580 research outputs found
Correction: Forrester, N.L.; Coffey, L.L.; Weaver, S.C. Arboviral Bottlenecks and Challenges to Maintaining Diversity and Fitness during Mosquito Transmission. Viruses 2014, 6, 3991–4004
No full textIn the original manuscript, Forrester, N.L.; Coffey, L.L.; Weaver, S.C. Arboviral Bottlenecks and Challenges to Maintaining Diversity and Fitness during Mosquito Transmission. Viruses 2014, 6, 3991–4004, Figure 1 contains an error, the third bottle was absent from the figure:[...
Turn, turn, turn: alternative ways of presenting songs
No full textIn this article the author describes original ways of using song lyrics in language learning classes
The SUMOylation pathway suppresses arbovirus replication in Aedes aegypti cells
No full textMosquitoes are responsible for the transmission of many clinically important arboviruses that cause significant levels of annual mortality and socioeconomic health burden worldwide. Deciphering the mechanisms by which mosquitoes modulate arbovirus infection is crucial to understand how viral-host interactions promote vector transmission and human disease. SUMOylation is a post-translational modification that leads to the covalent attachment of the Small Ubiquitin-like MOdifier (SUMO) protein to host factors, which in turn can modulate their stability, interaction networks, sub-cellular localisation, and biochemical function. While the SUMOylation pathway is known to play a key role in the regulation of host immune defences to virus infection in humans, the importance of this pathway during arbovirus infection in mosquito vectors, such as Aedes aegypti (Ae. aegypti), remains unknown. Here we characterise the sequence, structure, biochemical properties, and tissue-specific expression profiles of component proteins of the Ae. aegypti SUMOylation pathway. We demonstrate significant biochemical differences between Ae. aegypti and Homo sapiens SUMOylation pathways and identify cell-type specific patterns of SUMO expression in Ae. aegypti tissues known to support arbovirus replication. Importantly, depletion of core SUMOylation effector proteins (SUMO, Ubc9 and PIAS) in Ae. aegypti cells led to enhanced levels of arbovirus replication from three different families; Zika (Flaviviridae), Semliki Forest (Togaviridae), and Bunyamwera (Bunyaviridae) viruses. Our findings identify an important role for mosquito SUMOylation in the cellular restriction of arboviruses that may directly influence vector competence and transmission of clinically important arboviruses
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Exploring animal models of two 21st century pandemics: Zika virus and SARS-CoV-2
No full textZika virus (ZIKV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are the etiologic agents responsible for the two major pandemics of the 21st century (so far). By virtue of its capacity for mosquito-borne, sexual, and vertical transmission, as well as its association with congenital Zika syndrome (CZS), ZIKV remains a significant global public health risk. Mounting evidence identifies the male reproductive tract as a significant ZIKV reservoir; however, data regarding the duration of ZIKV persistence, potential for sexual transmission, and male genitourinary sequelae remain sparse. Furthermore, while microcephaly is a well-documented, extreme manifestation of CZS, there are cases of normocephalic newborns with confirmed prenatal ZIKV exposure but no observable congenital defects exhibiting neurologic deficits and behavioral abnormalities over time. These and other long-term developmental sequelae to prenatal ZIKV infection are not well described.I addressed these gaps in knowledge using archived tissues from 1) 51 ZIKV-inoculated male macaques from past collaborative research projects; and 2) two juvenile rhesus macaque infants exposed prenatally to ZIKV. In the male macaque cohort, I identified persistent ZIKV RNA and infectious virus in testis, epididymis, seminal vesicle, and prostate gland of sexually mature male macaques, with detection as late as 60 days post-inoculation. ZIKV RNA localized primarily to testicular stem cells/sperm precursors and epithelial cells, including Sertoli cells, epididymal duct epithelium, and glandular epithelia of the seminal vesicle and prostate gland. ZIKV infection was associated with microscopic evidence of inflammation in the epididymis and prostate gland of sexually mature males, which could have significant effects on male fertility. In the two juvenile macaques, I identified CNS microcalcifications and macrostructural developmental abnormalities within the CNS visual pathway, specifically disorganization, blending of layers, laminar discontinuities, and regions of low cell density within the lateral geniculate nucleus.COVID-19 disease, caused by SARS-CoV-2, varies from asymptomatic to severe respiratory disease, progressing to acute respiratory distress syndrome (ARDS), multiorgan dysfunction, and death in a subset of patients. Clinical evidence of coagulopathy and microscopic indicators of pulmonary vascular damage are increasingly reported; however, published autopsy data in human patients remain relatively scarce and SARS-CoV-2 induced vascular lesions have not been fully characterized. I used a previously described Syrian golden hamster model of COVID-19 disease to demonstrate that regions of active SARS-CoV-2 induced pulmonary inflammation exhibit ultrastructural evidence of endothelial injury with platelet marginalization and marked perivascular and subendothelial mononuclear inflammation composed primarily of macrophages. SARS-CoV-2 antigen/RNA was not associated with affected blood vessels. Taken together, these findings suggest that the prominent microscopic vascular lesions in SARS-CoV-2 inoculated hamsters (and by extrapolation, humans) are primarily due to indirect endothelial damage, likely secondary to immune dysfunction.These studies emphasize the importance of animal models such as nonhuman primates and hamsters to study pathogenesis of emerging viral diseases
Distribution of fitness in populations of dengue viruses.
No full textGenetically diverse RNA viruses like dengue viruses (DENVs) segregate into multiple, genetically distinct, lineages that temporally arise and disappear on a regular basis. Lineage turnover may occur through multiple processes such as, stochastic or due to variations in fitness. To determine the variation of fitness, we measured the distribution of fitness within DENV populations and correlated it with lineage extinction and replacement. The fitness of most members within a population proved lower than the aggregate fitness of populations from which they were drawn, but lineage replacement events were not associated with changes in the distribution of fitness. These data provide insights into variations in fitness of DENV populations, extending our understanding of the complexity between members of individual populations
Defective interfering viral particles in acute dengue infections.
No full textWhile much of the genetic variation in RNA viruses arises because of the error-prone nature of their RNA-dependent RNA polymerases, much larger changes may occur as a result of recombination. An extreme example of genetic change is found in defective interfering (DI) viral particles, where large sections of the genome of a parental virus have been deleted and the residual sub-genome fragment is replicated by complementation by co-infecting functional viruses. While most reports of DI particles have referred to studies in vitro, there is some evidence for the presence of DI particles in chronic viral infections in vivo. In this study, short fragments of dengue virus (DENV) RNA containing only key regulatory elements at the 3' and 5' ends of the genome were recovered from the sera of patients infected with any of the four DENV serotypes. Identical RNA fragments were detected in the supernatant from cultures of Aedes mosquito cells that were infected by the addition of sera from dengue patients, suggesting that the sub-genomic RNA might be transmitted between human and mosquito hosts in defective interfering (DI) viral particles. In vitro transcribed sub-genomic RNA corresponding to that detected in vivo could be packaged in virus like particles in the presence of wild type virus and transmitted for at least three passages in cell culture. DENV preparations enriched for these putative DI particles reduced the yield of wild type dengue virus following co-infections of C6-36 cells. This is the first report of DI particles in an acute arboviral infection in nature. The internal genomic deletions described here are the most extensive defects observed in DENV and may be part of a much broader disease attenuating process that is mediated by defective viruses
What I Wished I Knew When Starting As a Professor: An Interview with Robert Abramovitch, Lark Coffey, Thomas Kehl-Fie, and Rita Tamayo
No full textRecommended from our members
What I Wished I Knew When Starting As a Professor: An Interview with Robert Abramovitch, Lark Coffey, Thomas Kehl-Fie, and Rita Tamayo
No full textRecommended from our members
Investigating and Modeling Alphavirus Emergence in the Peruvian Amazon Basin
No full textArthropod-borne viruses (arboviruses) present a regularly re-emerging public health threat to humans worldwide, with tens of millions becoming infected and falling ill each year, mostly in the southern hemisphere. Arboviral emergence can be influence by many factors, such as viral evolution, arthropod vector spread, land-use changes, and more. Anticipating and responding to emergence should be of paramount public health importance. This dissertation is focused on two arboviruses: Venezuelan equine encephalitis virus (VEEV, Alphavirus venezuelan) and Mayaro virus (MAYV, Alphavirus mayaro), in the context of the Amazon Basin Region of Peru, specifically Iquitos, Peru and the surrounding area. Both VEEV and MAYV have a documented history in Iquitos, but updated human data have not been published since 2006. As such, the epidemiology and current risk posed to the communities in the areas is unknown. Chapter 2 of this dissertation is a serosurvey that measures the presence of antibodies in individuals capable of neutralizing either VEEV or MAYV and assesses associated risk factors from samples and questionnaire data collected across two timepoints: 2022-2023 and 2024. Longitudinal serosurveys, such as the one described in this work, help us understand present epidemiology, how it changes over time, and anticipate future risk. The odds of VEEV seropositivity were found to increase significantly for people in their 20s and over 40 years old and those who live in a rural site compared to those under 20 and living in non-rural sites. Increased odds of MAYV seropositivity were found in all age groups older than 29 years and those who live in a peri-urban site compared to those 29 or younger and living in rural or urban sites. We collected follow-up samples from 300 participants ~2 years later and found VEEV (N=20) and MAYV (N=15) exposures. Increased odds of VEEV exposures were found in those 30-49 years old. Increased odds of MAYV exposures were found in those who recently entered the forest and live in rural site. PRNT titers remained relatively stable between sampling periods for those who were seropositive at the first sampling period. We detected 7 participants within our study with cross-reactive antibodies, of which 4 were truly co-positive at the first sampling period and 2 at the second sampling period. Overall, our study fills a nearly 20-year gap in seropositivity data for MAYV and VEEV in the Peruvian Amazon Basin, provides the longest MAYV neutralizing antibody (Nab) durability assessment to date, and showcases recent circulation of both MAYV and VEEV in our rural and peri-urban study sites. After establishing that a pathogen continues to pose a threat to humans, as demonstrated in Chapter 2, work can begin on prevention and control. For viruses, this traditionally means vaccine development. However, unlike VEEV, MAYV non-human primate models have only begun development in recent years, a crucial element for vaccine development and licensure. Chapter 3 pursues the establishment of rhesus macaques as a model of MAYV disease in humans and assesses transmission potential from rhesus macaques to the urban-dwelling Aedes (Ae.) aegypti mosquito that has not been shown to be a MAYV vector in nature but poses the risk of initiating urban outbreaks. Rhesus macaques developed a range of MAYV viremias, rash, and joint inflammation similar to what has been observed in humans. Additionally, the viremia magnitude was significantly higher in the animals inoculated with a higher dose of virus intravenously compared to the animals that were inoculated with a lower dose subcutaneously (Ordinary one-way ANOVA, p<0.05); however, resulting pathology was not different between inoculation dose and route groups. Only Ae. aegypti mosquitoes that fed on macaques 2 days post inoculation became infected, with 2% of blood-fed mosquitoes having infectious virus in their saliva 10 days post feed, demonstrating the potential for Ae. aegypti to transmit MAYV. This underscores the continued, and anticipating future, public health risk posed by MAYV.The work in this dissertation provides updated sero-epidemiological data on VEEV and MAYV in the Amazon Basin Region of Peru, further evidence that rhesus macaques can act as a model of MAYV disease, and demonstrates the competence of Ae. aegypti in MAYV transmission from primates, together demonstrating the continued public health threat posed by these viruses
Impacts of environment-derived microbiota on vector competence of Aedes aegypti for Zika virus
No full textArthropod borne viral (Arboviral) disease accounts for 17% of the total infectious disease burden, afflicting over 100 million people annually. Global expansion of mosquito-borne arboviruses demands integrated approaches to vector control and public health surveillance. However, disparate outcomes in laboratory vector competence studies complicates risk assessment of mosquito species as vectors. While the contribution of mosquito and viral genetics has enjoyed much attention, the effects of mosquito microbiota on arboviral transmission potential are poorly understood. For Aedes aegypti, which is an effective vector for many arboviruses including Zika virus (ZIKV), the microbiota is primarily environmentally derived and dominantly resides in the gut. Chapter 1 reviews the current knowledge of Ae. aegypti vector competence for Zika virus as well as known effects that mosquito microbiota have on vector competence. Chapter 2 assesses the impact of microbes acquired from the larval habitat on Ae. aegypti development and ZIKV transmission. Adult female mosquitoes that emerged from microbially rich larval water derived from cemetery headstones were found to harbor more diverse microbiota and consistently lower ZIKV infection and transmission rates than their laboratory counterparts reared in laboratory tap water. However, microbial community compositions varied between experiments despite a consistent phenotype. Together, the results suggest that wild Ae. aegypti are likely less competent vectors than conventionally determined in the lab where larvae are typically reared in tap water, and that this effect is mediated by mosquito interactions with their microbiota. Chapter 3 investigates the reversibility of larval microbe-mediated refraction of ZIKV after developmental maturity. A higher dissemination rate was observed in Ae. aegypti depleted of gut microbes during pupation, and this was linked to reduced blood digestion efficiency. Results of this work suggest an immuno-metabolomic mechanism by which gut microbes confer resistance to ZIKV dissemination, by way of nonstructural midgut modifications. Overall, work presented in this dissertation emphasizes the importance of environmental microbes as a source of variation in infection susceptibility that demands consideration when conducting vector competence studies. It also highlights the complex interactions between mosquito, virus, and all the symbionts in between that play shape transmission out in nature
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