Bioluminescence Imaging Reveals Systemic Dissemination of Herpes Simplex Virus Type 1 in the Absence of Interferon Receptors

Abstract

Herpes simplex virus type 1 (HSV-1) can produce disseminated, systemic infection in neonates and patients with AIDS or other immunocompromising diseases, resulting in significant morbidity and mortality in spite of antiviral therapy. Components of host immunity that normally limit HSV-1 to localized epithelial and neuronal infection remain incompletely defined. We used in vivo bioluminescence imaging to determine effects of type I and II interferons (IFNs) on replication and tropism of HSV-1 infection in mice with genetic deficiency of type I, type II, or both type I and II IFN receptors. Following footpad or ocular infection of mice lacking type I IFN receptors, HSV-1 spread to parenchymal organs, including lung, liver, spleen, and regional lymph nodes, but mice survived. Deletion of type I and II IFN receptors produced quantitatively greatest and most widespread dissemination of virus to visceral organs and the nervous system, and these mice invariably died after ocular or footpad infection. Type II receptor knockout and wild-type mice had comparable viral replication and localization, with no systemic spread of HSV-1 or lethality. Therefore, while isolated deficiency of type II IFN receptors did not affect pathogenesis, loss of these receptors in combination with genetic deletion of type I receptors had a profound effect on susceptibility to HSV-1. These data demonstrate different effects of type I and II IFNs in limiting systemic dissemination of HSV-1 and further validate the use of bioluminescence imaging for studies of viral pathogenesis.

Re-Evaluating Natural Resistance to Herpes Simplex Virus Type 1

“…Likewise, the zosteriform spread of HSV-1 strain KOS-GFP in the facial epithelia of C57BL/6 scid mice and BALB/c scid mice was qualitatively similar at all times after inoculation. Although no differences were noted in the spread of KOS-GFP across the faces of C57BL/6 scid and BALB/c scid mice, it should be noted that differences in spread within the peripheral nervous system may be detectable by more sensitive methods (e.g., the method of Summers et al [57] or Luker et al [34]). Finally, comparison of pathogenesis and death confirmed our expectation that C57BL/6 scid mice would survive infection with HSV-1 strain McKrae for slightly longer (0.5 days) than BALB/c scid mice.…”

APOBEC1-Mediated Editing and Attenuation of Herpes Simplex Virus 1 DNA Indicate That Neurons Have an Antiviral Role during Herpes Simplex Encephalitis

“…For instance, the depletion of macrophages during HSV-1 infection in mice was demonstrated previously to lead to a higher survival rate (34). On the other hand, uncontrolled virus dissemination can also lead to a fatal outcome in mice missing the type I interferon receptor (14,33). Needless to say, a balance must be struck between the host immune response and the extent of virus infection.…”

<em>In Vivo</em> Imaging Systems (IVIS) Detection of a Neuro-Invasive Encephalitic Virus

“…While the addition of a second subgenomic promoter and the luciferase gene results in further attenuation of the recombinant virus compared to wild type TC83, this attenuation does not appear to alter the clinical course of the disease within the first 6 days of infection 5 .We expect to see a loss of the luciferase gene through replication of the virus over time but again this is not seen until later in the development of disease. Development of other pathogenic vectors, viral and bacterial, confirms the potential and efficiency of IVIS and luciferase across multiple fields of pathogen research [6][7][8][9] .…”