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Ocular avirulence of a herpes simplex virus type 1 strain is associated with heightened sensitivity to alpha/beta
Y H Su1, J E Oakes, R N Lausch
1Department of Microbiology and Immunology, University of South Alabama, College of Medicine, Mobile 36688.
Abstract:
BALB/c mice infected on the scarified cornea with herpes simplex virus type 1 strain 35 [HSV-1(35)] rarely developed ocular disease even at challenge doses as high as 10(7) PFU per eye. In contrast, HSV-1(RE) consistently induced stromal keratitis at an inoculum of 2 x 10(4) PFU. The goal of this study was to determine the reason for the difference in virulence between the two HSV strains. Both HSV-1 strains replicated to similar titers in excised corneal "buttons." However, after in vivo infection of the cornea, the growth of strain 35 was evident only during the first 24 h postinfection, whereas the replication of strain RE persisted for at least 4 days. In vitro tests revealed that HSV-1(35) was greater than 10 times more sensitive to alpha/beta interferon (IFN-alpha/beta) than HSV-1(RE). Both strains induced comparable serum levels of IFN after intraperitoneal inoculation. The kinetics of HSV-1(35) clearance from the eye was markedly altered by treatment with rabbit anti-IFN-alpha/beta. Virus titers exceeding 10(4) PFU per eye could be demonstrated 4 to 5 days postinfection in mice given a single inoculation of antiserum 1 h after infection. Furthermore, anti-IFN treatment in 3-week-old mice infected with HSV-1(35) led to the development of clinically apparent corneal disease which subsequently progressed to stromal keratitis in the majority of recipients. These results indicate that the striking difference in the capacity of HSV-1(35) and HSV-1(RE) to induce corneal disease was related to the inherently greater sensitivity of strain 35 to IFN-alpha/beta produced by the host in response to infection.
Insights
Herpes simplex virus type 1 strain 35 rarely causes ocular disease because it is highly sensitive to host interferon-alpha/beta (IFN-alpha/beta). Neutralizing IFN-alpha/beta in mice infected with HSV-1(35) led to severe stromal keratitis, demonstrating the cytokine's protective role.
Area of Science:
- Virology
- Immunology
- Ophthalmology
Background:
- Herpes simplex virus type 1 (HSV-1) strains exhibit varying virulence in ocular infections.
- Ocular disease severity, specifically stromal keratitis, differs significantly between HSV-1 strain 35 and HSV-1(RE).
Purpose of the Study:
- To elucidate the molecular and immunological basis for the differential virulence of HSV-1 strain 35 and HSV-1(RE) in corneal infections.
- To investigate the role of host immune responses, particularly interferon-alpha/beta (IFN-alpha/beta), in controlling HSV-1 ocular pathogenesis.
Main Methods:
- Comparative analysis of HSV-1 strain replication in vivo and in vitro.
- Assessment of susceptibility to IFN-alpha/beta for both viral strains.
- Evaluation of the impact of anti-IFN-alpha/beta antibody treatment on HSV-1 ocular disease progression in a murine model.
Main Results:
- HSV-1 strain 35 showed limited in vivo replication in the cornea compared to HSV-1(RE).
- HSV-1 strain 35 was significantly more sensitive (>10-fold) to IFN-alpha/beta inhibition than HSV-1(RE).
- Anti-IFN-alpha/beta treatment of mice infected with HSV-1(35) resulted in sustained viral replication and the development of severe stromal keratitis.
Conclusions:
- The reduced virulence of HSV-1 strain 35 in ocular infections is attributed to its heightened sensitivity to host-produced IFN-alpha/beta.
- IFN-alpha/beta plays a critical role in limiting HSV-1 replication and preventing the development of stromal keratitis.