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. 2005 Nov 7;202(9):1185-90.
doi: 10.1084/jem.20051376. Epub 2005 Oct 31.

A role for dual viral hits in causation of subacute sclerosing panencephalitis

Michael B A Oldstone  1 , Samuel Dales, Antoinette Tishon, Hanna Lewicki, Lee Martin
Affiliations

A role for dual viral hits in causation of subacute sclerosing panencephalitis

Michael B A Oldstone et al. J Exp Med. .

Abstract

Subacute sclerosing panencephalitis (SSPE) is a progressive fatal neurodegenerative disease associated with persistent infection of the central nervous system (CNS) by measles virus (MV), biased hypermutations of the viral genome affecting primarily the matrix (M) gene with the conversion of U to C and A to G bases, high titers of antibodies to MV, and infiltration of B cells and T cells into the CNS. Neither the precipitating event nor biology underlying the MV infection is understood, nor is their any satisfactory treatment. We report the creation of a transgenic mouse model that mimics the cardinal features of SSPE. This was achieved by initially infecting mice expressing the MV receptor with lymphocytic choriomeningitis virus Cl 13, a virus that transiently suppressed their immune system. Infection by MV 10 days later resulted in persistent MV infection of neurons. Analysis of brains from infected mice showed the biased U to C hypermutations in the MV M gene and T and B lymphocyte infiltration. These sera contained high titers of antibodies to MV. Thus, a small animal model is now available to both molecularly probe the pathogenesis of SSPE and to test a variety of therapies to treat the disease.

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Figures

Figure 1.
Figure 1.
Persistent MV infection in the transgene mice. The SSPE tg mouse model was generated by first creating tg mice expressing the MV receptor CD46 (reference 12) and then breeding these mice on a Rag1−/− background (references 19, 30). (A, C, and E–H) MV replication in individual 6–8-wk-old mice given MV strain Edmonston i.c. All mice died by day 65. Mean time to death ± SD of 47 ± 4 d after viral inoculation. A and C, 50×; E–H, 100×. Equivalent virus replication was seen in all such MV-infected CD46 × Rag1−/− mice throughout the CNS. However, when mice were given 5 × 107 or 107, but not 5 × 106, syngeneic splenocytes either 3 d before or 3 d after MV challenge, 10 out of 10 mice in each group survived >200 d. (B and D) Representative image from the hippocampus (B) and cortex (D) of 10 out of 10 mice receiving 107 or 5 × 107 splenic lymphocytes 3 d before MV challenge, respectively (50×). When five Rag1−/− or five CD46 mice alone were inoculated i.c. with 105 MV, all failed to express MV RNA or protein in the CNS. (I and J) Photomicrographs from an electron microscopic study of an MV-infected neuron in the cortex (I) and hippocampus (J) from a CD46 × Rag1−/− tg mouse. The arrows in I indicate four collections of viral nucleocapsid inclusions (44,800×), whereas J shows cytoplasmic inclusions (78,000×) of loosely coiled viral nucleocapsid helices. In the CNS, only neurons were shown to contain MV antigens.
Figure 2.
Figure 2.
Anatomical location and frequency of 69 A to G hypermutations. The hypermutations were recorded in the MV M gene open reading frame from one representative mouse out of five studied. 12 cDNA clones were isolated, and each position of A to G changes in the MV M is marked with an asterisk. Data showing the A to G changes from base 215 to 340 are displayed. For our initial set of five MV M sequences from this mouse, one MV M clone was isolated that possessed 20 A to G changes and also ablated a unique Alu I site within the MV M sequence. This observation allowed us to screen for additional Alu I− hypermutated M sequences from this as well as other mice. 11 additional hypermutated MV M sequences were uncovered using the Alu I screen, strongly suggesting that an MV with 20 A to G M gene changes arose, replicated, and underwent further mutation leading to a total number of 69 A to G changes. Quantitation of Alu I− versus Alu I+ MV M clones from this mouse revealed that ∼40% of the MV M clones were hypermutated to A to G changes. The Alu I screen also revealed the presence and clonal expansion of hypermutated M genes in the other mice analyzed. These four other mice had 62, 91, 113, and 135 unique A to G changes, respectively. The clonal expansion of one MV M with a total of 69 A to G mutations is indicated. (bottom) Several of these mutations are shown and compared with the authentic sequence of the inoculated MV. a.a., amino acid.
Figure 3.
Figure 3.
Data implicating a dual viral hit mechanism for causing persistent MV SSPE-like infection. The first hit is immunosuppressive LCMV Cl 13 given i.v. at a dose of 2 × 106. (A–C) When 105 PFU of MV is administered i.c. 10 d later, the neurons of all inoculated mice become persistently infected with MV. LCMV Cl 13 infects DCs (references 25, 26) and impairs their antigen-presenting capacity so they cannot activate naive T cells or B cells. The result is transient immunosuppression beginning at days 4–5 after LCMV inoculation; peak suppression occurs at days 10–15 and slowly diminishes thereafter, lasting for ∼60 d. A–C are from three individual mice given MV 10 d after LCMV Cl 13 inoculation and killed at 150 (A), 200 (B), and 240 (C) d, respectively, after MV inoculation. Sections are peroxidase stained with antibody to MV, and abundant brown staining neurons are indicated by arrows. (D) Presence of CD4 T cells in the leptomeninges. (E) B cells around blood vessels in the brain parenchyma. (F) CD8 T cells in the brain parenchyma by themselves. Arrowheads in D–F indicate several of these lymphocytes. CD4 and CD8 T lymphocytes and B cells were found in all three locations in four out of four mice studied 200 d after receiving MV and 210 d after receiving LCMV Cl 13.
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