scholarly journals African-lineage Zika virus replication dynamics and maternal-fetal interface infection in pregnant rhesus macaques

2020 ◽  
Author(s):  
Chelsea M. Crooks ◽  
Andrea M. Weiler ◽  
Sierra L. Rybarczyk ◽  
Mason Bliss ◽  
Anna S. Jaeger ◽  
...  
Keyword(s):  
Zika Virus ◽  
Rhesus Macaques ◽  
High Titer ◽  
In Vivo Studies ◽  
Genetic Lineage ◽  
African Lineage ◽  
Asian Lineage ◽  
The Impact ◽  
Maternal Fetal Interface

ABSTRACTFollowing the Zika virus (ZIKV) outbreak in the Americas, ZIKV was causally associated with microcephaly and a range of neurological and developmental symptoms, termed congenital Zika syndrome (CZS). The isolates responsible for this outbreak belonged to the Asian lineage of ZIKV. However, in-vitro and in-vivo studies assessing the pathogenesis of African-lineage ZIKV demonstrated that African-lineage isolates often replicated to high titer and caused more severe pathology than Asian-lineage isolates. To date, the pathogenesis of African-lineage ZIKV in a translational model, particularly during pregnancy, has not been rigorously characterized. Here we infected four pregnant rhesus macaques with a low-passage strain of African-lineage ZIKV and compared its pathogenesis to a cohort of four pregnant rhesus macaques infected with an Asian-lineage isolate and a cohort of mock-infected controls. Viral replication kinetics were not significantly different between the two experimental groups and both groups developed robust neutralizing antibody titers above levels considered to be protective. There was no evidence of significant fetal head growth restriction or gross fetal harm at delivery in either group. However, a significantly higher burden of ZIKV vRNA was found in maternal-fetal interface tissues in the macaques exposed to an African-lineage isolate. Our findings suggest that ZIKV isolates of any genetic lineage pose a threat to women and their infants.IMPORTANCEZIKV was first identified over 70 years ago in Africa, but most of our knowledge of ZIKV is based on studies of the distinct Asian genetic lineage, which caused the outbreak in the Americas in 2015-16. In its most recent update, the WHO stated that improved understanding of African-lineage pathogenesis during pregnancy must be a priority. Recent detection of African-lineage isolates in Brazil underscores the need to understand the impact of these viruses. Here we provide the first comprehensive assessment of African-lineage ZIKV infection during pregnancy in a translational non-human primate model. We show African-lineage isolates replicate with similar kinetics to Asian-lineage isolates and are capable of infecting the placenta. However, there was no evidence of more severe outcomes with African-lineage isolates. Our results highlight both the threat that African-lineage ZIKV poses to women and their infants and the need for future epidemiological and translational in-vivo studies with African-lineage ZIKV.

scholarly journals African-lineage Zika virus replication dynamics and maternal-fetal interface infection in pregnant rhesus macaques

2021 ◽  
Author(s):  
Chelsea M. Crooks ◽  
Andrea M. Weiler ◽  
Sierra L. Rybarczyk ◽  
Mason Bliss ◽  
Anna S. Jaeger ◽  
...  
Keyword(s):  
Zika Virus ◽  
Rhesus Macaques ◽  
High Titer ◽  
In Vivo Studies ◽  
Genetic Lineage ◽  
African Lineage ◽  
Asian Lineage ◽  
The Impact ◽  
Maternal Fetal Interface

Following the Zika virus (ZIKV) outbreak in the Americas, ZIKV was causally associated with microcephaly and a range of neurological and developmental symptoms, termed congenital Zika syndrome (CZS). The viruses responsible for this outbreak belonged to the Asian lineage of ZIKV. However, in-vitro and in-vivo studies assessing the pathogenesis of African-lineage ZIKV demonstrated that African-lineage isolates often replicated to high titer and caused more severe pathology than Asian-lineage isolates. To date, the pathogenesis of African-lineage ZIKV in a translational model, particularly during pregnancy, has not been rigorously characterized. Here we infected four pregnant rhesus macaques with a low-passage strain of African-lineage ZIKV and compared its pathogenesis to a cohort of four pregnant rhesus macaques infected with an Asian-lineage isolate and a cohort of mock-inoculated controls. Viral replication kinetics were not significantly different between the two experimental groups and both groups developed robust neutralizing antibody titers above levels considered to be protective. There was no evidence of significant fetal head growth restriction or gross fetal harm at delivery (1-1.5 weeks prior to full term) in either group. However, a significantly higher burden of ZIKV vRNA was found in maternal-fetal interface tissues in the macaques exposed to an African-lineage isolate. Our findings suggest that ZIKV of any genetic lineage poses a threat to pregnant individuals and their infants. IMPORTANCE ZIKV was first identified in 1947 in Africa, but most of our knowledge of ZIKV is based on studies of the distinct Asian genetic lineage, which caused the outbreak in the Americas in 2015-16. In its most recent update, the WHO stated that improved understanding of African-lineage pathogenesis during pregnancy must be a priority. Recent detection of African-lineage isolates in Brazil underscores the need to understand the impact of these viruses. Here we provide the first comprehensive assessment of African-lineage ZIKV infection during pregnancy in a translational non-human primate model. We show African-lineage isolates replicate with similar kinetics to Asian-lineage isolates and can infect the placenta. However, there was no evidence of more severe outcomes with African-lineage isolates. Our results highlight both the threat that African-lineage ZIKV poses to pregnant individuals and their infants and the need for future epidemiological and translational in-vivo studies with African-lineage ZIKV.

scholarly journals Comparative Pathogenesis of Asian and African-Lineage Zika Virus in Indian Rhesus Macaque’s and Development of a Non-Human Primate Model Suitable for the Evaluation of New Drugs and Vaccines

2018 ◽  
Author(s):  
Jonathan O. Rayner ◽  
Raj Kalkeri ◽  
Scott Goebel ◽  
Zhaohui Cai ◽  
Brian Green ◽  
...  
Keyword(s):  
Immune Response ◽  
Zika Virus ◽  
Rhesus Macaques ◽  
New Drugs ◽  
Primate Model ◽  
Robust Immune Response ◽  
African Lineage ◽  
Limit Of Quantitation ◽  
Asian Lineage ◽  
Human Primate

The establishment of a well characterized non-human primate model of Zika virus (ZIKV) infection is critical for the development of medical interventions. In this study, challenging Indian rhesus macaques (IRMs) with ZIKV strains of the Asian lineage resulted in dose dependent peak viral loads between days 2 and 5 post infection; and a robust immune response which protected the animals from homologous and heterologous re-challenge. In contrast, viremia in IRMs challenged with an African lineage strain was below the assays lower limit of quantitation and the immune response was insufficient to protect from re-challenge. These results corroborate previous observations but are contrary to reports using other African strains obviating the need for additional studies to elucidate the variables contributing to the disparities. Nonetheless, the utility of an Asian lineage ZIKV IRM model for countermeasures development was verified by vaccinating animals with a formalin inactivated reference vaccine and demonstrating sterilizing immunity against a subsequent subcutaneous challenge.

scholarly journals Prior dengue immunity enhances Zika virus infection of the maternal-fetal interface in rhesus macaques

2021 ◽  
Author(s):  
C. M. Crooks ◽  
A. M. Weiler ◽  
S. L. Rybarczyk ◽  
M. I. Bliss ◽  
A. S. Jaeger ◽  
...  
Keyword(s):  
Zika Virus ◽  
Rhesus Macaques ◽  
Maternal Plasma ◽  
Adverse Outcomes ◽  
Zikv Infection ◽  
Primate Model ◽  
Denv Serotypes ◽  
The Impact ◽  
Human Primate ◽  
Maternal Fetal Interface

ABSTRACTConcerns have arisen that pre-existing immunity to dengue virus (DENV) could enhance Zika virus (ZIKV) disease, due to the homology between ZIKV and DENV and the observation of antibody-dependent enhancement (ADE) among DENV serotypes. To date, no study has examined the impact of pre-existing DENV immunity on ZIKV pathogenesis during pregnancy in a translational non-human primate model. Here we show that prior DENV-2 exposure enhanced ZIKV infection of maternal-fetal interface tissues in macaques. However, pre-existing DENV immunity had no detectable impact on ZIKV replication kinetics in maternal plasma, and all pregnancies progressed to term without adverse outcomes or gross fetal abnormalities detectable at delivery. Understanding the risks of ADE to pregnant women worldwide is critical as vaccines against DENV and ZIKV are developed and licensed and as DENV and ZIKV continue to circulate.

scholarly journals Transcriptional signatures of Zika virus infection in astrocytes

2021 ◽  
Author(s):  
Blake Schouest ◽  
Tiffany A. Peterson ◽  
Dawn M. Szeltner ◽  
Elizabeth A. Scheef ◽  
Melody Baddoo ◽  
...  
Keyword(s):  
Zika Virus ◽  
Rhesus Macaques ◽  
Response Patterns ◽  
Zikv Infection ◽  
African Lineage ◽  
Important Target ◽  
Asian Lineage ◽  
Human Infections ◽  
The Brain ◽  
Infant Rhesus

AbstractAstrocytes are an early and important target of Zika virus (ZIKV) infection in the developing brain, but the impacts of infection on astrocyte function remain controversial. Given that nonhuman primate (NHP) models of ZIKV infection replicate aspects of neurologic disease seen in human infections, we cultured primary astrocytes from the brain tissue of infant rhesus macaques and then infected the cells with Asian or African lineage ZIKV to identify transcriptional patterns associated with infection in these cells. The African lineage virus appeared to have greater infectivity and promote stronger antiviral signaling, but infection by either strain ultimately produced typical virus response patterns. Both viruses induced hypoxic stress, but the Asian lineage strain additionally had an effect on metabolic and lipid biosynthesis pathways. Together, these findings describe an NHP astrocyte model that may be used to assess transcriptional signatures following ZIKV infection.

scholarly journals Previous exposure to dengue virus is associated with increased Zika virus burden at the maternal-fetal interface in rhesus macaques

2021 ◽  
Vol 15 (7) ◽  
pp. e0009641
Author(s):  
Chelsea M. Crooks ◽  
Andrea M. Weiler ◽  
Sierra L. Rybarczyk ◽  
Mason I. Bliss ◽  
Anna S. Jaeger ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Zika Virus ◽  
Rhesus Macaques ◽  
Maternal Plasma ◽  
Adverse Outcomes ◽  
Primate Model ◽  
Denv Serotypes ◽  
The Impact ◽  
Human Primate ◽  
Maternal Fetal Interface

Concerns have arisen that pre-existing immunity to dengue virus (DENV) could enhance Zika virus (ZIKV) disease, due to the homology between ZIKV and DENV and the observation of antibody-dependent enhancement (ADE) among DENV serotypes. To date, no study has examined the impact of pre-existing DENV immunity on ZIKV pathogenesis during pregnancy in a translational non-human primate model. Here we show that macaques with a prior DENV-2 exposure had a higher burden of ZIKV vRNA in maternal-fetal interface tissues as compared to DENV-naive macaques. However, pre-existing DENV immunity had no detectable impact on ZIKV replication kinetics in maternal plasma, and all pregnancies progressed to term without adverse outcomes or gross fetal abnormalities detectable at delivery. Understanding the risks of ADE to pregnant women worldwide is critical as vaccines against DENV and ZIKV are developed and licensed and as DENV and ZIKV continue to circulate.

scholarly journals Trends in Managing Cardiac and Orthopaedic Device-Associated Infections by Using Therapeutic Biomaterials

Polymers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1556
Author(s):  
Stefania Scialla ◽  
Giorgia Martuscelli ◽  
Francesco Nappi ◽  
Sanjeet Singh Avtaar Singh ◽  
Adelaide Iervolino ◽  
...  
Keyword(s):  
Clinical Medicine ◽  
Preventive Treatment ◽  
Active Surface ◽  
In Vivo Studies ◽  
Antibiotic Resistant ◽  
Implanted Medical Devices ◽  
Hospital Acquired ◽  
Systemic Antibiotics ◽  
The Impact

Over the years, there has been an increasing number of cardiac and orthopaedic implanted medical devices, which has caused an increased incidence of device-associated infections. The surfaces of these indwelling devices are preferred sites for the development of biofilms that are potentially lethal for patients. Device-related infections form a large proportion of hospital-acquired infections and have a bearing on both morbidity and mortality. Treatment of these infections is limited to the use of systemic antibiotics with invasive revision surgeries, which had implications on healthcare burdens. The purpose of this review is to describe the main causes that lead to the onset of infection, highlighting both the biological and clinical pathophysiology. Both passive and active surface treatments have been used in the field of biomaterials to reduce the impact of these infections. This includes the use of antimicrobial peptides and ionic liquids in the preventive treatment of antibiotic-resistant biofilms. Thus far, multiple in vivo studies have shown efficacious effects against the antibiotic-resistant biofilm. However, this has yet to materialize in clinical medicine.

67 Current Status and Future Prospective of the Use of Plant Bioactive Compounds in Dairy and Beef Cattle

2021 ◽  
Vol 99 (Supplement_1) ◽  
pp. 132-132
Author(s):  
Sergio Calsamiglia ◽  
Maria Rodriguez-Prado ◽  
Gonzalo Fernandez-Turren ◽  
Lorena Castillejos
Keyword(s):  
Beef Cattle ◽  
Essential Oils ◽  
Average Daily Gain ◽  
Rumen Fermentation ◽  
Production Performance ◽  
In Vivo Studies ◽  
Current Status ◽  
The Impact

Abstract In the last 20 years there has been extensive in vitro research on the effects of plant extracts and essential oils on rumen microbial fermentation. The main objectives have been to improve energy metabolism through a reduction in methane emissions and an increase in propionate production; and to improve protein metabolism by reducing proteolysis and deamination. While the positive results from in vitro studies has stimulated the release of commercial products based on blends of essential oils, there is limited in vivo evidence on the rumen fermentation and production performance effects. A literature search was conducted to select in vivo studies where information on rumen fermentation and animal performance was reported. For dairy cattle, we identified 37 studies of which 21 were adequate to test production performance. Ten studies reported increases and 3 decreases in milk yield. For beef cattle, we identified 20 studies with rumen fermentation profile and 22 with performance data. Average daily gain improved in 7 and decreased in 1 study. Only 1 out of 16 studies reported an improvement in feed efficiency. Data indicate that out of more than 500 products tested in vitro, only around 20 have been tested in vivo in different mixtures and doses. The use of statistical approaches will allow to describe the conditions, doses and responses in dairy and beef cattle performance. The search for postruminal effects offers another alternative use. Evidence for effects on the intestinal and systemic effects on the immune system and antioxidant status (i.e., capsicum, garlic, eugenol, cinnamaldehyde curcuma, catechins, anethol or pinene), and in the modulation of metabolic regulation (capsicum, cinnamaldehyde, curcuma or garlic) may open the opportunity for future applications. However, stability of the product in the GI tract, description of the mechanisms of action and the impact of these changes on performance needs to be further demonstrated.

scholarly journals Kinetics of Asian and African Zika Virus Lineages over Single-cycle and Multi-cycle Growth in Culture: gene expression, cell killing, virus production, and mathematical modeling

2021 ◽  
Author(s):  
Huicheng Shi ◽  
John Yin
Keyword(s):  
Cell Culture ◽  
Zika Virus ◽  
Virus Production ◽  
Congenital Defects ◽  
Scale Production ◽  
African Lineage ◽  
Intact Virus ◽  
One Step ◽  
Step Growth ◽  
Asian Lineage

Since 2014, an Asian lineage of Zika virus has caused outbreaks, and it has been associated with neurological disorders in adults and congenital defects in newborns. The resulting threat of the Zika virus to human health has prompted the development of new vaccines, which have yet to be approved for human use. Vaccines based on the attenuated or chemically inactivated virus will require large-scale production of the intact virus to meet potential global demands. Intact viruses are produced by infecting cultures of susceptible cells, a dynamic process that spans from hours to days and has yet to be optimized. Here, we infected Vero cells adhesively cultured in well-plates with two Zika virus strains: a recently isolated strain from the Asian lineage, and a cell-culture-adapted strain from the African lineage. At different time points post-infection, virus particles in the supernatant were quantified; further, microscopy images were used to quantify cell density and the proportion of cells expressing viral protein. These measurements were performed across multiple replicate samples of one-step infections every four hours over 60 hours and for multi-step infections every four to 24 hours over 144 hours, generating a rich dataset. For each set of data, mathematical models were developed to estimate parameters associated with cell infection and virus production. The African-lineage strain was found to produce a 14-fold higher yield than the Asian-lineage strain in one-step growth and a 7-fold higher titer in multi-step growth, suggesting a benefit of cell-culture adaptation for developing a vaccine strain. We found that image-based measurements were critical for discriminating among different models, and different parameters for the two strains could account for the experimentally observed differences. An exponential-distributed delay model performed best in accounting for multi-step infection of the Asian strain, and it highlighted the significant sensitivity of virus titer to the rate of viral degradation, with implications for optimization of vaccine production. More broadly, this work highlights how image-based measurements can contribute to discrimination of virus-culture models for the optimal production of inactivated and attenuated whole-virus vaccines.

scholarly journals Impact of the Order of Initiation of Fluconazole and Amphotericin B in Sequential or Combination Therapy on Killing of Candida albicans In Vitro and in a Rabbit Model of Endocarditis and Pyelonephritis

2001 ◽  
Vol 45 (2) ◽  
pp. 485-494 ◽  
Author(s):  
Arnold Louie ◽  
Pamela Kaw ◽  
Partha Banerjee ◽  
Weiguo Liu ◽  
George Chen ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Amphotericin B ◽  
Induced Resistance ◽  
Rabbit Model ◽  
In Vivo Studies ◽  
Infection Model ◽  
Simultaneous Exposure ◽  
The Impact

ABSTRACT In vitro time-kill studies and a rabbit model of endocarditis and pyelonephritis were used to define the impact that the order of exposure of Candida albicans to fluconazole (FLC) and amphotericin B (AMB), as sequential and combination therapies, had on the susceptibility of C. albicans to AMB and on the outcome. The contribution of FLC-induced resistance to AMB for C. albicans also was assessed. In vitro, AMB monotherapy rapidly killed each of four C. albicans strains; FLC alone was fungistatic. Preincubation of these fungi with FLC for 18 h prior to exposure to AMB decreased their susceptibilities to AMB for 8 to >40 h. Induced resistance to AMB was transient, but the duration of resistance increased with the length of FLC preincubation. Yeast sequentially incubated with FLC followed by AMB plus FLC (FLC→AMB+FLC) showed fungistatic growth kinetics similar to that of fungi that were exposed to FLC alone. This antagonistic effect persisted for at least 24 h. Simultaneous exposure of C. albicans to AMB and FLC [AMB+FLC(simult)] demonstrated activity similar to that with AMB alone for AMB concentrations of ≥1 μg/ml; antagonism was seen using an AMB concentration of 0.5 μg/ml. The in vitro findings accurately predicted outcomes in our rabbit infection model. In vivo, AMB monotherapy and treatment with AMB for 24 h followed by AMB plus FLC (AMB→AMB+FLC) rapidly sterilized kidneys and cardiac vegetations. AMB+FLC(simult) and FLC→AMB treatments were slower in clearing fungi from infected tissues. FLC monotherapy and FLC→AMB+FLC were both fungistatic and were the least active regimens. No adverse interaction was observed between AMB and FLC for the AMB→FLC regimen. However, FLC→AMB treatment was slower than AMB alone in clearing fungi from tissues. Thus, our in vitro and in vivo studies both demonstrate that preexposure of C. albicans to FLC reduces fungal susceptibility to AMB. The length of FLC preexposure and whether AMB is subsequently used alone or in combination with FLC determine the duration of induced resistance to AMB.

scholarly journals Hyperstimulation of CaSR in human MSCs by biomimetic apatite inhibits endochondral ossification via temporal down-regulation of PTH1R

2018 ◽  
Vol 115 (27) ◽  
pp. E6135-E6144 ◽  
Author(s):  
Melika Sarem ◽  
Miriam Heizmann ◽  
Andrea Barbero ◽  
Ivan Martin ◽  
V. Prasad Shastri
Keyword(s):  
Endochondral Ossification ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
In Vivo Studies ◽  
Human Mscs ◽  
Down Regulation ◽  
Calcium Sensing ◽  
Biomimetic Apatite ◽  
The Impact

In adult bone injuries, periosteum-derived mesenchymal stem/stromal cells (MSCs) form bone via endochondral ossification (EO), whereas those from bone marrow (BM)/endosteum form bone primarily through intramembranous ossification (IMO). We hypothesized that this phenomenon is influenced by the proximity of MSCs residing in the BM to the trabecular bone microenvironment. Herein, we investigated the impact of the bone mineral phase on human BM-derived MSCs’ choice of ossification pathway, using a biomimetic bone-like hydroxyapatite (BBHAp) interface. BBHAp induced hyperstimulation of extracellular calcium-sensing receptor (CaSR) and temporal down-regulation of parathyroid hormone 1 receptor (PTH1R), leading to inhibition of chondrogenic differentiation of MSCs even in the presence of chondroinductive factors, such as transforming growth factor-β1 (TGF-β1). Interestingly rescuing PTH1R expression using human PTH fragment (1–34) partially restored chondrogenesis in the BBHAp environment. In vivo studies in an ectopic site revealed that the BBHAp interface inhibits EO and strictly promotes IMO. Furthermore, CaSR knockdown (CaSR KD) disrupted the bone-forming potential of MSCs irrespective of the absence or presence of the BBHAp interface. Our findings confirm the expression of CaSR in human BM-derived MSCs and unravel a prominent role for the interplay between CaSR and PTH1R in regulating MSC fate and the choice of pathway for bone formation.

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