Deletion of T cells bearing the V beta8.1 T-cell receptor following mouse mammary tumor virus 7 integration confers resistance to murine cerebral malaria

Abstract

Plasmodium berghei ANKA induces a fatal neurological syndrome known as cerebral malaria (CM) in susceptible mice. Host genetic elements are among the key factors determining susceptibility or resistance to CM. Analysis of mice of the same H-2 haplotype revealed that mouse mammary tumor virus 7 (MTV-7) integration into chromosome 1 is one of the key factors associated with resistance to neurological disease during P. berghei ANKA infection. We investigated this phenomenon by infecting a series of recombinant inbred mice (CXD2), derived from BALB/c (susceptible to CM) and DBA/2 (resistant to CM) mice, with P. berghei ANKA. We observed differences in susceptibility to CM induced by this Plasmodium strain. Mice with the MTV-7 sequence in their genome were resistant to CM, whereas those without integration of this gene were susceptible. Thus, an integrated proviral open reading frame or similar genomic sequences may confer protection against neuropathogenesis during malaria, at least in mice.

FIG. 1.

Profiles of MTV integration in the various (CXD2) RI strains. Genomic DNA was digested with EcoRI, subjected to electrophoresis in a 0.7% agarose gel, and Southern blotted. The membrane was then probed with envelope (A) or long terminal repeat (B) probes. Lambda HindIII DNA was used as a molecular mass marker.

FIG. 2.

Fluorescence-activated cell sorting analysis of PBL from the various (CXD2) RI strains. Data indicate the mean percentage ± the standard deviation of Vβ⁺ cells among CD3⁺ cells from two separate experiments. Mice (n = 3) were tested individually for each RI strain.

FIG. 3.

Kaplan-Meier graph of survival from CM of (CXD2) RI strains of mice. All mice were infected intraperitoneally with 10⁶ P. berghei ANKA clone 1.49L pRBCs. Neurological manifestations appeared 7 to 13 days after parasite inoculation. Mice that escaped CM died 20 to 28 days after inoculation from anemia due to hyperparasitemia. Results for BALB/c (n = 20), DBA/2 (n = 19), (CXD2) D (n = 17), (CXD2) E (n = 20), (CXD2) F (n = 8), (CXD2) J (n = 7), (CXD2) K (n = 23), and (CXD2) N (n = 8) mice are shown. The results were obtained from two separate experiments.

FIG. 4.

Parasitemia curve for the various (CXD2) RI strains of mice infected with P. berghei ANKA clone 1.49L. Results for BALB/c (n = 20), DBA/2 (n = 19), (CXD2) D (n = 17), (CXD2) E (n = 20), (CXD2) F (n = 8), (CXD2) J (n = 7), (CXD2) K (n = 23), and (CXD2) N (n = 8) mice are shown. The results are expressed as the mean parasitemias per day for two separate experiments.

FIG. 5.

Frequency of CM in MTV-7⁺ and MTV-7⁻ (CXD2) RI mice. The results are expressed as the percent occurrence of CM in MTV-7⁺ (n = 115) and MTV-7⁻ (n = 53) mice.

FIG. 6.

Parasitemia curve for MTV-7⁺ (n = 63) and MTV-7⁻ (n = 20) RI mice infected with P. berghei ANKA clone 1.49L. The results are expressed as the mean percentage of erythrocytes infected from two separate experiments. D13, day 13 after parasite inoculation.