Last data update: Apr 29, 2024. (Total: 46658 publications since 2009)
Records 1-11 (of 11 Records) |
Query Trace: McDonald EM [original query] |
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Prolonged shedding of Zika virus in human semen is associated with male reproductive tract inflammation.
Vogt MB , McDonald EM , Delorey M , Mead PS , Hook SA , Hinckley AF , Werre SR , Brault AC , Duggal NK . J Infect Dis 2022 226 (7) 1140-1150 Zika virus (ZIKV) is a mosquito-borne flavivirus that causes congenital defects. Sexual transmission of ZIKV was confirmed in a recent epidemic; however, mechanisms behind ZIKV infection and persistence in the male reproductive tract are unknown. Previously, we found that ∼33% of men with symptomatic ZIKV infections shed ZIKV RNA in semen, and some men shed ZIKV RNA for >3 months. Here, we evaluated the semen of 49 ZIKV-infected men to identify immune factors correlating with long-term ZIKV shedding in semen and ZIKV-infected cell types in semen. We found prolonged ZIKV RNA shedding in semen was associated with male reproductive tract inflammation, indicated by higher leukocyte counts and inflammatory cytokine concentrations in semen of long-term versus short-term shedders. Additionally, we found ZIKV RNA in seminal leukocytes and epithelial cells. This study of human semen from ZIKV-infected men provides critical insights into impacts of ZIKV on male reproductive tract health. |
Zika virus replication in myeloid cells during acute infection is vital to viral dissemination and pathogenesis in a mouse model
McDonald EM , Anderson J , Wilusz J , Ebel GD , Brault AC . J Virol 2020 94 (21) Zika virus (ZIKV) can establish infection in immune privileged sites such as the testes, eye and placenta. Whether ZIKV infection of white blood cells is required for dissemination of the virus to immune privileged sites has not been definitively shown. To assess whether initial ZIKV replication in myeloid cell populations is critical for dissemination during acute infection, recombinant ZIKVs were generated that could not replicate in these specific cells. ZIKV was cell-restricted by insertion of a complementary sequence to a myeloid-specific microRNA in the 3'untranslated region. Following inoculation of a highly sensitive immunodeficient mouse model, crucial immune parameters, such as quantification of leukocyte cell subsets, cytokine and chemokine secretion, and viremia were assessed. Decreased neutrophil numbers in the spleen were observed during acute infection with myeloid-restricted ZIKV that precluded the generation of viremia and viral dissemination to peripheral organs. Mice inoculated with a non-target microRNA control ZIKV demonstrated increased expression of key cytokines and chemokines critical for neutrophil and monocyte recruitment and increased neutrophil influx in the spleen. In addition, ZIKV-infected Ly6C(hi) monocytes were identified in vivo in the spleen. Mice inoculated with myeloid-restricted ZIKV exhibited similar trends as PBS-sham inoculated mice, including a lack of inflammatory cytokine production and a decrease in Ly6C(hi) ZIKV RNA positive monocytes.ImportanceMyeloid cells, including monocytes, play a crucial role in immune responses to pathogens. Monocytes have also been implicated as "Trojan horses" during viral infections, carrying infectious virus particles to immune privileged sites and/or to sites protected by physical blood-tissue barriers, such as the blood-testis barrier and the blood-brain barrier. In this study, we found that myeloid cells are crucial to Zika virus (ZIKV) pathogenesis. By engineering ZIKV clones to encode myeloid-specific microRNA target sequences, viral replication was inhibited in myeloid cells by harnessing the RNAi pathway. Severely immunodeficient mice inoculated with myeloid-restricted ZIKV did not demonstrate clinical signs of disease and survived infection. Furthermore, viral dissemination to peripheral organs was not observed in these mice. Lastly, we identified Ly6C(mid/hi) murine monocytes as the major myeloid cell population that disseminates ZIKV. |
Duration of seminal Zika viral RNA shedding in immunocompetent mice inoculated with Asian and African genotype viruses.
McDonald EM , Duggal NK , Delorey MJ , Oksanish J , Ritter JM , Brault AC . Virology 2019 535 1-10 Prior to the emergence of Asian genotype Zika virus (ZIKV) in the Western hemisphere, sexual transmission in humans was documented. Sexual transmission by African genotype ZIKVs has not been assessed in laboratory animal models, due to rapid and high mortality rates of immunodeficient mice following inoculation. To overcome these limitations, immunocompetent C57Bl/6 mice were used to longitudinally assess Asian and African genotype ZIKV sexual transmission potential. Furthermore, to determine if enhanced pathogenesis of African genotype ZIKVs is due to structural determinants, PRVABC59 prM/E was replaced with African MR766 prM/E (chimeric ZIKV). The African genotype and chimeric ZIKV elicited greater pathogenic effects in the male reproductive tract and generated higher viremias. Yet, the duration, magnitude and efficiency of seminal shedding of infectious virus and viral RNA were similar between chimeric-, African and Asian genotype ZIKV-inoculated mice. These data show that increased male reproductive tract pathology does not increase sexual transmission potential. |
Mutations present in a low-passage Zika virus isolate result in attenuated pathogenesis in mice
Duggal NK , McDonald EM , Weger-Lucarelli J , Hawks SA , Ritter JM , Romo H , Ebel GD , Brault AC . Virology 2019 530 19-26 Zika virus (ZIKV) infection can result in neurological disorders including Congenital Zika Syndrome in infants exposed to the virus in utero. Pregnant women can be infected by mosquito bite as well as by sexual transmission from infected men. Herein, the variants of ZIKV within the male reproductive tract and ejaculates were assessed in inoculated mice. We identified two non-synonymous variants at positions E-V330L and NS1-W98G. These variants were also present in the passage three PRVABC59 isolate and infectious clone relative to the patient serum PRVABC59 sequence. In subsequent studies, ZIKV E-330L was less pathogenic in mice than ZIKV E-330V as evident by increased average survival times. In Vero cells, ZIKV E-330L/NS1-98G outcompeted ZIKV E-330V/NS1-98W within 3 passages. These results suggest that the E-330L/NS1-98G variants are attenuating in mice and were enriched during cell culture passaging. Cell culture propagation of ZIKV could significantly affect animal model development and vaccine efficacy studies. |
Infection of epididymal epithelial cells and leukocytes drives seminal shedding of Zika virus in a mouse model
McDonald EM , Duggal NK , Ritter JM , Brault AC . PLoS Negl Trop Dis 2018 12 (8) e0006691 While primarily a mosquito-borne virus, Zika virus (ZIKV; genus Flavivirus in the Flaviviridae family) is capable of being sexually transmitted. Thirty to fifty percent of men with confirmed ZIKV infection shed ZIKV RNA in their semen, and prolonged viral RNA shedding in semen can occur for more than 6 months. The cellular reservoir of ZIKV in semen is unknown, although spermatozoa have been shown to contain ZIKV RNA and antigen. Yet, spermatozoa are not a requisite for sexual transmission, as at least one case of ZIKV sexual transmission involved a vasectomized man. To determine the cellular reservoirs of ZIKV in semen, an established animal model of sexual transmission was used. The majority of virus detected in the seminal fluid of infected mice during the peak timing of sexual transmission was from the supernatant fraction, suggesting cell-free ZIKV may be largely responsible for sexual transmission. However, some ZIKV RNA was cell-associated. In the testes and epididymides of infected mice, intracellular staining of ZIKV RNA was more pronounced in spermatogenic precursors (spermatocytes and spermatogonia) than in spermatids. Visualization of intracellular negative strand ZIKV RNA demonstrated ZIKV replication intermediates in leukocytes, immature spermatids and epididymal epithelial cells in the male urogenital tract. Epididymal epithelial cells were the principal source of negative-strand ZIKV RNA during the peak timing of sexual transmission potential, indicating these cells may be the predominant source of infectious cell-free ZIKV in seminal fluid. These data promote a more complete understanding of sexual transmission of ZIKV and will inform further model development for future studies on persistent ZIKV RNA shedding. |
Zika Virus Shedding in Semen of Symptomatic Infected Men.
Mead PS , Duggal NK , Hook SA , Delorey M , Fischer M , Olzenak McGuire D , Becksted H , Max RJ , Anishchenko M , Schwartz AM , Tzeng WP , Nelson CA , McDonald EM , Brooks JT , Brault AC , Hinckley AF . N Engl J Med 2018 378 (15) 1377-1385 BACKGROUND: Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that has been linked to adverse birth outcomes. Previous reports have shown that person-to-person transmission can occur by means of sexual contact. METHODS: We conducted a prospective study involving men with symptomatic ZIKV infection to determine the frequency and duration of ZIKV shedding in semen and urine and to identify risk factors for prolonged shedding in these fluids. Specimens were obtained twice per month for 6 months after illness onset and were tested by real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay for ZIKV RNA and by Vero cell culture and plaque assay for infectious ZIKV. RESULTS: A total of 1327 semen samples from 184 men and 1038 urine samples from 183 men were obtained 14 to 304 days after illness onset. ZIKV RNA was detected in the urine of 7 men (4%) and in the semen of 60 (33%), including in semen samples from 22 of 36 men (61%) who were tested within 30 days after illness onset. ZIKV RNA shedding in semen decreased substantially during the 3 months after illness onset but continued for 281 days in 1 man (1%). Factors that were independently associated with prolonged RNA shedding included older age, less frequent ejaculation, and the presence of certain symptoms at the time of initial illness. Infectious ZIKV was isolated from 3 of 78 semen samples with detectable ZIKV RNA, all obtained within 30 days after illness onset and all with at least 7.0 log10 ZIKV RNA copies per milliliter of semen. CONCLUSIONS: ZIKV RNA was commonly present in the semen of men with symptomatic ZIKV infection and persisted in some men for more than 6 months. In contrast, shedding of infectious ZIKV appeared to be much less common and was limited to the first few weeks after illness onset. (Funded by the Centers for Disease Control and Prevention.). |
Sexual transmission of Zika virus enhances in utero transmission in a mouse model
Duggal NK , McDonald EM , Ritter JM , Brault AC . Sci Rep 2018 8 (1) 4510 Zika virus (ZIKV) is an emerging mosquito-borne virus that can cause ZIKV congenital syndrome when a pregnant woman is infected. Sexual transmission has also been described for ZIKV, though the relationship between sexual transmission and vertical transmission has not been investigated. Here, viral dissemination to the female reproductive tract and fetuses was assessed in immunodeficient (AG129) female mice that were exposed to ZIKV by subcutaneous (s.c.) inoculation, intravaginal (ivag.) inoculation, or sexual transmission from infected male AG129 mice. Pregnant females had significantly increased ZIKV dissemination to the female reproductive tract compared to non-pregnant females when exposed by s.c. or ivag. inoculation. Sexual transmission resulted in significantly greater morbidity and mortality in females and higher ZIKV titers in the female reproductive tract than s.c. or ivag. inoculation. Ovaries from females infected sexually contained ZIKV RNA within the ovarian follicles. Furthermore, ZIKV titers were significantly higher in fetuses from dams exposed sexually compared to fetuses from dams exposed by s.c. or ivag. inoculation. These results demonstrate that sexual transmission enhances dissemination of ZIKV to the female reproductive tract and developing fetuses in a mouse model. |
A Zika vaccine targeting NS1 protein protects immunocompetent adult mice in a lethal challenge model
Brault AC , Domi A , McDonald EM , Talmi-Frank D , McCurley N , Basu R , Robinson HL , Hellerstein M , Duggal NK , Bowen RA , Guirakhoo F . Sci Rep 2017 7 (1) 14769 Zika virus (ZIKV) is a mosquito-borne flavivirus that has rapidly extended its geographic range around the world. Its association with abnormal fetal brain development, sexual transmission, and lack of a preventive vaccine have constituted a global health concern. Designing a safe and effective vaccine requires significant caution due to overlapping geographical distribution of ZIKV with dengue virus (DENV) and other flaviviruses, possibly resulting in more severe disease manifestations in flavivirus immune vaccinees such as Antibody-Dependent Enhancement (ADE, a phenomenon involved in pathogenesis of DENV, and a risk associated with ZIKV vaccines using the envelope proteins as immunogens). Here, we describe the development of an alternative vaccine strategy encompassing the expression of ZIKV non-structural-1 (NS1) protein from a clinically proven safe, Modified Vaccinia Ankara (MVA) vector, thus averting the potential risk of ADE associated with structural protein-based ZIKV vaccines. A single intramuscular immunization of immunocompetent mice with the MVA-ZIKV-NS1 vaccine candidate provided robust humoral and cellular responses, and afforded 100% protection against a lethal intracerebral dose of ZIKV (strain MR766). This is the first report of (i) a ZIKV vaccine based on the NS1 protein and (ii) single dose protection against ZIKV using an immunocompetent lethal mouse challenge model. |
Pathogenesis and sexual transmission of Spondweni and Zika viruses
McDonald EM , Duggal NK , Brault AC . PLoS Negl Trop Dis 2017 11 (10) e0005990 The Spondweni serogroup of viruses (Flaviviridae, Flavivirus) is comprised of Spondweni virus (SPONV) and Zika virus (ZIKV), which are mosquito-borne viruses capable of eliciting human disease. Numerous cases of ZIKV sexual transmission in humans have been documented following the emergence of the Asian genotype in the Americas. The African ZIKV genotype virus was previously implicated in the first reported case of ZIKV sexual transmission. Reports of SPONV infection in humans have been associated with non-specific febrile illness, but no association with sexual transmission has been reported. In order to assess the relative efficiency of sexual transmission of different ZIKV strains and the potential capacity of SPONV to be sexually transmitted, viral loads in the male reproductive tract and in seminal fluids were assessed in interferon alpha/beta and -gamma receptor deficient (AG129) mice. Male mice were inoculated subcutaneously with Asian genotype ZIKV strains PRVABC59 (Puerto Rico, 2015), FSS13025 (Cambodia, 2010), or P6-740 (Malaysia, 1966); African genotype ZIKV strain DakAr41524 (Senegal, 1984); or SPONV strain SAAr94 (South Africa, 1955). Infectious virus was detected in 60-72% of ejaculates collected from AG129 mice inoculated with ZIKV strains. In contrast, only 4% of ejaculates from SPONV-inoculated AG129 males were found to contain infectious virus, despite viral titers in the testes that were comparable to those of ZIKV-inoculated mice. Based on these results, future studies should be undertaken to assess the role of viral genetic determinants and host tropism that dictate the differential sexual transmission potential of ZIKV and SPONV. |
Differential neurovirulence of African and Asian genotype Zika virus isolates in outbred immunocompetent mice
Duggal NK , Ritter JM , McDonald EM , Romo H , Guirakhoo F , Davis BS , Chang GJ , Brault AC . Am J Trop Med Hyg 2017 97 (5) 1410-1417 Although first isolated almost 70 years ago, Zika virus (ZIKV; Flavivirus, Flaviviridae) has only recently been associated with significant outbreaks of disease in humans. Several severe ZIKV disease manifestations have also been recently documented, including fetal malformations, such as microcephaly, and Guillain-Barre syndrome in adults. Although principally transmitted by mosquitoes, sexual transmission of ZIKV has been documented. Recent publications of several interferon receptor knockout mouse models have demonstrated ZIKV-induced disease. Herein, outbred immunocompetent CD-1/ICR adult mice were assessed for susceptibility to disease by intracranial (i.c.) and intraperitoneal (i.p.) inoculation with the Ugandan prototype strain (MR766; African genotype), a low-passage Senegalese strain (DakAr41524; African genotype) and a recent ZIKV strain isolated from a traveler infected in Puerto Rico (PRVABC59; Asian genotype). Morbidity was not observed in mice inoculated by the i.p. route with either MR766 or PRVABC59 for doses up to 6 log10 PFU. In contrast, CD-1/ICR mice inoculated i.c. with the MR766 ZIKV strain exhibited an 80-100% mortality rate that was age independent. The DakAr41524 strain delivered by the i.c route caused 30% mortality, and the Puerto Rican ZIKV strain failed to elicit mortality but did induce a serum neutralizing immune response in 60% of mice. These data provide a potential animal model for assessing neurovirulence determinants of different ZIKV strains as well as a potential immunocompetent challenge model for assessing protective efficacy of vaccine candidates. |
Primary care opportunities to prevent unintentional home injuries: A focus on children and older adults
McDonald EM , Mack K , Shields WC , Lee RP , Gielen AC . Am J Lifestyle Med 2016 2016 (2) 96-106 Unintentional injuries are a persistent public health problem in the United States. A new health care landscape has the potential to create a clinical environment that fosters greater involvement by health care providers in injury prevention. The aim of this article is to provide evidence supporting the need for engagement by primary care providers in unintentional home injury prevention along with examples of how this could be accomplished. We know a great deal about what population groups are at risk for certain types of injuries. We also know that many injuries can be prevented through policies, programs, and resources that ensure safe environments and promote safe behaviors. For example, the Centers for Disease Control and Prevention's STEADI (Stopping Elderly Accidents, Deaths, and Injuries) initiative comprises clinical decision support tools and educational materials for health care providers. Two effective interventions that have demonstrated a reduction in falls among children are the redesign of baby walkers (engineering) and the mandated use of window guards (enforcement). Primary care clinicians can play a key role in promoting their patient's safety. Taken collectively, a focused attention on preventing unintentional home injuries by primary care providers can contribute to the reduction of injuries and result in optimal health for all. |
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- Page last updated:Apr 29, 2024
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