HSV-1 strain McKrae is more neuroinvasive than HSV-1 KOS after corneal or vaginal inoculation in mice

Abstract

Strains of HSV-1 have been noted to vary in their pathogenesis. We compared the replication of strains KOS and McKrae in mice by two routes of infection, ocular and vaginal. Peripheral replication of KOS was similar (cornea) or attenuated over time (vagina) compared with McKrae; however, McKrae replicated in the nervous system to significantly higher levels than KOS after inoculation by either route. Host genetic background strongly influenced the capacity for virus entry into the nervous system from the vagina. KOS and McKrae replicated equivalently after intracranial inoculation, indicating that McKrae's pathogenic phenotype is linked to neuroinvasiveness rather than neurovirulence.

Fig. 1

Corneal infection with HSV-1 McKrae results in higher titers in the nervous system than HSV-1 KOS. KOS or McKrae was inoculated onto the scarified corneas of (A and B) B6 mice at 1×10⁶ pfu per eye, or (C and D) BALB.B mice at 2×10⁵ pfu/eye. (A and C) Titer of virus shed in tear film over time post-infection. (B and D) Titer of virus in nervous system tissues was determined 5 d (B6) or 4 d (BALB.B) post-infection. Values are the geometric means ± SEM of 5 to 6 mice per group (B6) or 7 mice per group (BALB.B) and are the combined results of two independent experiments for each mouse strain. Dashed lines represent limit of detection in the assay. *, P = 0.0125; ***, P = 0.0006 to <0.0001.

Fig. 2

Intracranial inoculation yields equivalent titers of HSV-1 KOS and McKrae. Groups of 5 to 7 mice were inoculated i.c. with 1×10³ pfu of virus. Values are the geometric mean titers ± SEM of virus detected in brain tissue of (A) B6 mice and (B) BALB.B mice 24 h and 48 h after infection, and are the combined results of two independent experiments each. The increase from 24 to 48 h was statistically significant (P = 0.0265 to 0.0001).

Fig. 3

HSV-1 McKrae is more virulent than KOS after intravaginal infection. KOS or McKrae was inoculated i.vag. into (A–C) B6 mice at 2×10⁶ pfu per mouse, or (D–F) BALB.B mice at 1×10⁶ pfu/mouse. (A and D) Titer of virus shed from the vaginal mucosa over time post-infection. (B and E) Genital disease scores, determined in masked fashion based on the scale 0, normal; 1 slight erythema and edema; 2 marked erythema and edema; 3, presence of lesions. (C and F) Titer of virus in nervous system tissues 7 d post-infection. Values are the geometric mean + SEM of 7 to 8 B6 or BALB.B mice per group and are the combined results of two independent experiments. Dashed lines represent limit of detection in the assay. *, P = 0.031 to 0.0112; **, P = 0.0052 to 0.004; ***, P = 0.0002 to <0.0001.