Publications by authors named "Heather Simmons"

54 Publications

Early Embryonic Loss Following Intravaginal Zika Virus Challenge in Rhesus Macaques.

Front Immunol 2021 17;12:686437. Epub 2021 May 17.

Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI, United States.

Zika virus (ZIKV) is an arthropod-borne virus (arbovirus) and is primarily transmitted by species mosquitoes; however, ZIKV can also be sexually transmitted. During the initial epidemic and in places where ZIKV is now considered endemic, it is difficult to disentangle the risks and contributions of sexual versus vector-borne transmission to adverse pregnancy outcomes. To examine the potential impact of sexual transmission of ZIKV on pregnancy outcome, we challenged three rhesus macaques () three times intravaginally with 1 x 10 PFU of a low passage, African lineage ZIKV isolate (ZIKV-DAK) in the first trimester (~30 days gestational age). Samples were collected from all animals initially on days 3 through 10 post challenge, followed by twice, and then once weekly sample collection; ultrasound examinations were performed every 3-4 days then weekly as pregnancies progressed. All three dams had ZIKV RNA detectable in plasma on day 3 post-ZIKV challenge. At approximately 45 days gestation (17-18 days post-challenge), two of the three dams were found with nonviable embryos by ultrasound. Viral RNA was detected in recovered tissues and at the maternal-fetal interface (MFI) in both cases. The remaining viable pregnancy proceeded to near term (~155 days gestational age) and ZIKV RNA was detected at the MFI but not in fetal tissues. These results suggest that sexual transmission of ZIKV may represent an underappreciated risk of pregnancy loss during early gestation.
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http://dx.doi.org/10.3389/fimmu.2021.686437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165274PMC
May 2021

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

J Virol 2021 Jun 2:JVI0222020. Epub 2021 Jun 2.

Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, WI, USA.

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. 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.
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http://dx.doi.org/10.1128/JVI.02220-20DOI Listing
June 2021

Clinical Management of Gastrointestinal Disease in the Common Marmoset (Callithrix jacchus).

ILAR J 2021 May 15. Epub 2021 May 15.

Wisconsin National Primate Research Center at the University of Wisconsin-Madison, Madison, Wisconsin, USA.

Gastrointestinal disease is a frequently encountered problem among captive common marmoset (Callithrix jacchus) colonies. Management can be challenging due to the number of etiologies responsible for gastrointestinal disease in this species, limitations on diagnostic capabilities, and lack of effective treatments. Understanding commonly described GI diseases in the captive marmoset can provide insight on the impact these diseases have on research studies and aid in the development of appropriate management strategies. A review of commonly encountered GI disease processes as well as routinely implicated causes of GI disease in the common marmoset are provided. Current strategies in clinical management of GI disease in the common marmoset, including approaches to colony health, diagnostic testing, and commonly employed treatments are discussed.
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http://dx.doi.org/10.1093/ilar/ilab012DOI Listing
May 2021

Autologous transplant therapy alleviates motor and depressive behaviors in parkinsonian monkeys.

Nat Med 2021 04 1;27(4):632-639. Epub 2021 Mar 1.

Waisman Center, University of Wisconsin-Madison, Madison, WI, USA.

Degeneration of dopamine (DA) neurons in the midbrain underlies the pathogenesis of Parkinson's disease (PD). Supplement of DA via L-DOPA alleviates motor symptoms but does not prevent the progressive loss of DA neurons. A large body of experimental studies, including those in nonhuman primates, demonstrates that transplantation of fetal mesencephalic tissues improves motor symptoms in animals, which culminated in open-label and double-blinded clinical trials of fetal tissue transplantation for PD. Unfortunately, the outcomes are mixed, primarily due to the undefined and unstandardized donor tissues. Generation of induced pluripotent stem cells enables standardized and autologous transplantation therapy for PD. However, its efficacy, especially in primates, remains unclear. Here we show that over a 2-year period without immunosuppression, PD monkeys receiving autologous, but not allogenic, transplantation exhibited recovery from motor and depressive signs. These behavioral improvements were accompanied by robust grafts with extensive DA neuron axon growth as well as strong DA activity in positron emission tomography (PET). Mathematical modeling reveals correlations between the number of surviving DA neurons with PET signal intensity and behavior recovery regardless autologous or allogeneic transplant, suggesting a predictive power of PET and motor behaviors for surviving DA neuron number.
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http://dx.doi.org/10.1038/s41591-021-01257-1DOI Listing
April 2021

AgSecure Africa Programme: A Blended Training Approach for Africa.

J Vet Med Educ 2021 Jan 25:e20200047. Epub 2021 Jan 25.

An innovative training program entitled "AgSecure Africa Programme" was developed in partnership with the South African Agricultural Research Council-Onderstepoort Veterinary Research (ARC-OVR) to train veterinarians, animal health technicians, researchers and laboratory personnel. Three blended courses consisting of both virtual and in person delivery were provided with the intent of contributing to the better prevention, detection and control of infectious diseases of livestock and poultry of significant importance for the region with a strong emphasis on transboundary animal diseases. A "train the trainer" model of instruction was employed to equip participants with the ability to train and share knowledge with colleagues and small-holder farmers in their various communities and regions. The design of this program was to increase the capacity of veterinarians and veterinary diagnosticians to safely and accurately diagnose infectious livestock diseases and to also empower small-holder farmers with the knowledge needed to safely and securely manage their livestock and be a first line defense in the prevention and control of infectious livestock diseases. Quantitative and qualitative evaluations were used to measure the impact of the trainings which revealed significant increases in knowledge gains. Course materials were submitted and approved for accreditation by the South African Veterinary Council (SAVC) becoming the first international training program to achieve this. Approval of these courses led to licensed veterinarians and animal health technicians being awarded continuing professional development credits upon their successful completion of courses. A larger goal was to build training capacity, not only for South Africa, but also for the region.
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http://dx.doi.org/10.3138/jvme-2020-0047DOI Listing
January 2021

Brain pathology caused in the neonatal macaque by short and prolonged exposures to anticonvulsant drugs.

Neurobiol Dis 2021 02 29;149:105245. Epub 2020 Dec 29.

Department of Neurology, University of Wisconsin, School of Medicine, Madison, WI, USA. Electronic address:

Barbiturates and benzodiazepines are potent GABA receptor agonists and strong anticonvulsants. In the developing brain they can cause neuronal and oligodendroglia apoptosis, impair synaptogenesis, inhibit neurogenesis and trigger long-term neurocognitive sequelae. In humans, the vulnerable period is projected to extend from the third trimester of pregnancy to the third year of life. Infants with seizures and epilepsies may receive barbiturates, benzodiazepines and their combinations for days, months or years. How exposure duration affects neuropathological sequelae is unknown. Here we investigated toxicity of phenobarbital/midazolam (Pb/M) combination in the developing nonhuman primate brain. Neonatal rhesus monkeys received phenobarbital intravenously, followed by infusion of midazolam over 5 (n = 4) or 24 h (n = 4). Animals were euthanized at 8 or 36 h and brains examined immunohistochemically and stereologically. Treatment was well tolerated, physiological parameters remained at optimal levels. Compared to naïve controls, Pb/M exposed brains displayed widespread apoptosis affecting neurons and oligodendrocytes. Pattern and severity of cell death differed depending on treatment-duration, with more extensive neurodegeneration following longer exposure. At 36 h, areas of the brain not affected at 8 h displayed neuronal apoptosis, while oligodendroglia death was most prominent at 8 h. A notable feature at 36 h was degeneration of neuronal tracts and trans-neuronal death of neurons, presumably following their disconnection from degenerated presynaptic partners. These findings demonstrate that brain toxicity of Pb/M in the neonatal primate brain becomes more severe with longer exposures and expands trans-synaptically. Impact of these sequelae on neurocognitive outcomes and the brain connectome will need to be explored.
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http://dx.doi.org/10.1016/j.nbd.2020.105245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856070PMC
February 2021

Development of a Geropathology Grading Platform for nonhuman primates.

Aging Pathobiol Ther 2020 ;2(1):16-19

Department of Comparative Medicine, School of Medicine, University of Washington, Seattle, WA, USA.

A geropathology grading platform (GGP) for assessing age-related lesions has been established and validated for in inbred strain of mice. Because nonhuman primates (NHPs) share significant similarities in aging and spontaneous chronic diseases with humans, they provide excellent translational value for correlating histopathology with biological and pathological events associated with increasing age. Descriptive age-associated pathology has been described for rhesus macaques and marmosets, but a grading platform similar to the mouse GGP does not exist. The value of these NHP models is enhanced by considerable historical data from clinical, bio-behavioral, and social domains that align with health span in these animals. Successful adaptation of the mouse GGP for NHPs will include 1) expanding the range of organs examined; 2) standardizing necropsy collection, tissue trimming, and descriptive lesion terminology; 3) expanding beyond rhesus macaques and marmosets to include other commonly used NHPs in research; and 4) creating a national resource for age-related pathology to complement the extensive in-life datasets. Adaptation of the GGP to include translational models other than mice will be crucial to advance geropathology designed to enhance aging research.
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http://dx.doi.org/10.31491/apt.2020.03.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717498PMC
January 2020

Transplantation of T-cell receptor α/β-depleted allogeneic bone marrow in nonhuman primates.

Exp Hematol 2021 01 8;93:44-51. Epub 2020 Nov 8.

Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, WI; Department of Pathology and Laboratory Medicine, School of Medicine, University of Wisconsin-Madison, Madison, WI; Department of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Madison, WI. Electronic address:

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a potentially curative treatment for hematologic cancers and chronic infections such as human immunodeficiency virus (HIV). Its success in these settings is attributed to the ability of engrafting immune cells to eliminate cancer cells or deplete the HIV reservoir (graft-versus-host effect [GvHE]). However, alloHSCT is commonly associated with graft-versus-host diseases (GvHDs) causing significant morbidity and mortality, thereby requiring development of novel allogeneic HSCT protocols and therapies promoting GvHE without GvHD using physiologically relevant preclinical models. Here we evaluated the outcomes of major histocompatibility complex-matched T-cell receptor α/β-depleted alloHSCT in Mauritian cynomolgus macaques (MCMs). Following T-cell receptor α/β depletion, bone marrow cells were transplanted into major histocompatibility complex-identical MCMs conditioned with total body irradiation. GvHD prophylaxis included sirolimus alone in two animals or tacrolimus with cyclophosphamide in another two animals. Posttransplant chimerism was determined by sequencing diagnostic single-nucleotide polymorphisms to quantify the amounts of donor and recipient cells present in blood. Animals treated posttransplant with sirolimus developed nearly complete chimerism with acute GvHD. In the cyclophosphamide and tacrolimus treatment group, animals developed mixed chimerism without GvHD, with long-term engraftment observed in one animal. None of the animals developed cytomegalovirus infection. These studies indicate the feasibility of alloHSCT engraftment without GvHD in an MHC-identical MCM model following complete myeloablative conditioning and anti-GvHD prophylaxis with posttransplant cyclophosphamide and tacrolimus. Further exploration of this model will provide a platform for elucidating the mechanisms of GvHD and GvHE and for testing novel alloHSCT modalities for HIV infection.
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http://dx.doi.org/10.1016/j.exphem.2020.09.198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855119PMC
January 2021

Quantitative definition of neurobehavior, vision, hearing and brain volumes in macaques congenitally exposed to Zika virus.

PLoS One 2020 22;15(10):e0235877. Epub 2020 Oct 22.

Department of Veterinary and Biomedical Sciences, University of Minnesota, Minneapolis, Minnesota, United States of America.

Congenital Zika virus (ZIKV) exposure results in a spectrum of disease ranging from severe birth defects to delayed onset neurodevelopmental deficits. ZIKV-related neuropathogenesis, predictors of birth defects, and neurodevelopmental deficits are not well defined in people. Here we assess the methodological and statistical feasibility of a congenital ZIKV exposure macaque model for identifying infant neurobehavior and brain abnormalities that may underlie neurodevelopmental deficits. We inoculated five pregnant macaques with ZIKV and mock-inoculated one macaque in the first trimester. Following birth, growth, ocular structure/function, brain structure, hearing, histopathology, and neurobehavior were quantitatively assessed during the first week of life. We identified the typical pregnancy outcomes of congenital ZIKV infection, with fetal demise and placental abnormalities. We estimated sample sizes needed to define differences between groups and demonstrated that future studies quantifying brain region volumes, retinal structure, hearing, and visual pathway function require a sample size of 14 animals per group (14 ZIKV, 14 control) to detect statistically significant differences in at least half of the infant exam parameters. Establishing the parameters for future studies of neurodevelopmental outcomes following congenital ZIKV exposure in macaques is essential for robust and rigorous experimental design.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235877PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7580995PMC
November 2020

Discovery of a Novel Simian Pegivirus in Common Marmosets () with Lymphocytic Enterocolitis.

Microorganisms 2020 Sep 30;8(10). Epub 2020 Sep 30.

Department of Pathology and Laboratory Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53711, USA.

From 2010 to 2015, 73 common marmosets () housed at the Wisconsin National Primate Research Center (WNPRC) were diagnosed postmortem with lymphocytic enterocolitis. We used unbiased deep-sequencing to screen the blood of deceased enterocolitis-positive marmosets for viruses. In five out of eight common marmosets with lymphocytic enterocolitis, we discovered a novel pegivirus not present in ten matched, clinically normal controls. The novel virus, which we named Southwest bike trail virus (SOBV), is most closely related (68% nucleotide identity) to a strain of simian pegivirus A isolated from a three-striped night monkey (). We screened 146 living WNPRC common marmosets for SOBV, finding an overall prevalence of 34% (50/146). Over four years, 85 of these 146 animals died or were euthanized. Histological examination revealed 27 SOBV-positive marmosets from this cohort had lymphocytic enterocolitis, compared to 42 SOBV-negative marmosets, indicating no association between SOBV and disease in this cohort ( = 0.0798). We also detected SOBV in two of 33 (6%) clinically normal marmosets screened during transfer from the New England Primate Research Center, suggesting SOBV could be exerting confounding influences on comparisons of common marmoset studies from multiple colonies.
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http://dx.doi.org/10.3390/microorganisms8101509DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599636PMC
September 2020

Zika virus in rhesus macaque semen and reproductive tract tissues: a pilot study of acute infection†.

Biol Reprod 2020 10;103(5):1030-1042

Wisconsin National Primate Research Center, Madison, WI, USA.

Although sexual transmission of Zika virus (ZIKV) is well-documented, the viral reservoir(s) in the male reproductive tract remains uncertain in humans and immune-intact animal models. We evaluated the presence of ZIKV in a rhesus macaque pilot study to determine persistence in semen, assess the impact of infection on sperm functional characteristics, and define the viral reservoir in the male reproductive tract. Five adult male rhesus monkeys were inoculated with 105 PFU of Asian-lineage ZIKV isolate PRVABC59, and two males were inoculated with the same dose of African-lineage ZIKV DAKAR41524. Viremia and viral RNA (vRNA) shedding in semen were monitored, and a cohort of animals were necropsied for tissue collection to assess tissue vRNA burden and histopathology. All animals exhibited viremia for limited periods (1-11 days); duration of shedding did not differ significantly between viral isolates. There were sporadic low levels of vRNA in the semen from some, but not all animals. Viral RNA levels in reproductive tract tissues were also modest and present in the epididymis in three of five cases, one case in the vas deferens, but not detected in testis, seminal vesicles or prostate. ZIKV infection did not impact semen motility parameters as assessed by computer-assisted sperm analysis. Despite some evidence of prolonged ZIKV RNA shedding in human semen and high tropism of ZIKV for male reproductive tract tissues in mice deficient in Type 1 interferon signaling, in the rhesus macaques assessed in this pilot study, we did not consistently find ZIKV RNA in the male reproductive tract.
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http://dx.doi.org/10.1093/biolre/ioaa137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609866PMC
October 2020

An International Collaborative Approach to Developing Training Guidelines for Veterinary Paraprofessionals.

J Vet Med Educ 2020 Oct 9;47(5):546-554. Epub 2020 Jun 9.

Veterinary paraprofessionals (VPPs) are engaged worldwide in animal health management, disease surveillance and food safety control. In many countries, particularly developing countries, VPPs are critical to national veterinary services provision. Until recently, there were no globally recognized training requirements for VPPs. Recognition of VPPs' qualifications and roles, and requirements for registration, vary greatly between jurisdictions. To address these issues, the World Organisation for Animal Health (OIE) has developed competency and curricular guidelines for VPPs. A collaborative approach was essential to this mission. Extensive consultation with individuals and agencies representing various countries, animal health and veterinary sectors, and forms of expertise, was undertaken. Collaborative methods included the formation of a guidelines development group whose diversity reflected project needs, the use of existing OIE Member Country data to understand roles of VPPs globally, conducting stakeholder surveys to collate VPP competency expectations and solicit feedback on draft guidelines, and in-country missions to validate draft curricular models. The initial deliverable from this work was publication of Competency Guidelines for VPPs. This document provides recommendations on the knowledge, skills, attitudes, and aptitudes that could be expected of VPPs following effective training. The companion document, OIE Curricular Guidelines for VPPs, provides recommendations on coursework structure and content to achieve these competencies. These guidelines will assist countries worldwide in more effectively training and qualifying VPPs so that they can contribute positively to the provision of veterinary services. Another potential impact is to catalyze the review of educational and regulatory standards regarding the respective work rights and activities of veterinarians and VPPs.
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http://dx.doi.org/10.3138/jvme-2019-0086DOI Listing
October 2020

Bench to Shop™: An Interdisciplinary Training Program for Transitioning of Transboundary Animal Disease Research to Commercialization.

J Vet Med Educ 2021 Jun 12;48(3):301-309. Epub 2020 Mar 12.

Transboundary animal diseases (TADs) are livestock diseases characterized as highly contagious, fast-spreading, and capable of producing high morbidity and mortality. Accidental or intentional introduction of these diseases into the United States could devastate the economy, food security, and public health. Training of researchers, scientists and animal health workers is often limited to prevention and diagnosis with little emphasis on the importance of translating knowledge to the development of new products for the prevention, detection and control of outbreaks. The Bench to Shop™ training program was developed to fill this gap and applied an innovative blended-learning method through the use of an online platform, a 3-week experiential training, and a 1-month follow-up project. The program specifically targeted next-generation researchers, including PhD students, post-doctoral researchers, and early-career faculty. A total of 17 trainees, in two cohorts, were selected through a national and international recruitment process. Program evaluation consisted of focus groups, follow-up interviews, and pre- and post-tests of didactic material, revealing statistically significant gains in knowledge. Participants expanded their professional networks with leaders in industry and regulatory agencies related to production and/or commercialization of TAD products and deepened their commitment toward keeping our country safe from TADs. Post-program impacts on trainees included advancing products toward commercialization, partnering with connections made through the program, and demonstrating dedication to homeland security by pursuing product development related educational and career opportunities. Overall, results suggest this program provides an added value and should be readily available to the current and future workforce.
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http://dx.doi.org/10.3138/jvme.2019-0048DOI Listing
June 2021

Post mortem evaluation of inflammation, oxidative stress, and PPARγ activation in a nonhuman primate model of cardiac sympathetic neurodegeneration.

PLoS One 2020 7;15(1):e0226999. Epub 2020 Jan 7.

Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, WI, United States of America.

Cardiac dysautonomia is a common nonmotor symptom of Parkinson's disease (PD) associated with loss of sympathetic innervation to the heart and decreased plasma catecholamines. Disease-modifying strategies for PD cardiac neurodegeneration are not available, and biomarkers of target engagement are lacking. Systemic administration of the catecholaminergic neurotoxin 6-hydroxydopamine (6-OHDA) recapitulates PD cardiac dysautonomia pathology. We recently used positron emission tomography (PET) to visualize and quantify cardiac sympathetic innervation, oxidative stress, and inflammation in adult male rhesus macaques (Macaca mulatta; n = 10) challenged with 6-OHDA (50mg/kg; i.v.). Twenty-four hours post-intoxication, the animals were blindly and randomly assigned to receive daily doses of the peroxisome proliferator-activated receptor gamma (PPARγ) agonist pioglitazone (n = 5; 5mg/kg p.o.) or placebo (n = 5). Quantification of PET radioligand uptake showed increased oxidative stress and inflammation one week after 6-OHDA which resolved to baseline levels by twelve weeks, at which time pioglitazone-treated animals showed regionally preserved sympathetic innervation. Here we report post mortem characterization of heart and adrenal tissue in these animals compared to age and sex matched normal controls (n = 5). In the heart, 6-OHDA-treated animals showed a significant loss of sympathetic nerve fibers density (tyrosine hydroxylase (TH)-positive fibers). The anatomical distribution of markers of sympathetic innervation (TH) and inflammation (HLA-DR) significantly correlated with respective in vivo PET findings across left ventricle levels and regions. No changes were found in alpha-synuclein immunoreactivity. Additionally, CD36 protein expression was increased at the cardiomyocyte intercalated discs following PPARγ-activation compared to placebo and control groups. Systemic 6-OHDA decreased adrenal medulla expression of catecholamine producing enzymes (TH and aromatic L-amino acid decarboxylase) and circulating levels of norepinephrine, which were attenuated by PPARγ-activation. Overall, these results validate in vivo PET findings of cardiac sympathetic innervation, oxidative stress, and inflammation and illustrate cardiomyocyte CD36 upregulation as a marker of PPARγ target engagement.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226999PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946159PMC
April 2020

Sequelae of Fetal Infection in a Non-human Primate Model of Listeriosis.

Front Microbiol 2019 11;10:2021. Epub 2019 Sep 11.

Wisconsin National Primate Research Center, University of Wisconsin - Madison, Madison, WI, United States.

(Lm) is a common environmental bacterium that thrives on vegetation and soil matter, but can infect humans if contaminated food products are ingested, resulting in severe disease in immunosuppressed populations, including pregnant women and newborns. To better understand how the unique immunological milieu of pregnancy increases susceptibility to infection, we study listeriosis in cynomolgus macaques, a non-human primate that closely resembles humans in placentation and in the physiology, and immunology of pregnancy. Non-human primates are naturally susceptible to Lm infection, and spontaneous abortions due to listeriosis are known to occur in outdoor macaque colonies, making them ideal models to understand the disease pathogenesis and host-pathogen relationship of listeriosis. We have previously shown that Lm infection in the first trimester has a high rate of miscarriage. This study expands on our previous findings by assessing how the quantity of Lm as well as stage of pregnancy at the time of exposure may influence disease susceptibility. In the current study we inoculated a cohort of macaques with a lower dose of Lm than our previous study and although this did not result in fetal demise, there was evidence of inflammation and fetal distress. Animals that were reinfected with an equivalent or higher dose of the same strain of Lm resulted in approximately half of cases continuing to term and half ending in fetal demise. These cases had inconsistent bacterial colonization of the fetal compartment, suggesting that Lm does not need to directly infect the placenta to cause adverse pregnancy outcomes. Timed surgical collection of tissues following inoculation demonstrated that transmission from mother to fetus can occur as soon as 5 days post-inoculation. Lastly, third trimester inoculation resulted in pregnancy loss in 3 out of 4 macaques, accompanied by characteristic pathology and Lm colonization. Collectively, our studies demonstrate that common laboratory culture tests may not always recover Lm despite known maternal ingestion. Notably, we also find it is possible for maternal infection to resolve in some cases with no discernible adverse outcome; however, such cases had evidence of a sterile intrauterine inflammatory response, with unknown consequences for fetal development.
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http://dx.doi.org/10.3389/fmicb.2019.02021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749046PMC
September 2019

Impact of ferumoxytol magnetic resonance imaging on the rhesus macaque maternal-fetal interface†.

Biol Reprod 2020 02;102(2):434-444

Wisconsin National Primate Research Center (WNPRC), Madison, Wisconsin, USA.

Ferumoxytol is a superparamagnetic iron oxide nanoparticle used off-label as an intravascular magnetic resonance imaging (MRI) contrast agent. Additionally, ferumoxytol-uptake by macrophages facilitates detection of inflammatory sites by MRI through ferumoxytol-induced image contrast changes. Therefore, ferumoxytol-enhanced MRI holds great potential for assessing vascular function and inflammatory response, critical to determine placental health in pregnancy. This study sought to assess the fetoplacental unit and selected maternal tissues, pregnancy outcomes, and fetal well-being after ferumoxytol administration. In initial developmental studies, seven pregnant rhesus macaques were imaged with or without ferumoxytol administration. Pregnancies went to term with vaginal delivery and infants showed normal growth rates compared to control animals born the same year that did not undergo MRI. To determine the impact of ferumoxytol on the maternal-fetal interface (MFI), fetal well-being, and pregnancy outcome, four pregnant rhesus macaques at ~100 gestational day underwent MRI before and after ferumoxytol administration. Collection of the fetoplacental unit and selected maternal tissues was performed 2-3 days following ferumoxytol administration. A control group that did not receive ferumoxytol or MRI was used for comparison. Iron levels in fetal and MFI tissues did not differ between groups, and there was no significant difference in tissue histopathology with or without exposure to ferumoxytol, and no effect on placental hormone secretion. Together, these results suggest that the use of ferumoxytol and MRI in pregnant rhesus macaques does not negatively impact the MFI and can be a valuable experimental tool in research with this important animal model.
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http://dx.doi.org/10.1093/biolre/ioz181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016288PMC
February 2020

Risk of Zika microcephaly correlates with features of maternal antibodies.

J Exp Med 2019 10 14;216(10):2302-2315. Epub 2019 Aug 14.

Hospital Santo Amaro, Salvador, Bahia, Brazil.

Zika virus (ZIKV) infection during pregnancy causes congenital abnormalities, including microcephaly. However, rates vary widely, and the contributing risk factors remain unclear. We examined the serum antibody response to ZIKV and other flaviviruses in Brazilian women giving birth during the 2015-2016 outbreak. Infected pregnancies with intermediate or higher ZIKV antibody enhancement titers were at increased risk to give birth to microcephalic infants compared with those with lower titers (P < 0.0001). Similarly, analysis of ZIKV-infected pregnant macaques revealed that fetal brain damage was more frequent in mothers with higher enhancement titers. Thus, features of the maternal antibodies are associated with and may contribute to the genesis of ZIKV-associated microcephaly.
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http://dx.doi.org/10.1084/jem.20191061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781003PMC
October 2019

Neurophysiological Characterization of a Non-Human Primate Model of Traumatic Spinal Cord Injury Utilizing Fine-Wire EMG Electrodes.

Sensors (Basel) 2019 Jul 27;19(15). Epub 2019 Jul 27.

The Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, WI 53715, USA.

This study aims to characterize traumatic spinal cord injury (TSCI) neurophysiologically using an intramuscular fine-wire electromyography (EMG) electrode pair. EMG data were collected from an agonist-antagonist pair of tail muscles of Macaca fasicularis, pre- and post-lesion, and for a treatment and control group. The EMG signals were decomposed into multi-resolution subsets using wavelet transforms (WT), then the relative power (RP) was calculated for each individual reconstructed EMG sub-band. Linear mixed models were developed to test three hypotheses: (i) asymmetrical volitional activity of left and right side tail muscles (ii) the effect of the experimental TSCI on the frequency content of the EMG signal, (iii) and the effect of an experimental treatment. The results from the electrode pair data suggested that there is asymmetry in the EMG response of the left and right side muscles (-value < 0.001). This is consistent with the construct of limb dominance. The results also suggest that the lesion resulted in clear changes in the EMG frequency distribution in the post-lesion period with a significant increment in the low-frequency sub-bands (D4, D6, and A6) of the left and right side, also a significant reduction in the high-frequency sub-bands (D1 and D2) of the right side (-value < 0.001). The preliminary results suggest that using the of the EMG data, the fine-wire intramuscular EMG electrode pair are a suitable method of monitoring and measuring treatment effects of experimental treatments for spinal cord injury (SCI).
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http://dx.doi.org/10.3390/s19153303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6695770PMC
July 2019

Mild hypothermia ameliorates anesthesia toxicity in the neonatal macaque brain.

Neurobiol Dis 2019 10 5;130:104489. Epub 2019 Jun 5.

Department of Psychiatry, School of Medicine, Washington University, St Louis, WA, USA.

Sedatives and anesthetics can injure the developing brain. They cause apoptosis of neurons and oligodendrocytes, impair synaptic plasticity, inhibit neurogenesis and trigger long-term neurocognitive deficits. The projected vulnerable period in humans extends from the third trimester of pregnancy to the third year of life. Despite all concerns, there is no ethically and medically acceptable alternative to the use of sedatives and anesthetics for surgeries and painful interventions. Development of measures that prevent injury while allowing the medications to exert their desired actions has enormous translational value. Here we investigated protective potential of hypothermia against histological toxicity of the anesthetic sevoflurane in the developing nonhuman primate brain. Neonatal rhesus monkeys underwent sevoflurane anesthesia over 5 h. Body temperature was regulated in the normothermic (>36.5 °C), mild hypothermic (35-36.5 °C) and moderately hypothermic (<35 °C) range. Animals were euthanized at 8 h and brains examined immunohistochemically (activated caspase 3) and stereologically to quantify apoptotic neuronal and oligodendroglial death. Sevoflurane anesthesia was well tolerated at all temperatures, with oxygen saturations, end tidal CO and blood gases remaining at optimal levels. Compared to controls, sevoflurane exposed brains displayed significant apoptosis in gray and white matter affecting neurons and oligodendrocytes. Mild hypothermia (35-36.5 °C) conferred significant protection from apoptotic brain injury, whereas moderate hypothermia (<35 °C) did not. Hypothermia ameliorates anesthesia-induced apoptosis in the neonatal primate brain within a narrow temperature window (35-36.5 °C). Protection is lost at temperatures below 35 °C. Given the mild degree of cooling needed to achieve significant brain protection, application of our findings to humans should be explored further.
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http://dx.doi.org/10.1016/j.nbd.2019.104489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689440PMC
October 2019

Colonic inflammation affects myenteric alpha-synuclein in nonhuman primates.

J Inflamm Res 2019 7;12:113-126. Epub 2019 May 7.

Preclinical Parkinson's Research Program, Wisconsin National Primate Research Center, University of Wisconsin - Madison, Madison, WI, USA.

Parkinson's disease (PD) patients frequently present gastrointestinal (GI) dysfunction that, in many cases, predates the onset of motor symptoms. In PD, the presynaptic protein alpha-synuclein (α-syn) undergoes pathological changes, including phosphorylation and aggregation leading to the formation of Lewy bodies, which can be found in neurons of the enteric nervous system (ENS). Inflammation has been proposed as a possible trigger of α-syn pathology. Interestingly, patients with inflammatory bowel disease and irritable bowel syndrome, conditions associated with GI inflammation, are at higher risk of developing PD. Captive common marmosets develop colitis, providing a natural platform to assess the relationship between α-syn pathology and GI inflammation. Sections of proximal colon from marmosets with colitis (n=5; 5.3±2.3 years old; 4 male) and normal controls (n=5; 4.1±1.6 years old; 1 male) were immunostained against protein gene product 9.5 (PGP9.5), human leukocyte antigen DR (HLA-DR), cluster of differentiation 3 (CD3), cluster of differentiation 20 (CD20), glial fibrillary acidic protein (GFAP), 8-hydroxy-2'-deoxyguanosine (8-OHdG), α-syn, and serine 129 phosphorylated α-syn (p-α-syn). Immunoreactivity of each staining in the myenteric plexus was quantified using NIH ImageJ software. Marmosets with colitis had significantly increased expression of inflammatory markers (HLA-DR, <0.02; CD3, <0.008), oxidative stress (8-OHdG, <0.05), and p-α-syn (<0.02) and decreased expression of α-syn (<0.04) in the colonic myenteric ganglia compared to normal, healthy controls. Colonic inflammation is associated with changes in α-syn expression and phosphorylation in the myenteric plexus of common marmosets. Future evaluation of the vagus nerve and brain of animals with colitis will be key to assess the contribution of colitis-induced ENS α-syn pathology to PD-like pathology in the brain.
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http://dx.doi.org/10.2147/JIR.S196552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511240PMC
May 2019

Zika viruses of African and Asian lineages cause fetal harm in a mouse model of vertical transmission.

PLoS Negl Trop Dis 2019 04 17;13(4):e0007343. Epub 2019 Apr 17.

Department of Veterinary and Biomedical Sciences, University of Minnesota, Twin Cities; St. Paul, MN, United States of America.

Congenital Zika virus (ZIKV) infection was first linked to birth defects during the American outbreak in 2015/2016. It has been proposed that mutations unique to the Asian/American-genotype explain, at least in part, the ability of Asian/American ZIKV to cause congenital Zika syndrome (CZS). Recent studies identified mutations in ZIKV infecting humans that arose coincident with the outbreak in French Polynesia and were stably maintained during subsequent spread to the Americas. Here we show that African ZIKV can infect and harm fetuses and that the S139N substitution that has been associated with the American outbreak is not essential for fetal harm. Our findings, in a vertical transmission mouse model, suggest that ZIKV will remain a threat to pregnant women for the foreseeable future, including in Africa, Southeast Asia, and the Americas. Additional research is needed to better understand the risks associated with ZIKV infection during pregnancy, both in areas where the virus is newly endemic and where it has been circulating for decades.
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http://dx.doi.org/10.1371/journal.pntd.0007343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488094PMC
April 2019

Quantitative ultrasound and apoptotic death in the neonatal primate brain.

Neurobiol Dis 2019 07 2;127:554-562. Epub 2019 Apr 2.

Department of Neurology, University of Wisconsin, School of Medicine, Madison, WI, USA. Electronic address:

Apoptosis is triggered in the developing mammalian brain by sedative, anesthetic or antiepileptic drugs during late gestation and early life. Whether human children are vulnerable to this toxicity mechanism remains unknown, as there are no imaging techniques to capture it. Apoptosis is characterized by distinct structural features, which affect the way damaged tissue scatters ultrasound compared to healthy tissue. We evaluated whether apoptosis, triggered by the anesthetic sevoflurane in the brains of neonatal rhesus macaques, can be detected using quantitative ultrasound (QUS). Neonatal (n = 15) rhesus macaques underwent 5 h of sevoflurane anesthesia. QUS images were obtained through the sagittal suture at 0.5 and 6 h. Brains were collected at 8 h and examined immunohistochemically to analyze apoptotic neuronal and oligodendroglial death. Significant apoptosis was detected in white and gray matter throughout the brain, including the thalamus. We measured a change in the effective scatterer size (ESS), a QUS biomarker derived from ultrasound echo signals obtained with clinical scanners, after sevoflurane-anesthesia in the thalamus. Although initial inclusion of all measurements did not reveal a significant correlation, when outliers were excluded, the change in the ESS between the pre- and post-anesthesia measurements correlated strongly and proportionally with the severity of apoptotic death. We report for the first time in vivo changes in QUS parameters, which may reflect severity of apoptosis in the brains of infant nonhuman primates. These findings suggest that QUS may enable in vivo studies of apoptosis in the brains of human infants following exposure to anesthetics, antiepileptics and other brain injury mechanisms.
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http://dx.doi.org/10.1016/j.nbd.2019.03.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6588418PMC
July 2019

Neutrophil progenitor populations of rhesus macaques.

J Leukoc Biol 2019 01 5;105(1):113-121. Epub 2018 Nov 5.

Immunology Services Unit, Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA.

Captive-bred rhesus macaques of Indian origin represent one of the most important large animal models for infectious disease, solid organ transplantation, and stem cell research. There is a dearth of information defining hematopoietic development, including neutrophil leukocyte differentiation in this species using multicolor flow cytometry. In the current study, we sought to identify cell surface markers that delineate neutrophil progenitor populations with characteristic immunophenotypes. We defined four different postmitotic populations based on their CD11b and CD87 expression pattern, and further refined their immunophenotypes using CD32, CD64, lactoferrin, and myeloperoxidase as antigenic markers. The four subsets contained myelocyte, metamyelocyte, band, and segmented neutrophil populations. We compared our flow cytometry-based classification with the classical nuclear morphology-based classification. We found overlap of immunological phenotype between populations of different nuclear morphology and identified phenotypically different subsets within populations of similar nuclear morphology. We assessed the responsiveness of these populations to stimulatory signals, such as LPS, fMLP, or PMA, and demonstrated significant differences between human and rhesus macaque neutrophil progenitors. In this study, we provided evidence for species-specific features of granulopoiesis that ultimately manifested in the divergent immunophenotypes of the fully differentiated segmented neutrophils of humans and rhesus macaques. Additionally, we found functional markers that can be used to accurately quantify neutrophil progenitors by flow cytometry. Although these markers do not coincide with the classical nuclear-morphology-based grading, they enable us to perform functional studies monitoring immunophenotypic markers.
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http://dx.doi.org/10.1002/JLB.1TA1117-431RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398341PMC
January 2019

Miscarriage and stillbirth following maternal Zika virus infection in nonhuman primates.

Nat Med 2018 08 2;24(8):1104-1107. Epub 2018 Jul 2.

Department of Pediatrics, University of Washington, Seattle, WA, USA.

Zika virus (ZIKV) infection is associated with congenital defects and pregnancy loss. Here, we found that 26% of nonhuman primates infected with Asian/American ZIKV in early gestation experienced fetal demise later in pregnancy despite showing few clinical signs of infection. Pregnancy loss due to asymptomatic ZIKV infection may therefore be a common but under-recognized adverse outcome related to maternal ZIKV infection.
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http://dx.doi.org/10.1038/s41591-018-0088-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082723PMC
August 2018

Molecularly barcoded Zika virus libraries to probe in vivo evolutionary dynamics.

PLoS Pathog 2018 03 28;14(3):e1006964. Epub 2018 Mar 28.

Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.

Defining the complex dynamics of Zika virus (ZIKV) infection in pregnancy and during transmission between vertebrate hosts and mosquito vectors is critical for a thorough understanding of viral transmission, pathogenesis, immune evasion, and potential reservoir establishment. Within-host viral diversity in ZIKV infection is low, which makes it difficult to evaluate infection dynamics. To overcome this biological hurdle, we constructed a molecularly barcoded ZIKV. This virus stock consists of a "synthetic swarm" whose members are genetically identical except for a run of eight consecutive degenerate codons, which creates approximately 64,000 theoretical nucleotide combinations that all encode the same amino acids. Deep sequencing this region of the ZIKV genome enables counting of individual barcodes to quantify the number and relative proportions of viral lineages present within a host. Here we used these molecularly barcoded ZIKV variants to study the dynamics of ZIKV infection in pregnant and non-pregnant macaques as well as during mosquito infection/transmission. The barcoded virus had no discernible fitness defects in vivo, and the proportions of individual barcoded virus templates remained stable throughout the duration of acute plasma viremia. ZIKV RNA also was detected in maternal plasma from a pregnant animal infected with barcoded virus for 67 days. The complexity of the virus population declined precipitously 8 days following infection of the dam, consistent with the timing of typical resolution of ZIKV in non-pregnant macaques and remained low for the subsequent duration of viremia. Our approach showed that synthetic swarm viruses can be used to probe the composition of ZIKV populations over time in vivo to understand vertical transmission, persistent reservoirs, bottlenecks, and evolutionary dynamics.
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http://dx.doi.org/10.1371/journal.ppat.1006964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891079PMC
March 2018

Model of Traumatic Spinal Cord Injury for Evaluating Pharmacologic Treatments in Cynomolgus Macaques ().

Comp Med 2018 02;68(1):63-73

Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, Division of Physical Medicine and Rehabilitation, Department of Medicine, McMaster University, Canada, Department of Physical Medicine and Rehabilitation, Hamilton Health Sciences, St Joseph's Hamilton Healthcare, Hamilton, Ontario, Canada;, Email:

Here we present the results of experiments involving cynomolgus macaques, in which a model of traumatic spinal cord injury (TSCI) was created by using a balloon catheter inserted into the epidural space. Prior to the creation of the lesion, we inserted an EMG recording device to facilitate measurement of tail movement and muscle activity before and after TSCI. This model is unique in that the impairment is limited to the tail: the subjects do not experience limb weakness, bladder impairment, or bowel dysfunction. In addition, 4 of the 6 subjects received a combination treatment comprising thyrotropin releasing hormone, selenium, and vitamin E after induction of experimental TSCI. The subjects tolerated the implantation of the recording device and did not experience adverse effects due the medications administered. The EMG data were transformed into a metric of volitional tail moment, which appeared to be valid measure of initial impairment and subsequent natural or treatment-related recovery. The histopathologic assessment demonstrated widespread axon loss at the site of injury and areas cephalad and caudad. Histopathology revealed evidence of continuing inflammation, with macrophage activation. The EMG data did not demonstrate evidence of a statistically significant treatment effect.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824141PMC
February 2018

Ocular and uteroplacental pathology in a macaque pregnancy with congenital Zika virus infection.

PLoS One 2018 30;13(1):e0190617. Epub 2018 Jan 30.

Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.

Congenital Zika virus (ZIKV) infection impacts fetal development and pregnancy outcomes. We infected a pregnant rhesus macaque with a Puerto Rican ZIKV isolate in the first trimester. The pregnancy was complicated by preterm premature rupture of membranes (PPROM), intraamniotic bacterial infection and fetal demise 49 days post infection (gestational day 95). Significant pathology at the maternal-fetal interface included acute chorioamnionitis, placental infarcts, and leukocytoclastic vasculitis of the myometrial radial arteries. ZIKV RNA was disseminated throughout fetal tissues and maternal immune system tissues at necropsy, as assessed by quantitative RT-PCR for viral RNA. Replicating ZIKV was identified in fetal tissues, maternal uterus, and maternal spleen by fluorescent in situ hybridization for viral replication intermediates. Fetal ocular pathology included a choroidal coloboma, suspected anterior segment dysgenesis, and a dysplastic retina. This is the first report of ocular pathology and prolonged viral replication in both maternal and fetal tissues following congenital ZIKV infection in a rhesus macaque. PPROM followed by fetal demise and severe pathology of the visual system have not been described in macaque congenital ZIKV infection previously. While this case of ZIKV infection during pregnancy was complicated by bacterial infection with PPROM, the role of ZIKV on this outcome cannot be precisely defined, and further nonhuman primate studies will determine if increased risk for PPROM or other adverse pregnancy outcomes are associated with congenital ZIKV infection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0190617PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5790226PMC
February 2018

Pegivirus avoids immune recognition but does not attenuate acute-phase disease in a macaque model of HIV infection.

PLoS Pathog 2017 Oct 26;13(10):e1006692. Epub 2017 Oct 26.

Wisconsin National Primate Research Center, Madison, Wisconsin, United States of America.

Human pegivirus (HPgV) protects HIV+ people from HIV-associated disease, but the mechanism of this protective effect remains poorly understood. We sequentially infected cynomolgus macaques with simian pegivirus (SPgV) and simian immunodeficiency virus (SIV) to model HIV+HPgV co-infection. SPgV had no effect on acute-phase SIV pathogenesis-as measured by SIV viral load, CD4+ T cell destruction, immune activation, or adaptive immune responses-suggesting that HPgV's protective effect is exerted primarily during the chronic phase of HIV infection. We also examined the immune response to SPgV in unprecedented detail, and found that this virus elicits virtually no activation of the immune system despite persistently high titers in the blood over long periods of time. Overall, this study expands our understanding of the pegiviruses-an understudied group of viruses with a high prevalence in the global human population-and suggests that the protective effect observed in HIV+HPgV co-infected people occurs primarily during the chronic phase of HIV infection.
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http://dx.doi.org/10.1371/journal.ppat.1006692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5675458PMC
October 2017

Highly efficient maternal-fetal Zika virus transmission in pregnant rhesus macaques.

PLoS Pathog 2017 May 25;13(5):e1006378. Epub 2017 May 25.

Department of Pediatrics and Human Vaccine Institute, Duke University Medical Center, Durham, North Carolina, United States of America.

Infection with Zika virus (ZIKV) is associated with human congenital fetal anomalies. To model fetal outcomes in nonhuman primates, we administered Asian-lineage ZIKV subcutaneously to four pregnant rhesus macaques. While non-pregnant animals in a previous study contemporary with the current report clear viremia within 10-12 days, maternal viremia was prolonged in 3 of 4 pregnancies. Fetal head growth velocity in the last month of gestation determined by ultrasound assessment of head circumference was decreased in comparison with biparietal diameter and femur length within each fetus, both within normal range. ZIKV RNA was detected in tissues from all four fetuses at term cesarean section. In all pregnancies, neutrophilic infiltration was present at the maternal-fetal interface (decidua, placenta, fetal membranes), in various fetal tissues, and in fetal retina, choroid, and optic nerve (first trimester infection only). Consistent vertical transmission in this primate model may provide a platform to assess risk factors and test therapeutic interventions for interruption of fetal infection. The results may also suggest that maternal-fetal ZIKV transmission in human pregnancy may be more frequent than currently appreciated.
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http://dx.doi.org/10.1371/journal.ppat.1006378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444831PMC
May 2017

Acute Fetal Demise with First Trimester Maternal Infection Resulting from in a Nonhuman Primate Model.

mBio 2017 02 21;8(1). Epub 2017 Feb 21.

Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, Wisconsin, USA

Infection with during pregnancy is associated with miscarriage, preterm birth, and neonatal complications, including sepsis and meningitis. While the risk of these conditions is thought to be greatest during the third trimester of pregnancy, the determinants of fetoplacental susceptibility to infection, the contribution of gestational age, and the progression of disease at the maternal-fetal interface are poorly understood. We developed a nonhuman primate model of listeriosis to better understand antecedents of adverse pregnancy outcomes in early pregnancy. Four pregnant cynomolgus macaques () received a single intragastric inoculation between days 36 and 46 of gestation with 10 CFU of an strain isolated from a previous cluster of human listeriosis cases that resulted in adverse pregnancy outcomes. Fecal shedding, maternal bacteremia, and fetal demise were consistently noted within 7 to 13 days. Biopsy specimens of maternal liver, spleen, and lymph node displayed variable inflammation and relatively low bacterial burden. In comparison, we observed greater bacterial burden in the decidua and placenta and the highest burden in fetal tissues. Histopathology indicated vasculitis, fibrinoid necrosis, and thrombosis of the decidual spiral arteries, acute chorioamnionitis and villitis in the placenta, and hematogenous infection of the fetus. Vascular pathology suggests early impact of infection on spiral arteries in the decidua, which we hypothesize precipitates subsequent placentitis and fetal demise. These results demonstrate that tropism for the maternal reproductive tract results in infection of the decidua, placenta, and the fetus itself during the first trimester of pregnancy. Although listeriosis is known to cause significant fetal morbidity and mortality, it is typically recognized in the third trimester of human pregnancy. Its impact on early pregnancy is poorly defined. Here we provide evidence that exposure to in the first trimester poses a greater risk of fetal loss than currently appreciated. Similarities in human and nonhuman primate placentation, physiology, and reproductive immunology make this work highly relevant to human pregnancy. We highlight the concept that the maternal immune response that protects the mother from serious disease is unable to protect the fetus, a concept relevant to classic TORCH (oxoplasmosis, ther, ubella, ytomegalovirus, and erpes) infections and newly illuminated by current Zika virus outbreaks. Studies with this model, using the well-understood organism , will permit precise analysis of host-pathogen interactions at the maternal-fetal interface and have broad significance to both recognized and emerging infections in the setting of pregnancy.
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http://dx.doi.org/10.1128/mBio.01938-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5358912PMC
February 2017