High diversity and ancient common ancestry of lymphocytic choriomeningitis virus

Abstract

Lymphocytic choriomeningitis virus (LCMV) is the prototype of the family Arenaviridae. LCMV can be associated with severe disease in humans, and its global distribution reflects the broad dispersion of the primary rodent reservoir, the house mouse (Mus musculus). Recent interest in the natural history of the virus has been stimulated by increasing recognition of LCMV infections during pregnancy, and in clusters of LCMV-associated fatal illness among tissue transplant recipients. Despite its public health importance, little is known regarding the genetic diversity or distribution of virus variants. Genomic analysis of 29 LCMV strains collected from a variety of geographic and temporal sources showed these viruses to be highly diverse. Several distinct lineages exist, but there is little correlation with time or place of isolation. Bayesian analysis estimates the most recent common ancestor to be 1,000-5,000 years old, and this long history is consistent with complex phylogeographic relationships of the extant virus isolates.

Figure 1

Bayesian coalescent analysis of lymphocytic choriomeningitis virus (LCMV) based on the small (S) gene segment. The maximum clade credibility tree generated from analysis of available LCMV S segment sequences is shown. Branch lengths are proportional to the number of substitutions/site/year. Depicted at the main nodes are the time to most recent common ancestor estimates (TMRCA) based on Bayesian coalescent analysis of the virus sequences and isolation dates without inclusion of the Bulgarian strain for which no reliable isolation date was available. Posterior probabilities are listed below the branches for supported nodes. Scale bar indicates nucleotide substitutions per site.

Figure 2

Bayesian coalescent analysis of lymphocytic choriomeningitis virus (LCMV) based on the large (L) gene segment. The maximum clade credibility tree generated from analysis of available LCMV L segment sequences is shown. Branch lengths are proportional to the number of substitutions/site/year. Depicted at the main nodes are the time to most recent common ancestor estimates based on Bayesian coalescent analysis of the virus sequences and isolation dates without inclusion of the Bulgarian strain for which no reliable isolation date was available. Posterior probabilities are listed below the branches for supported nodes. Scale bar indicates nucleotide substitutions per site.

Figure A1

Schematic of lymphocytic choriomeningitis virus (LCMV) Z open reading frame.The N-terminal myristoylation site (31), RING motif, and late domains are all highly conserved among the LCMV strains analyzed. Unexpectedly, the Z protein of the H935_Georgia_1984 virus strain is 1 aa longer than all the others.

Figure A2

Schematic of lymphocytic choriomeningitis virus (LCMV) L open reading frame. The previously identified domains and catalytic core motifs of the LCMV L polymerase (32) were found to be highly conserved among all strains analyzed. Dandenong, Dandenong_Australia_2006 virus strain; GA84, H935_Georgia_1984 virus strain; A, all influenza virus type A strains.

Figure A3

Schematic of lymphocytic choriomeningitis virus (LCMV) nucleoprotein open reading frame. Nucleoprotein protein motifs (33) were found to be highly conserved among all strains analyzed. A, all influenza virus type A strains.

Figure A4

Schematic of lymphocytic choriomeningitis virus (LCMV) GPC open reading frame. The protein motifs previously identified in the Armstrong strain, such as the 2 hydrophobic domains in the signal peptide, the myristoylation site in G2, and most of the potential glycosylation sites found in other arenaviruses, are well conserved (34).