The Isolated in Utero Environment Is Conducive to the Emergence of RNA and DNA Virus Variants

Udenze, Daniel; Trus, Ivan; Munyanduki, Henry; Bérubé, Nathalie G.; Karniychuk, Uladzimir

doi:10.3390/v13091827

Cited by 7 publications

(11 citation statements)

References 41 publications

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“…Pregnant pigs were randomly assigned into Control, E+102CpG, E/NS1+176CpG and WT groups. Results from the pig exposed to the only wild-type virus were partially reported in our previous study (22). All animals were housed in identical isolated rooms at VIDO.…”

Section: Animal Experimentsmentioning

confidence: 73%

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CpG content in the Zika virus genome affects infection phenotypes in the adult brain and fetal lymph nodes

Udenze

Trus²,

Bérubé³

et al. 2022

Front. Immunol.

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Increasing the number of CpG dinucleotides in RNA viral genomes, while preserving the original amino acid composition, leads to impaired infection which does not cause disease. Beneficially, impaired infection evokes antiviral host immune responses providing a cutting-edge vaccine approach. For example, we previously showed that CpG-enriched Zika virus variants cause attenuated infection phenotypes and protect against lethal challenge in mice. While CpG recoding is an emerging and promising vaccine approach, little is known about infection phenotypes caused by recoded viruses in vivo, particularly in non-rodent species. Here, we used well-established mouse and porcine models to study infection phenotypes of the CpG-enriched neurotropic and congenital virus—Zika virus, directly in the target tissues—the brain and placenta. Specifically, we used the uttermost challenge and directly injected mice intracerebrally to compare infection phenotypes caused by wild-type and two CpG-recoded Zika variants and model the scenario where vaccine strains breach the blood-brain barrier. Also, we directly injected porcine fetuses to compare in utero infection phenotypes and model the scenario where recoded vaccine strains breach the placental barrier. While overall infection kinetics were comparable between wild-type and recoded virus variants, we found convergent phenotypical differences characterized by reduced pathology in the mouse brain and reduced replication of CpG-enriched variants in fetal lymph nodes. Next, using next-generation sequencing for the whole virus genome, we compared the stability of de novo introduced CpG dinucleotides during prolonged virus infection in the brain and placenta. Most de novo introduced CpG dinucleotides were preserved in sequences of recoded Zika viruses showing the stability of vaccine variants. Altogether, our study emphasized further directions to fine-tune the CpG recoding vaccine approach for better safety and can inform future immunization strategies.

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Section: Animal Experimentsmentioning

confidence: 73%

“…In addition, the genomic regions amplified with primers that contained nucleotide mismatches within the binding sites were omitted. The detailed computational protocol used in this paper for iVar was previously published ( 22 ).…”

Section: Methodsmentioning

confidence: 99%

CpG content in the Zika virus genome affects infection phenotypes in the adult brain and fetal lymph nodes

Udenze

Trus²,

Bérubé³

et al. 2022

Front. Immunol.

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“…Eight female Landrace-cross pigs were purchased from the university high-health status herd free from porcine reproductive and respiratory virus (PRRSV), porcine parvovirus (PPV), congenital porcine circovirus 2 (PCV2), and porcine circovirus 3 (PCV3), which can cause fetal infection in pigs. Accordingly, maternal and fetal samples were negative for PRRSV, PPV, PCV2, and PCV3 in virus-specific PCR assays [35,43]. Before delivering to containment, six pigs were synchronized and bred with semen from a single donor to reduce biological variability; two pigs (G and H) remained non-pregnant.…”

Section: Animal Experimentsmentioning

confidence: 99%

Japanese encephalitis virus persists in the human reproductive epithelium and porcine reproductive tissues

Chapagain

Singh

et al. 2022

PLoS Negl Trop Dis

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Japanese encephalitis virus (JEV) is the emerging and geographically expanding flavivirus and the major causative agent of encephalitis in humans in Asia. There are risks of JEV introduction into the Americas given a large population of amplifying hosts—pigs and wild boars, and insect vectors—Culex mosquitoes. There are emerging concerns about vector-free ways of flavivirus transmission, for example sexual and transplacental Zika virus transmissions, which may change flavivirus epidemiology and expand the geographical range to territories with no insect vectors. It is unknown whether JEV has tropism in the female lower reproductive tract and the potential for sexual transmission in humans. While clinical outcomes of transplacental JEV infection are described in humans and pigs, cellular targets and tissue tropism in the upper reproductive tract are also unknown. Here, we studied JEV infection phenotypes and host transcriptional responses in human reproductive epithelial cells. We found that JEV caused persistent infection and cytopathology in the vaginal epithelium, endometrial epithelium, and trophoblast. Human vaginal epithelial cells infected with JEV had altered transcriptional responses associated with inflammation and disruption of epithelial barrier function. Also, using pigs—the native amplifying host for JEV, we confirmed JEV tropism in the female lower and upper reproductive tracts. We discovered that JEV persists in the vaginal mucosa for at least 28 days and pigs shed the virus in vaginal secretions. We also found JEV persistence in the endometrium and placenta with transplacental and fetal infections. Altogether, we discovered that JEV targets the vaginal epithelium and has the potential for sexual transmission in humans. We also contributed to a better understanding of JEV pathogenesis during transplacental infection. Further studies are needed to better understand the interactions of JEV with reproductive tissues, how persistent infection affects female reproductive functions, and the risks for non-vector transmission.

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“…Another study showed that ZIKV diversity in infected mice varied by organs and inoculation routes; however only non-pregnant animals were used, so again fetal tissues were not evaluated [ 14 ]. A recent study evaluated ZIKV diversity in a pregnant pig via in utero inoculation of individual conceptuses and identified some tissue-specific variants as well as a low level of convergent evolution [ 15 ]. Unfortunately, in that study, none of the fetal brains were positive for ZIKV at the study endpoint so variants involved in neuroinvasion could not be evaluated [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

“…A recent study evaluated ZIKV diversity in a pregnant pig via in utero inoculation of individual conceptuses and identified some tissue-specific variants as well as a low level of convergent evolution [ 15 ]. Unfortunately, in that study, none of the fetal brains were positive for ZIKV at the study endpoint so variants involved in neuroinvasion could not be evaluated [ 15 ]. To our knowledge, no study thus far has evaluated whole genome ZIKV diversity within animals during early and late stages of vertical transmission and fetal neuroinvasion.…”

Section: Introductionmentioning

confidence: 99%

Zika virus diversity in mice is maintained during early vertical transmission from placenta to fetus, but reduced in fetal bodies and brains at late stages of infection

Evans,

Winkler,

Anzick

et al. 2023

PLoS Negl Trop Dis

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Since emerging in French Polynesia and Brazil in the 2010s, Zika virus (ZIKV) has been associated with fetal congenital disease. Previous studies have compared ancestral and epidemic ZIKV strains to identify strain differences that may contribute to vertical transmission and fetal disease. However, within-host diversity in ZIKV populations during vertical transmission has not been well studied. Here, we used the established anti-interferon treated Rag1-/- mouse model of ZIKV vertical transmission to compare genomic variation within ZIKV populations in matched placentas, fetal bodies, and fetal brains via RNASeq. At early stages of vertical transmission, the ZIKV populations in the matched placentas and fetal bodies were similar. Most ZIKV single nucleotide variants were present in both tissues, indicating little to no restriction in transmission of ZIKV variants from placenta to fetus. In contrast, at later stages of fetal infection there was a sharp reduction in ZIKV diversity in fetal bodies and fetal brains. All fetal brain ZIKV populations were comprised of one of two haplotypes, containing either a single variant or three variants together, as largely homogenous populations. In most cases, the dominant haplotype present in the fetal brain was also the dominant haplotype present in the matched fetal body. However, in two of ten fetal brains the dominant ZIKV haplotype was undetectable or present at low frequencies in the matched placenta and fetal body ZIKV populations, suggesting evidence of a strict selective bottleneck and possible selection for certain variants during neuroinvasion of ZIKV into fetal brains.

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The Isolated in Utero Environment Is Conducive to the Emergence of RNA and DNA Virus Variants

Cited by 7 publications

References 41 publications

CpG content in the Zika virus genome affects infection phenotypes in the adult brain and fetal lymph nodes

CpG content in the Zika virus genome affects infection phenotypes in the adult brain and fetal lymph nodes

Japanese encephalitis virus persists in the human reproductive epithelium and porcine reproductive tissues

Zika virus diversity in mice is maintained during early vertical transmission from placenta to fetus, but reduced in fetal bodies and brains at late stages of infection

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