Involvement of STAT4 in IgG Subtype Switching and Ocular HSV-1 Replication in Mice

Overview

Journal Mol Vis

Specialties Cell Biology
Molecular Biology
Ophthalmology

Date 2010 Jan 28

PMID 20104254

Citations 6

Authors

Sariah J Allen

Kevin R Mott

Homayon Ghiasi

Affiliations

Soon will be listed here.

Abstract

Purpose: To assess the relative impact of elevated T-helper 2 (T(H)2)- and reduced T-Helper 1 (T(H)1)-dependent immune responses on ocular herpes simplex virus type 1 (HSV-1) infection.

Methods: Signal transducer and activator of transcription protein 4 knockout mice (BALB/c-STAT4(-/-)) and wild-type BALB/c control mice were immunized with avirulent HSV-1 strain KOS or were mock-immunized. Three weeks after the third immunization, neutralizing antibody titers were determined by plaque reduction assays. Following ocular infection with virulent HSV-1 strain McKrae, viral replication in the eye, blepharitis, corneal scarring (CS), survival, and immunoglobulin (Ig) isotypes in sera were determined.

Results: Vaccinated STAT4(-/-) and BALB/c mice contained significant and similar neutralizing antibody titers and were completely protected against HSV-1-induced death and CS. In contrast to vaccinated STAT4(-/-) mice, mock-vaccinated STAT4(-/-) mice had higher ocular HSV-1 titers than mock-vaccinated BALB/c mice on days 2-3 post-ocular infection. There were also significant differences in the levels of IgG2a, IgG2b, and IgG3 in the sera of STAT4(-/-) mice when compared to the control BALB/c mice.

Conclusions: These results suggest that the absence of T(H)1 cytokine responses did alter protection against viral replication and IgG isotypes but not eye disease or survival.

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References

Bot A, Rodrigo E, Wolfe T, Bot S, von Herrath M . Infection-triggered regulatory mechanisms override the role of STAT 4 in control of the immune response to influenza virus antigens. J Virol. 2003; 77(10):5794-800. PMC: 154013. DOI: 10.1128/jvi.77.10.5794-5800.2003. View

Thierfelder W, Van Deursen J, Yamamoto K, Tripp R, Sarawar S, Carson R . Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells. Nature. 1996; 382(6587):171-4. DOI: 10.1038/382171a0. View

McKendall R, Woo W . Murine IgG subclass responses to herpes simplex virus type 1 and polypeptides. J Gen Virol. 1988; 69 ( Pt 4):847-57. DOI: 10.1099/0022-1317-69-4-847. View

Ihle J . Cytokine receptor signalling. Nature. 1995; 377(6550):591-4. DOI: 10.1038/377591a0. View

Kaplan M, Sun Y, Hoey T, Grusby M . Impaired IL-12 responses and enhanced development of Th2 cells in Stat4-deficient mice. Nature. 1996; 382(6587):174-7. DOI: 10.1038/382174a0. View

Abbas A, Murphy K, Sher A . Functional diversity of helper T lymphocytes. Nature. 1996; 383(6603):787-93. DOI: 10.1038/383787a0. View

Zhong Z, Wen Z, Darnell Jr J . Stat3 and Stat4: members of the family of signal transducers and activators of transcription. Proc Natl Acad Sci U S A. 1994; 91(11):4806-10. PMC: 43877. DOI: 10.1073/pnas.91.11.4806. View

Barron B, Gee L, Hauck W, Kurinij N, DAWSON C, Jones D . Herpetic Eye Disease Study. A controlled trial of oral acyclovir for herpes simplex stromal keratitis. Ophthalmology. 1994; 101(12):1871-82. DOI: 10.1016/s0161-6420(13)31155-5. View

Liesegang T . Classification of herpes simplex virus keratitis and anterior uveitis. Cornea. 1999; 18(2):127-43. DOI: 10.1097/00003226-199903000-00001. View

10.

Li L, Sad S, Kagi D, Mosmann T . CD8Tc1 and Tc2 cells secrete distinct cytokine patterns in vitro and in vivo but induce similar inflammatory reactions. J Immunol. 1997; 158(9):4152-61. View

11.

Holz A, Bot A, COON B, Wolfe T, Grusby M, von Herrath M . Disruption of the STAT4 signaling pathway protects from autoimmune diabetes while retaining antiviral immune competence. J Immunol. 1999; 163(10):5374-82. View

12.

Finkelman F, Holmes J, Katona I, Urban Jr J, Beckmann M, Park L . Lymphokine control of in vivo immunoglobulin isotype selection. Annu Rev Immunol. 1990; 8:303-33. DOI: 10.1146/annurev.iy.08.040190.001511. View

13.

Ghiasi H, Cai S, Slanina S, Perng G, Nesburn A, Wechsler S . The role of interleukin (IL)-2 and IL-4 in herpes simplex virus type 1 ocular replication and eye disease. J Infect Dis. 1999; 179(5):1086-93. DOI: 10.1086/314736. View

14.

Coffman R, Mosmann T . Isotype regulation by helper T cells and lymphokines. Monogr Allergy. 1988; 24:96-103. View

15.

Quelle F, Shimoda K, Thierfelder W, Fischer C, Kim A, Ruben S . Cloning of murine Stat6 and human Stat6, Stat proteins that are tyrosine phosphorylated in responses to IL-4 and IL-3 but are not required for mitogenesis. Mol Cell Biol. 1995; 15(6):3336-43. PMC: 230567. DOI: 10.1128/MCB.15.6.3336. View

16.

Dasgupta G, Chentoufi A, Nesburn A, Wechsler S, BenMohamed L . New concepts in herpes simplex virus vaccine development: notes from the battlefield. Expert Rev Vaccines. 2009; 8(8):1023-35. PMC: 2760836. DOI: 10.1586/erv.09.60. View

17.

Nguyen L, Knipe D, Finberg R . Mechanism of virus-induced Ig subclass shifts. J Immunol. 1994; 152(2):478-84. View

18.

Wilhelmus K, DAWSON C, Barron B, Bacchetti P, Gee L, Jones D . Risk factors for herpes simplex virus epithelial keratitis recurring during treatment of stromal keratitis or iridocyclitis. Herpetic Eye Disease Study Group. Br J Ophthalmol. 1996; 80(11):969-72. PMC: 505673. DOI: 10.1136/bjo.80.11.969. View

19.

Dasgupta G, Nesburn A, Wechsler S, BenMohamed L . Developing an asymptomatic mucosal herpes vaccine: the present and the future. Future Microbiol. 2009; 5(1):1-4. PMC: 4512283. DOI: 10.2217/fmb.09.101. View

20.

Paul W, Seder R . Lymphocyte responses and cytokines. Cell. 1994; 76(2):241-51. DOI: 10.1016/0092-8674(94)90332-8. View