Differential Pathogenesis between Andes Virus Strains CHI-7913 and Chile-9717869 in Syrian Hamsters

Abstract

Hantavirus cardiopulmonary syndrome (HCPS) is a severe respiratory disease caused by orthohantaviruses in the Americas with a fatality rate as high as 35%. In South America, Andes orthohantavirus (Hantaviridae, Orthohantavirus, ANDV) is a major cause of HCPS, particularly in Chile and Argentina, where thousands of cases have been reported since the virus was discovered. Two strains of ANDV that are classically used for experimental studies of the virus are Chile-9717869, isolated from the natural reservoir, the long-tailed pygmy rice rat, and CHI-7913, an isolate from a lethal human case of HCPS. An important animal model for studying pathogenesis of HCPS is the lethal Syrian golden hamster model of ANDV infection. In this model, ANDV strain Chile-9717869 is uniformly lethal and has been used extensively for pathogenesis, vaccination, and therapeutic studies. Here we show that the CHI-7913 strain, despite having high sequence similarity with Chile-9717869, does not cause lethal disease in Syrian hamsters. CHI-7913, while being able to infect hamsters and replicate to moderate levels, showed a reduced ability to replicate within the tissues compared with Chile-9717869. Hamsters infected with CHI-7913 had reduced expression of cytokines IL-4, IL-6, and IFN-γ compared with Chile-9717869 infected animals, suggesting potentially limited immune-mediated pathology. These results demonstrate that certain ANDV strains may not be lethal in the classical Syrian hamster model of infection, and further exploration into the differences between lethal and non-lethal strains provide important insights into molecular determinants of pathogenic hantavirus infection. Importance: Andes orthohantavirus (ANDV) is a New World hantavirus that is a major cause of hantavirus cardiopulmonary syndrome (HCPS, also referred to as hantavirus pulmonary syndrome) in South America, particularly in Chile and Argentina. ANDV is one of the few hantaviruses for which there is a reliable animal model, the Syrian hamster model, which recapitulates important aspects of human disease. Here we infected hamsters with a human isolate of ANDV, CHI-7913, to assess its pathogenicity compared with the classical lethal Chile-9717869 strain. CHI-7913 had 22 amino acid differences compared with Chile-9717869, did not cause lethal disease in hamsters, and showed reduced ability to replicate in vivo. Our data indicate potentially important molecular signatures for pathogenesis of ANDV infection in hamsters and may lead to insights into what drives pathogenesis of certain hantaviruses in humans.

Andes virus genome mutations that are likely associated with animal-model attenuation and human person-to-person transmission

“…An established lethal animal model of ANDV infection, using golden hamsters ( Mesocricetus auratus (Waterhouse, 1839)) (12), was leveraged to compare the previously established pathogenicity of the ANDV strain ARG (ANDV/ARG p9) (17) and to assess the pathogenicity of ANDV/ARG p19. Eight 12-week-old golden hamsters (four males and four females, obtained from the Instituto Nacional de Producción de Biológicos in Buenos Aires) were exposed intramuscularly to 100 μL of mock inoculum (phosphate-buffered saline [PBS]).…”

“…To identify potential genotypic virulence markers in the ANDV/ARG genome, we initially focused on 23 specific SNPs that had been described between the golden hamster attenuated ANDV/CHI-7913 compared to golden hamster lethal ANDV/CHI-9717869 (17). We also mapped 5 additional SNPs between those genomes, as the NSs ORF was not included in the original comparison (17). In 23 of those 28 positions, ANDV/ARG p0 shared nucleotide bases with attenuated ANDV/CHI-7913.…”

“…An established lethal animal model of ANDV infection, using golden hamsters (Mesocricetus auratus (Waterhouse, 1839)) (12), was leveraged to compare the previously established pathogenicity of the ANDV strain ARG (ANDV/ARG p9) (17)…”

“…However, the golden hamster model did not produce lethal results when exposed to a closely related strain, ANDV/CHI-7913 (isolated from clinical samples from a fatal case that was a family contact of the index case of an outbreak near Santiago, Chile, in 1999) (16). These findings indicated that subtle strain-specific genomic differences may have dramatic phenotypic consequences (17).…”

Experimental Infection of Peromyscus Species Rodents with Sin Nombre Virus

“…We collected tissue samples (lung, heart, spleen, kidney) and either blood (days 7 and 14) or serum (days 21 and 42) samples from mice at 7, 14, 21, and 42 days postinfection (dpi) and evaluated them for the presence of viral (small-segment) RNA ( 10 ). We performed ELISA on serum samples, as previously described ( 12 ), to assess seroconversion.…”