scholarly journals Two sides of a coin: a Zika virus mutation selected in pregnant rhesus macaques promotes fetal infection in mice but at a cost of reduced fitness in nonpregnant macaques and diminished transmissibility by vectors

2020 ◽  
Author(s):  
Danilo Lemos ◽  
Jackson B. Stuart ◽  
William Louie ◽  
Anil Singapuri ◽  
Ana L. Ramírez ◽  
...  
Keyword(s):  
Zika Virus ◽  
Fetal Death ◽  
Rhesus Macaques ◽  
Low Frequency ◽  
Alternate Host ◽  
Transmission Cycle ◽  
Fetal Infection ◽  
Congenital Zika Syndrome ◽  
Pregnant Mice ◽  
Mouse Fetuses

ABSTRACTAlthough fetal death is now understood to be a severe outcome of congenital Zika syndrome, the role of viral genetics is still unclear. We sequenced Zika virus (ZIKV) from a rhesus macaque fetus that died after inoculation and identified a single intra-host mutation, M1404I, in the ZIKV polyprotein, located in NS2B. Targeted sequencing flanking position 1404 in 9 additional macaque mothers and their fetuses identified M1404I at sub-consensus frequency in the majority (5 of 9, 56%) of animals and some of their fetuses. Despite its repeated presence in pregnant macaques, M1404I occurs rarely in humans since 2015. Since the primary ZIKV transmission cycle is human-mosquito-human, mutations in one host must be retained in the alternate host to be perpetuated. We hypothesized that ZIKV I1404 increases fitness in non-pregnant macaques and pregnant mice but is less efficiently transmitted by vectors, explaining its low frequency in humans during outbreaks. By examining competitive fitness relative to M1404, we observed that I1404 produced lower viremias in non-pregnant macaques and was a weaker competitor in tissues. In pregnant wildtype mice ZIKV I1404 increased the magnitude and rate of placental infection and conferred fetal infection, contrasting with M1404, which was not detected in fetuses. Although infection and dissemination rates were not different, Ae. aegypti transmitted ZIKV I1404 more poorly than M1404. Our data highlight the complexity of arbovirus mutation-fitness dynamics, and suggest that intrahost ZIKV mutations capable of augmenting fitness in pregnant vertebrates may not necessarily spread efficiently via mosquitoes during epidemics.IMPORTANCEAlthough Zika virus infection of pregnant women can result in congenital Zika syndrome, the factors that cause the syndrome in some but not all infected mothers are still unclear. We identified a mutation that was present in some ZIKV genomes in experimentally inoculated pregnant rhesus macaques and their fetuses. Although we did not find an association between the presence of the mutation and fetal death, we performed additional studies with it in non-pregnant macaques, pregnant mice, and mosquitoes. We observed that the mutation increased the ability of the virus to infect mouse fetuses but decreased its capacity to produce high levels of virus in the blood of non-pregnant macaques and to be transmitted by mosquitoes. This study shows that mutations in mosquito-borne viruses like ZIKV that increase fitness in pregnant vertebrates may not spread in outbreaks when they compromise transmission via mosquitoes and fitness in non-pregnant hosts.

scholarly journals Two Sides of a Coin: a Zika Virus Mutation Selected in Pregnant Rhesus Macaques Promotes Fetal Infection in Mice but at a Cost of Reduced Fitness in Nonpregnant Macaques and Diminished Transmissibility by Vectors

2020 ◽  
Vol 94 (24) ◽  
Author(s):  
Danilo Lemos ◽  
Jackson B. Stuart ◽  
William Louie ◽  
Anil Singapuri ◽  
Ana L. Ramírez ◽  
...  
Keyword(s):  
Zika Virus ◽  
Fetal Death ◽  
Nonstructural Protein ◽  
Rhesus Macaques ◽  
Viral Fitness ◽  
Alternate Host ◽  
Content Type ◽  
Fetal Infection ◽  
Congenital Zika Syndrome ◽  
Pregnant Mice

ABSTRACT Although fetal death is now understood to be a severe outcome of congenital Zika syndrome, the role of viral genetics is still unclear. We sequenced Zika virus (ZIKV) from a rhesus macaque fetus that died after inoculation and identified a single intrahost substitution, M1404I, in the ZIKV polyprotein, located in nonstructural protein 2B (NS2B). Targeted sequencing flanking position 1404 in 9 additional macaque mothers and their fetuses identified M1404I at a subconsensus frequency in the majority (5 of 9, 56%) of animals and some of their fetuses. Despite its repeated presence in pregnant macaques, M1404I has occurred rarely in humans since 2015. Since the primary ZIKV transmission cycle is human-mosquito-human, mutations in one host must be retained in the alternate host to be perpetuated. We hypothesized that ZIKV I1404 increases viral fitness in nonpregnant macaques and pregnant mice but is less efficiently transmitted by vectors, explaining its low frequency in humans during outbreaks. By examining competitive fitness relative to that of ZIKV M1404, we observed that ZIKV I1404 produced lower viremias in nonpregnant macaques and was a weaker competitor in tissues. In pregnant wild-type mice, ZIKV I1404 increased the magnitude and rate of placental infection and conferred fetal infection, in contrast to ZIKV M1404, which was not detected in fetuses. Although infection and dissemination rates were not different, Aedes aegypti mosquitoes transmitted ZIKV I1404 more poorly than ZIKV M1404. Our data highlight the complexity of arbovirus mutation-fitness dynamics and suggest that intrahost ZIKV mutations capable of augmenting fitness in pregnant vertebrates may not necessarily spread efficiently via mosquitoes during epidemics. IMPORTANCE Although Zika virus infection of pregnant women can result in congenital Zika syndrome, the factors that cause the syndrome in some but not all infected mothers are still unclear. We identified a mutation that was present in some ZIKV genomes in experimentally inoculated pregnant rhesus macaques and their fetuses. Although we did not find an association between the presence of the mutation and fetal death, we performed additional studies with ZIKV with the mutation in nonpregnant macaques, pregnant mice, and mosquitoes. We observed that the mutation increased the ability of the virus to infect mouse fetuses but decreased its capacity to produce high levels of virus in the blood of nonpregnant macaques and to be transmitted by mosquitoes. This study shows that mutations in mosquito-borne viruses like ZIKV that increase fitness in pregnant vertebrates may not spread in outbreaks when they compromise transmission via mosquitoes and fitness in nonpregnant hosts.

scholarly journals Maternal immunity and antibodies to dengue virus promote infection and Zika virus–induced microcephaly in fetuses

2019 ◽  
Vol 5 (2) ◽  
pp. eaav3208 ◽  
Author(s):  
Abhay P. S. Rathore ◽  
Wilfried A. A. Saron ◽  
Ting Lim ◽  
Nusrat Jahan ◽  
Ashley L. St. John
Keyword(s):  
Dengue Virus ◽  
Zika Virus ◽  
First Trimester ◽  
Target Populations ◽  
Immune Mediated ◽  
Fetal Infection ◽  
Pregnant Mice ◽  
First Trimester Of Pregnancy ◽  
Special Concern ◽  
Immunocompetent Mice

Zika virus (ZIKV), an emergent flaviviral pathogen, has been linked to microcephaly in neonates. Although the risk is greatest during the first trimester of pregnancy in humans, timing alone cannot explain why maternal ZIKV infection leads to severe microcephaly in some fetuses, but not others. The antigenic similarities between ZIKV and dengue virus (DENV), combined with high levels of DENV immunity among ZIKV target populations in recent outbreaks, suggest that anti-DENV maternal antibodies could promote ZIKV-induced microcephaly. We demonstrated maternal-to-fetal ZIKV transmission, fetal infection, and disproportionate microcephaly in immunocompetent mice. We show that DENV-specific antibodies in ZIKV-infected pregnant mice enhance vertical ZIKV transmission and result in a severe microcephaly-like syndrome, which was dependent on the neonatal Fc receptor, FcRN. This novel immune-mediated mechanism of vertical transmission of viral infection is of special concern because ZIKV epidemic regions are also endemic to DENV.

scholarly journals Zika virus infection in immunocompetent pregnant mice causes fetal damage and placental pathology in the absence of fetal infection

2018 ◽  
Vol 14 (4) ◽  
pp. e1006994 ◽  
Author(s):  
Frank M. Szaba ◽  
Michael Tighe ◽  
Lawrence W. Kummer ◽  
Kathleen G. Lanzer ◽  
Jerrold M. Ward ◽  
...  
Keyword(s):  
Virus Infection ◽  
Zika Virus ◽  
Placental Pathology ◽  
Zika Virus Infection ◽  
Fetal Infection ◽  
Pregnant Mice

scholarly journals Implications of Zika virus and congenital Zika syndrome for the number of live births in Brazil

2018 ◽  
Vol 115 (24) ◽  
pp. 6177-6182 ◽  
Author(s):  
Marcia C. Castro ◽  
Qiuyi C. Han ◽  
Lucas R. Carvalho ◽  
Cesar G. Victora ◽  
Giovanny V. A. França
Keyword(s):  
Zika Virus ◽  
Fetal Death ◽  
Social Inequalities ◽  
World Health ◽  
Death Rates ◽  
Live Births ◽  
Abortion Complications ◽  
Congenital Zika Syndrome ◽  
Health Organization ◽  
The Impact

An increase in microcephaly, associated with an epidemic of Zika virus (ZIKV) in Brazil, prompted the World Health Organization to declare a Public Health Emergency of International Concern in February 2016. While knowledge on biological and epidemiological aspects of ZIKV has advanced, demographic impacts remain poorly understood. This study uses time-series analysis to assess the impact of ZIKV on births. Data on births, fetal deaths, and hospitalizations due to abortion complications for Brazilian states, from 2010 to 2016, were used. Forecasts for September 2015 to December 2016 showed that 119,095 fewer births than expected were observed, particularly after April 2016 (a reduction significant at 0.05), demonstrating a link between publicity associated with the ZIKV epidemic and the decline in births. No significant changes were observed in fetal death rates. Although no significant increases in hospitalizations were forecasted, after the ZIKV outbreak hospitalizations happened earlier in the gestational period in most states. We argue that postponement of pregnancy and an increase in abortions may have contributed to the decline in births. Also, it is likely that an increase in safe abortions happened, albeit selective by socioeconomic status. Thus, the ZIKV epidemic resulted in a generation of congenital Zika syndrome (CZS) babies that reflect and exacerbate regional and social inequalities. Since ZIKV transmission has declined, it is unlikely that reductions in births will continue. However, the possibility of a new epidemic is real. There is a need to address gaps in reproductive health and rights, and to understand CZS risk to better inform conception decisions.

scholarly journals Long-term protection of rhesus macaques from Zika virus reinfection

2019 ◽  
Author(s):  
Gage K. Moreno ◽  
Christina M. Newman ◽  
Michelle R. Koenig ◽  
Mariel S. Mohns ◽  
Andrea M. Weiler ◽  
...  
Keyword(s):  
Zika Virus ◽  
Neutralizing Antibodies ◽  
Protective Immunity ◽  
Vaccine Development ◽  
Rhesus Macaques ◽  
Herd Immunity ◽  
Minimal Length ◽  
Plasma Viremia ◽  
Zikv Infection ◽  
Congenital Zika Syndrome

AbstractBy the end of the 2016 Zika virus (ZIKV) outbreak, it is estimated that there were up to 100 million infections in the Americas. In approximately one in seven infants born to mothers infected during pregnancy, ZIKV has been linked to microcephaly, developmental delays, or other congenital disorders collectively known as congenital Zika syndrome (CZS). Guillain-Barré syndrome (GBS) in ZIKV infected adults. It is a global health priority to develop a vaccine against ZIKV that elicits long-lasting immunity, however, the durability of immunity to ZIKV is unknown. Previous studies in mice and nonhuman primates have been crucial in vaccine development but have not defined the duration of immunity generated by ZIKV infection. In this study, we rechallenged five rhesus macaques with ZIKV two years after a primary ZIKV infection. We show that primary ZIKV infection generates high titers of neutralizing antibodies (nAbs) that protect from detectable plasma viremia following rechallenge and persist for at least 27 months. While additional longitudinal studies are necessary with longer time frames, this study establishes a new experimentally defined minimal length of protective ZIKV immunity.Author SummaryZIKV emerged as a vector-borne pathogen capable of causing illness in infected adults and congenital birth defects in infants born to mothers infected during pregnancy. Despite the drop in ZIKV cases since the 2015-16 epidemic, questions concerning the prevalence and longevity of protective immunity have left vulnerable communities fearful that they may become the center of next ZIKV outbreak. While pre-existing herd immunity in regions of past outbreaks may dampen the potential for future outbreaks to occur, we currently do not know the longevity of protective immunity to ZIKV after a person becomes infected. Here, we establish a new experimentally defined minimal length of protective ZIKV immunity. We show that five rhesus macaques initially infected with ZIKV two years prior to rechallenge elicit a durable immune response that protected from detectable plasma viremia. While this work establishes a new minimal length of protective immunity, additional studies are necessary to define the maximum length of protective immunity following ZIKV infection.

Zika Virus Infection in Pregnancy, Microcephaly, and Maternal and Fetal Health: What We Think, What We Know, and What We Think We Know

2016 ◽  
Vol 141 (1) ◽  
pp. 26-32 ◽  
Author(s):  
Maria Gabriela Alvarado ◽  
David A. Schwartz
Keyword(s):  
Brain Damage ◽  
Zika Virus ◽  
Experimental Studies ◽  
Fetal Brain ◽  
Zikv Infection ◽  
Host Genetics ◽  
Fetal Infection ◽  
Congenital Zika Syndrome ◽  
Experimental Laboratory ◽  
Congenital Microcephaly

Context.—The global epidemic of Zika virus (ZIKV) infection has emerged as an important public health problem affecting pregnant women and their infants. Objectives.—To review the causal association between ZIKV infection during pregnancy and intrauterine fetal infection, microcephaly, brain damage, congenital malformation syndrome, and experimental laboratory models of fetal infection. Many questions remain regarding the risk factors, pathophysiology, epidemiology, and timing of maternal-fetal transmission and disease. These include mechanisms of fetal brain damage and microcephaly; the role of covariables, such as viral burden, duration of viremia, and host genetics, on vertical transmission; and the clinical and pathologic spectrum of congenital Zika syndrome. Additional questions include defining the potential long-term physical and neurobehavioral outcomes for infected infants, whether maternal or fetal host genetics influence the clinical outcome, and whether ZIKV infection can cause maternal morbidity. Finally, are experimental laboratory and animal models of ZIKV infection helpful in addressing maternal-fetal viral transmission and the development of congenital microcephaly? This communication provides current information and attempts to address some of these important questions. Data Sources.—Comprehensive review of published scientific literature. Conclusions.—Recent advances in epidemiology, clinical medicine, pathology, and experimental studies have provided a great amount of new information regarding vertical ZIKV transmission and the mechanisms of congenital microcephaly, brain damage, and congenital Zika syndrome in a relatively short time. However, much work still needs to be performed to more completely understand the maternal and fetal aspects of this new and emerging viral disease.

scholarly journals Potential for Zika virus to establish a sylvatic transmission cycle in the Americas

2016 ◽  
Author(s):  
Benjamin M. Althouse ◽  
Nikos Vasilakis ◽  
Amadou A. Sall ◽  
Mawlouth Diallo ◽  
Scott C. Weaver ◽  
...  
Keyword(s):  
Zika Virus ◽  
New World ◽  
Vector Competence ◽  
Host Population ◽  
Transmission Model ◽  
New World Monkeys ◽  
Sylvatic Cycle ◽  
Transmission Cycle ◽  
Force Of Infection ◽  
Congenital Zika Syndrome

AbstractZika virus (ZIKV) originated and continues to circulate in a sylvatic transmission cycle between non-human primate hosts and arboreal mosquitoes in tropical Africa. Recently ZIKV invaded the Americas, where it poses a threat to human health, especially to pregnant women and their infants. Here we examine the risk that ZIKV will establish a sylvatic cycle in the Americas, focusing on Brazil. We review the natural history of sylvatic ZIKV and present a mathematical dynamic transmission model to assess the probability of establishment of a sylvatic ZIKV transmission cycle in non-human primates and/or other mammals and arboreal mosquito vectors in Brazil. Brazil is home to multiple species of primates and mosquitoes potentially capable of ZIKV transmission, though direct assessment of host competence (ability to mount viremia sufficient to infect a feeding mosquito) and vector competence (ability to become infected with ZIKV and disseminate and transmit upon subsequent feedings) of New World species is lacking. Modeling reveals a high probability of establishment of sylvatic ZIKV across a large range of biologically plausible parameters. Probability of establishment is dependent on host population sizes and birthrates and ZIKV force of infection, but a network of as few as 6,000 primates with 10,000 mosquitoes is capable of supporting establishment of a ZIKV sylvatic cycle. Research on the susceptibility of New World monkeys or other small mammals to ZIKV, on the vector competence of New World Aedes, Sabethes, and Haemagogus mosquitoes for ZIKV, and on the geographic range of these species is urgently needed. A sylvatic cycle of ZIKV would make future elimination efforts in the Americas practically impossible, and paints a dire situation for the epidemiology of ZIKV and ending the ongoing outbreak of congenital Zika syndrome.

scholarly journals Long-Term Protection of Rhesus Macaques from Zika Virus Reinfection

2019 ◽  
Vol 94 (5) ◽  
Author(s):  
Gage K. Moreno ◽  
Christina M. Newman ◽  
Michelle R. Koenig ◽  
Mariel S. Mohns ◽  
Andrea M. Weiler ◽  
...  
Keyword(s):  
Zika Virus ◽  
Neutralizing Antibodies ◽  
Protective Immunity ◽  
Vaccine Development ◽  
Rhesus Macaques ◽  
Herd Immunity ◽  
Minimal Length ◽  
Plasma Viremia ◽  
Zikv Infection ◽  
Congenital Zika Syndrome

ABSTRACT By the end of the 2016 Zika virus (ZIKV) outbreak, it is estimated that there were up to 100 million infections in the Americas. In approximately one in seven infants born to mothers infected during pregnancy, ZIKV has been linked to microcephaly, developmental delays, or other congenital disorders collectively known as congenital Zika syndrome, as well as Guillain-Barré syndrome, in ZIKV-infected adults. It is a global health priority to develop a vaccine against ZIKV that elicits long-lasting immunity; however, the durability of immunity to ZIKV is unknown. Previous studies in mice and nonhuman primates have been crucial in vaccine development but have not defined the duration of immunity generated by ZIKV infection. In this study, we rechallenged five rhesus macaques with ZIKV 22 to 28 months after a primary ZIKV infection. We show that primary ZIKV infection generates high titers of neutralizing antibodies that protect from detectable plasma viremia following rechallenge and persist for at least 22 to 28 months. While additional longitudinal studies are necessary with longer time frames, this study establishes a new experimentally defined minimal length of protective ZIKV immunity. IMPORTANCE ZIKV emerged as a vector-borne pathogen capable of causing illness in infected adults and congenital birth defects in infants born to mothers infected during pregnancy. Despite the decrease in ZIKV cases since the 2015-2016 epidemic, questions concerning the prevalence and longevity of protective immunity have left vulnerable communities fearful that they may become the center of next ZIKV outbreak. Although preexisting herd immunity in regions of past outbreaks may dampen the potential for future outbreaks to occur, we currently do not know the longevity of protective immunity to ZIKV after a person becomes infected. Here, we establish a new experimentally defined minimal length of protective ZIKV immunity. We show that five rhesus macaques initially infected with ZIKV 22 to 28 months prior to rechallenge elicit a durable immune response that protected from detectable plasma viremia. This study establishes a new minimal length of protective immunity.

scholarly journals DNA vaccination before conception protects Zika virus–exposed pregnant macaques against prolonged viremia and improves fetal outcomes

2019 ◽  
Vol 11 (523) ◽  
pp. eaay2736 ◽  
Author(s):  
Koen K. A. Van Rompay ◽  
Rebekah I. Keesler ◽  
Amir Ardeshir ◽  
Jennifer Watanabe ◽  
Jodie Usachenko ◽  
...  
Keyword(s):  
Zika Virus ◽  
Fetal Loss ◽  
Fetal Brain ◽  
Neutralizing Antibody ◽  
Fetal Outcomes ◽  
Zikv Infection ◽  
Macaque Model ◽  
Fetal Infection ◽  
Congenital Zika Syndrome ◽  
Antibody Titers

Zika virus (ZIKV) infection of pregnant women is associated with congenital Zika syndrome (CZS) and no vaccine is available, although several are being tested in clinical trials. We tested the efficacy of ZIKV DNA vaccine VRC5283 in a rhesus macaque model of congenital ZIKV infection. Most animal vaccine experiments have a set pathogen exposure several weeks or months after vaccination. In the real world, people encounter pathogens years or decades after vaccination, or may be repeatedly exposed if the virus is endemic. To more accurately mimic how this vaccine would be used, we immunized macaques before conception and then exposed them repeatedly to ZIKV during early and mid-gestation. In comparison to unimmunized animals, vaccinated animals had a significant reduction in peak magnitude and duration of maternal viremia, early fetal loss, fetal infection, and placental and fetal brain pathology. Vaccine-induced neutralizing antibody titers on the day of first ZIKV exposure were negatively associated with the magnitude of maternal viremia, and the absence of prolonged viremia was associated with better fetal outcomes. These data support further clinical development of ZIKV vaccine strategies to protect against negative fetal outcomes.

scholarly journals Differential Type 1 IFN Gene Expression in CD14+ Placenta Cells Elicited by Zika Virus Infection During Pregnancy

2021 ◽  
Vol 1 ◽  
Author(s):  
Nicole N. Haese ◽  
Hannah Smith ◽  
Kosiso Onwuzu ◽  
Craig N. Kreklywich ◽  
Jessica L. Smith ◽  
...  
Keyword(s):  
Zika Virus ◽  
Immune Cell ◽  
Rhesus Macaques ◽  
Fetal Brain ◽  
Bioinformatic Analysis ◽  
Interferon Response ◽  
Zikv Infection ◽  
Expression Of Genes ◽  
Congenital Zika Syndrome

Zika virus (ZIKV) is an arthropod-borne Flavivirus that can also be transmitted vertically from infected mother to fetus. Infection of the fetus during pregnancy can lead to congenital malformations and severely impact fetal brain development causing a myriad of diseases now labeled Congenital Zika Syndrome (CZS). The mechanisms by which ZIKV crosses the placenta into the fetal circulation and the extent of ZIKV-induced changes remain unclear. We have previously shown that ZIKV infection of pregnant rhesus macaques results in abnormal oxygen transport across the placenta which may promote uterine vasculitis and placental villous damage. Changes in immune cell frequencies and activation status were also detected, as were distinct changes in the proportions of CD14+ cell subsets with an altered ratio of classical to non-classical CD14+ monocyte cells in both the maternal decidua and placental villous from ZIKV-infected animals compare to uninfected controls. In the current study, we performed single cell RNA sequencing on CD14+ cells isolated from the decidua of animals that were ZIKV infected at 31, 51, or 115 days of gestation (where term is ~168 days) compared to pregnant, time-matched uninfected controls. Bioinformatic analysis identified unique transcriptional phenotypes between CD14+ cells of infected and uninfected animals suggesting a distinct and sustained difference in transcriptomes between infected and uninfected CD14+ cells derived from the decidua. The timing of ZIKV infection had no effect on the CD14+ cell transcriptional profiles. Interestingly, ZIKV infection caused changes in expression of genes in pathways related to cellular stress and metabolism as well as immune response activation. Type 1 interferon response genes (ISGs) were among those that were differentially expressed following infection and these included members of the ISG12 family, IFI27 and IFI6. These ISGs have been recently described as effectors of the IFN response to flaviviruses. Supplementing our animal findings, in CD14+ cells isolated from human placenta, ZIKV infection similarly induced the expression of IFI27 and IFI6. Overall, our results showed that ZIKV infection during pregnancy induces the stable expression of antiviral genes within CD14+ cells of the placenta, which may provide an immune shield to protect the placenta from further infection and damage.

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