J Korean Med Sci 27: 27–35.
[21]  Collins CM, Boss JM, Speck SH (2009) Identification of infected B-cell populations by using a recombinant murine gammaherpesvirus 68 expressing a fluorescent protein. J Virol 83: 6484–6493.
[22]  Gray KS, Allen RD 3rd, Farrell ML, Forrest JC, Speck SH (2009) Alternatively initiated gene 50/RTA transcripts expressed during murine and human gammaherpesvirus reactivation from latency. J Virol 83: 314–328.
[23]  Gill MB, Wright DE, Smith CM, May JS, Stevenson PG (2009) Murid herpesvirus-4 lacking thymidine kinase reveals route-dependent requirements for host colonization. J Gen Virol 90: 1461–1470.
[24]  Mebius RE (2009) Lymphoid organs for peritoneal cavity immune response: milky spots. Immunity 30: 670–672.
[25]  Cai Q, Lan K, Verma SC, Si H, Lin D, et al. (2006) Kaposi's sarcoma-associated herpesvirus latent protein LANA interacts with HIF-1 alpha to upregulate RTA expression during hypoxia: Latency control under low oxygen conditions. J Virol 80: 7965–7975.
[26]  Polcicova K, Hrabovska Z, Mistrikova J, Tomaskova J, Pastorek J, et al. (2008) Up-regulation of Murid herpesvirus 4 ORF50 by hypoxia: possible implication for virus reactivation from latency. Virus Res 132: 257–262.
[27]  Fang HY, Hughes R, Murdoch C, Coffelt SB, Biswas SK, et al. (2009) Hypoxia-inducible factors 1 and 2 are important transcriptional effectors in primary macrophages experiencing hypoxia. Blood 114: 844–859.
[28]  Imtiyaz HZ, Simon MC (2010) Hypoxia-inducible factors as essential regulators of inflammation. Curr Top Microbiol Immunol 345: 105–120.
[29]  Berberich S, Dahne S, Schippers A, Peters T, Muller W, et al. (2008) Differential molecular and anatomical basis for B cell migration into the peritoneal cavity and omental milky spots. J Immunol 180: 2196–2203.
[30]  Berberich S, Forster R, Pabst O (2007) The peritoneal micromilieu commits B cells to home to body cavities and the small intestine. Blood 109: 4627–4634.
[31]  Lee BJ, Santee S, Von Gesjen S, Ware CF, Sarawar SR (2000) Lymphotoxin-alpha-deficient mice can clear a productive infection with murine gammaherpesvirus 68 but fail to develop splenomegaly or lymphocytosis. J Virol 74: 2786–2792.


comments powered by Disqus

Contact Us


微信:OALib Journal