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

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>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 dose₅₀and lethal dose₅₀was 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.</p> <p>Conclusion</p> <p>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.</p

Vaccine candidates for dengue virus type 1 (DEN1) generated by replacement of the structural genes of rDEN4 and rDEN4Δ30 with those of DEN1

BACKGROUND: Antigenic chimeric viruses have previously been generated in which the structural genes of recombinant dengue virus type 4 (rDEN4) have been replaced with those derived from DEN2 or DEN3. Two vaccine candidates were identified, rDEN2/4Δ30(ME) and rDEN3/4Δ30(ME), which contain the membrane (M) precursor and envelope (E) genes of DEN2 and DEN3, respectively, and a 30 nucleotide deletion (Δ30) in the 3' untranslated region of the DEN4 backbone. Based on the promising preclinical phenotypes of these viruses and the safety and immunogenicity of rDEN2/4Δ30(ME) in humans, we now describe the generation of a panel of four antigenic chimeric DEN4 viruses using either the capsid (C), M, and E (CME) or ME structural genes of DEN1 Puerto Rico/94 strain. RESULTS: Four antigenic chimeric viruses were generated and found to replicate efficiently in Vero cells: rDEN1/4(CME), rDEN1/4Δ30(CME), rDEN1/4(ME), and rDEN1/4Δ30(ME). With the exception of rDEN1/4(ME), each chimeric virus was significantly attenuated in a SCID-HuH-7 mouse xenograft model with a 25-fold or greater reduction in replication compared to wild type DEN1. In rhesus monkeys, only chimeric viruses with the Δ30 mutation appeared to be attenuated as measured by duration and magnitude of viremia. rDEN1/4Δ30(CME) appeared over-attenuated since it failed to induce detectable neutralizing antibody and did not confer protection from wild type DEN1 challenge. In contrast, rDEN1/4Δ30(ME) induced 66% seroconversion and protection from DEN1 challenge. Presence of the Δ30 mutation conferred a significant restriction in mosquito infectivity upon rDEN1/4Δ30(ME) which was shown to be non-infectious for Aedes aegypti fed an infectious bloodmeal. CONCLUSION: The attenuation phenotype in SCID-HuH-7 mice, rhesus monkeys, and mosquitoes and the protective immunity observed in rhesus monkeys suggest that rDEN1/4Δ30(ME) should be considered for evaluation in a clinical trial

La Crosse virus infectivity, pathogenesis, and immunogenicity in mice and monkeys-6

Ark 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 logPFU/tissue. Tissue samples collected from one moribund mouse.<p><b>Copyright information:</b></p><p>Taken from "La Crosse virus infectivity, pathogenesis, and immunogenicity in mice and monkeys"</p><p>http://www.virologyj.com/content/5/1/25</p><p>Virology Journal 2008;5():25-25.</p><p>Published online 11 Feb 2008</p><p>PMCID:PMC2276200.</p><p></p

La Crosse virus infectivity, pathogenesis, and immunogenicity in mice and monkeys-2

Tes. Changes in percent survival did not occur after day 10.<p><b>Copyright information:</b></p><p>Taken from "La Crosse virus infectivity, pathogenesis, and immunogenicity in mice and monkeys"</p><p>http://www.virologyj.com/content/5/1/25</p><p>Virology Journal 2008;5():25-25.</p><p>Published online 11 Feb 2008</p><p>PMCID:PMC2276200.</p><p></p

La Crosse virus infectivity, pathogenesis, and immunogenicity in mice and monkeys-5

Ark 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.<p><b>Copyright information:</b></p><p>Taken from "La Crosse virus infectivity, pathogenesis, and immunogenicity in mice and monkeys"</p><p>http://www.virologyj.com/content/5/1/25</p><p>Virology Journal 2008;5():25-25.</p><p>Published online 11 Feb 2008</p><p>PMCID:PMC2276200.</p><p></p