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. 2008 Feb 11:5:25.
doi: 10.1186/1743-422X-5-25.

La Crosse virus infectivity, pathogenesis, and immunogenicity in mice and monkeys

Richard S Bennett  1 , Christina M Cress, Jerrold M Ward, Cai-Yen Firestone, Brian R Murphy, Stephen S Whitehead
Affiliations

La Crosse virus infectivity, pathogenesis, and immunogenicity in mice and monkeys

Richard S Bennett et al. Virol J. .

Abstract

Background: La Crosse virus (LACV), family Bunyaviridae, was first identified as a human pathogen in 1960 after its isolation from a 4 year-old girl with fatal encephalitis in La Crosse, Wisconsin. LACV is a major cause of pediatric encephalitis in North America and infects up to 300,000 persons each year of which 70-130 result in severe disease of the central nervous system (CNS). As an initial step in the establishment of useful animal models to support vaccine development, we examined LACV infectivity, pathogenesis, and immunogenicity in both weanling mice and rhesus monkeys.

Results: Following intraperitoneal inoculation of mice, LACV replicated in various organs before reaching the CNS where it replicates to high titer causing death from neurological disease. The peripheral site where LACV replicates to highest titer is the nasal turbinates, and, presumably, LACV can enter the CNS via the olfactory neurons from nasal olfactory epithelium. The mouse infectious dose50 and lethal dose50 was similar for LACV administered either intranasally or intraperitoneally. LACV was highly infectious for rhesus monkeys and infected 100% of the animals at 10 PFU. However, the infection was asymptomatic, and the monkeys developed a strong neutralizing antibody response.

Conclusion: In mice, LACV likely gains access to the CNS via the blood stream or via olfactory neurons. The ability to efficiently infect mice intranasally raises the possibility that LACV might use this route to infect its natural hosts. Rhesus monkeys are susceptible to LACV infection and develop strong neutralizing antibody responses after inoculation with as little as 10 PFU. Mice and rhesus monkeys are useful animal models for LACV vaccine immunologic testing although the rhesus monkey model is not optimal.

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Figures

Figure 1
Figure 1
Tissue distribution of La Crosse virus following intraperitoneal (IP) inoculation of Swiss Webster mice with 102.5 PFU. aPercent of mice positive by plaque assay represented by shading: 100% black, 66% dark gray, 33% light gray, 0% no data entry. Mean virus titer calculated only for virus positive tissues. Areas left blank indicate virus titer below detection limit of 0.7 log10 PFU/tissue.
Figure 2
Figure 2
Tissue distribution of La Crosse virus following intraperitoneal (IP) inoculation of Swiss Webster mice with 104.5 PFU. aPercent of mice positive by plaque assay represented by shading: 100% black, 66% dark gray, 33% light gray, 0% no data entry. Mean virus titer calculated only for virus positive tissues. Areas left blank indicate virus titer below detection limit of 0.7 log10 PFU/tissue. bTissue samples collected from one moribund mouse.
Figure 3
Figure 3
LACV is highly virulent in mice inoculated by either the intraperitoneal (IP) or intranasal (IN) route. Percent survival for LACV/human/1960 after IP (left) or IN (right) inoculation routes. Changes in percent survival did not occur after day 10.
Figure 4
Figure 4
Histopathologic changes on day 6 in the CNS of LACV infected mice. (A) Perivascular cuffs and gliosis in the thalamus. H&E X400. (B) Neurons of the cervical spinal cord with degenerative changes of pale cytoplasm and vacuoles (arrows). H&E X1000. (C) Thalamus with apoptotic cells (arrows) and degenerative neurons (with swollen vacuolated nuclei). H&E X1000. (D) CD3+ lymphocytes in the meninges and blood vessels in the thalamus. Immunohistochemistry, hematoxylin counterstain, X200. (E) Macrophages (MAC-2 +) in perivascular cuffs and areas of gliosis in the hippocampus. Immunohistochemistry, hematoxylin counterstain X200.(F) TUNEL positive (brown) apoptotic bodies in the thalamus. Immunohistochemistry, hematoxylin counterstain X1000.
Figure 5
Figure 5
Viral antigen is detected in the CNS of LACV infected mice. (A) LACV antigen-positive cells in the mitral cell layer (arrow) and granule cell layer (arrowhead) of the main olfactory bulb. Abbreviations: AL-airway lumen, OE-olfactory epithelium, LP-lamina propria, TB-turbinate bone, ONL-olfactory nerve layer, GL-glomerular layer, EPL- external plexiform layer, M-mitral cell layer, GR-granule cell layer. Day 6, X100. (B) Low magnification of a coronal section of mouse brain showing abundant La Crosse viral antigen. Abbreviations: C-cerebral cortex, CAM-cornu ammonis of hippocampus, DG-dentate gyrus, HPA-posterior hypothalamic area, MP-premamillary nucleus, PAG-periaqueductal gray, PT-pretectum, R-reticular nucleus of thalamus, ZI- zona inserta. Day 6, X12.5. (C) Cervical spinal cord cross section showing abundant La Crosse viral antigen in grey matter. Abbreviations: GC-gray commissure, DH-dorsal horn, LH-lateral horn, VH-ventral horn. Day 6, X100. (D) Viral antigen in a punctate pattern in neurons (arrows) in the locus coeruleus. Day 5, X400. (E) Medulla oblongata with abundant LACV antigen in many neurons (arrow heads) with associated perivascular lymphocyte cuffing (indicated with arrows). Day 4, X200. (F) La Crosse viral antigen in the cytoplasm of medullary neurons (arrows). Day 6, X1000. All images immunohistochemistry, hematoxylin counterstain.
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References

    1. Calisher CH. Medically important arboviruses of the United States and Canada. Clin Microbiol Rev. 1994;7:89–116. - PMC - PubMed
    1. Rust RS, Thompson WH, Matthews CG, Beaty BJ, Chun RW. La Crosse and other forms of California encephalitis. J Child Neurol. 1999;14:1–14. doi: 10.1177/088307389901400101. - DOI - PubMed
    1. Obijeski JF, Bishop DH, Palmer EL, Murphy FA. Segmented genome and nucleocapsid of La Crosse virus. J Virol. 1976;20:664–675. - PMC - PubMed
    1. Gentsch JR, Rozhon EJ, Klimas RA, El Said LH, Shope RE, Bishop DH. Evidence from recombinant bunyavirus studies that the M RNA gene products elicit neutralizing antibodies. Virology. 1980;102:190–204. doi: 10.1016/0042-6822(80)90080-X. - DOI - PubMed
    1. Schuh T, Schultz J, Moelling K, Pavlovic J. DNA-based vaccine against La Crosse virus: protective immune response mediated by neutralizing antibodies and CD4+ T cells. Hum Gene Ther. 1999;10:1649–1658. doi: 10.1089/10430349950017653. - DOI - PubMed

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