An aged host promotes the evolution of avirulent coxsackievirus into a virulent strain

Abstract

The emergence of new, more pathogenic viruses necessitates elucidation of factors that promote viral evolution. Aging, a potential factor, is associated with increased susceptibility to viral infections. We used the enterovirus coxsackievirus B3 (CVB3) to investigate the effects of host age on pathogenicity and viral gene sequence. Old mice infected with a normally amyocarditic strain of CVB3, CVB3͞0, had significantly higher mean heart viral titers compared with CVB3͞0-infected adult mice. To determine whether a change in the CVB3͞0 viral population could contribute to the higher titers observed in the old infected mice, CVB3͞0 was passed once through an old or adult host and the changes in pathogenicity and viral genome were examined after subsequent infection of old or adult mice. Adult mice infected with CVB3͞0 that was passed through an old host (CVB3͞0 Old ) exhibited significantly higher heart viral titers, pathology, and weight loss than adult mice infected with either stock CVB3͞0 or CVB3͞0 passed through an adult host (CVB3͞0 Adult ). Sequence analysis of virus isolated from CVB3͞0 Old -infected mice revealed 13 specific and reproducible nucleotide changes. These changes result in a sequence that matches the virulent CVB3͞20 strain and are associated with promoting cardiovirulence. In contrast, we observed only one nucleotide change, low heart viral titers, and no heart and liver pathology in adult mice infected with CVB3͞0 Adult . These results demonstrate that the aged host promotes rapid selection of a pathogenic variant of CVB3 from an avirulent strain and introduces a host-virus paradigm for studies of viral infection in the aged.aging ͉ myocarditis ͉ oxidative stress ͉ pathology ͉ viral selection

Within‐Host Evolution for the Invasiveness of Commensal Bacteria: an Experimental Study of Bacteremias Resulting fromHaemophilus influenzaeNasal Carriage

“…Likewise, it is different from the evolution that takes place in chronic bacterial infections, such as those of Pseudomonas aeruginosa in patients with cystic fibrosis [36] or of Helicobacter pylori [37]. Although this phenomenon has been observed in viruses [38], to our knowledge, this is the first experimental evidence for precipitous virulence resulting from within-host evolution in bacteria. These results are consistent with observations that suggest that single point mutations can dramatically augment bacterial virulence [39].…”

Differential Macrophage Polarization in Male and Female BALB/c Mice Infected With Coxsackievirus B3 Defines Susceptibility to Viral Myocarditis

“…Cellular debris was removed by centrifugation, and viral titers were determined on HeLa cell monolayers using TCID 50 assay as previously described. 18 Cardiac myocytes from neonatal mice within 72 hour of birth were prepared as previously reported. 4 Primary cardiac myocytes (2ϫ10 5 ) were infected with 10 TCID 50 of the virus.…”

Involvement of NLRP3 inflammasome in CVB3-induced viral myocarditis

“…Mice were infected by an intraperitoneal injection with 10 5 50% tissue culture infectious dose (TCID50) of CVB3, and hearts from individual mice were aseptically harvested, weighted, and homogenized in complete basal Eagle's medium (DMEM) containing 2% FBS. Cellular debris was removed by centrifugation, and viral titers were determined on Hela cell monolayers using TCID 50 assay as previously described (19).…”