Biology subjects

Fagre, A. C.

Publications and source records attributed to Fagre, A. C..

8 recordsLinked to original sources

bioRxiv2025

Comparative susceptibility of Old World and New World bat cell lines to Zika virus: Insights into viral replication and inflammatory responses

BackgroundFrom the first isolation of Zika virus (ZIKV) in Uganda in 1947, ZIKV had primarily been associated with sporadic human cases in Africa and Asia until ZIKV emerged as an epidemic in the Americas in 2015. As ZIKV spread into new geographic regions, it now has the potential to interact with many novel potential host species whose susceptibility to the virus has yet to be determined. Bats, with their ability to fly and live in or near human structures, are plausible ZIKV reservoirs. However, their competence as hosts for ZIKV remains unresolved. In this study, we investigate the immune response of Old World and New World bats to ZIKV infection in vitro. ResultsWe demonstrate that Egyptian Rousette bat (Rousettus aegyptiacus; Old World) cells are susceptible to ZIKV, while we observed little to no ZIKV replication in Jamaican fruit bat (Artibeus jamaicensis) cells. Notably, both the Asian and African ZIKV lineages elicited a strong proinflammatory response in the R. aegyptiacus cell line including upregulation of IL6, CXCL8, and CCL5. These data contrast with the dampened inflammatory response detected in these bats to other viruses. ConclusionsThe findings reveal that R06E cells derived from Egyptian Rousette bats exhibit robust proinflammatory and antiviral responses upon Zika virus (ZIKV) infection, characterized by significant upregulation of proinflammatory cytokines. This suggests that while these cells support productive ZIKV replication, they also mount a strong immune response, challenging the notion of these bats as immune-tolerant reservoirs and indicating a more complex interaction with the virus.

microbiology↗

bioRxiv2023

Regulatory T Cell-like Response to SARS-CoV-2 in Jamaican Fruit Bats Transduced with Human ACE2

Insectivorous Old World horseshoe bats (Rhinolophus spp.) are the likely source of the ancestral SARS-CoV-2 prior to its spillover into humans and causing the COVID-19 pandemic. Natural coronavirus infections of bats appear to be principally confined to the intestines, suggesting fecal-oral transmission; however, little is known about the biology of SARS-related coronaviruses in bats. Previous experimental challenges of Egyptian fruit bats (Rousettus aegyptiacus) resulted in limited infection restricted to the respiratory tract, whereas insectivorous North American big brown bats (Eptesicus fuscus) showed no evidence of infection. In the present study, we challenged Jamaican fruit bats (Artibeus jamaicensis) with SARS-CoV-2 to determine their susceptibility. Infection was confined to the intestine for only a few days with prominent viral nucleocapsid antigen in epithelial cells, and mononuclear cells of the lamina propria and Peyers patches, but with no evidence of infection of other tissues; none of the bats showed visible signs of disease or seroconverted. Expression levels of ACE2 were low in the lungs, which may account for the lack of pulmonary infection. Bats were then intranasally inoculated with a replication-defective adenovirus encoding human ACE2 and 5 days later challenged with SARS-CoV-2. Viral antigen was prominent in lungs for up to 14 days, with loss of pulmonary cellularity during this time; however, the bats did not exhibit weight loss or visible signs of disease. From day 7, bats had low to moderate IgG antibody titers to spike protein by ELISA, and one bat on day 10 had low-titer neutralizing antibodies. CD4+ helper T cells became activated upon ex vivo recall stimulation with SARS-CoV-2 nucleocapsid peptide library and exhibited elevated mRNA expression of the regulatory T cell cytokines interleukin-10 and transforming growth factor-{beta}, which may have limited inflammatory pathology. Collectively, these data show that Jamaican fruit bats are poorly susceptibility to SARS-CoV-2 but that expression of human ACE2 in their lungs leads to robust infection and an adaptive immune response with low-titer antibodies and a regulatory T cell-like response that may explain the lack of prominent inflammation in the lungs. This model will allow for insight of how SARS-CoV-2 infects bats and how bat innate and adaptive immune responses engage the virus without overt clinical disease. Author SummaryBats are reservoir hosts of many viruses that infect humans, yet little is known about how they host these viruses, principally because of a lack of relevant and susceptible bat experimental infection models. Although SARS-CoV-2 originated in bats, no robust infection models of bats have been established. We determined that Jamaican fruit bats are poorly susceptible to SARS-CoV-2; however, their lungs can be transduced with human ACE2, which renders them susceptible to SARS-CoV-2. Despite robust infection of the lungs and diminishment of pulmonary cellularity, the bats showed no overt signs of disease and cleared the infection after two weeks. Despite clearance of infection, only low-titer antibody responses occurred and only a single bat made neutralizing antibody. Assessment of the CD4+ helper T cell response showed that activated cells expressed the regulatory T cell cytokines IL-10 and TGF{beta} that may have tempered pulmonary inflammation.

microbiology↗

bioRxiv2022

SARS-CoV-2 infects multiple species of North American deer mice and causes clinical disease in the California mouse

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the virus that causes coronavirus disease-19 (COVID-19), emerged in late 2019 in Wuhan, China and its rapid global spread has resulted in millions of deaths. An important public health consideration is the potential for SARS-CoV-2 to establish endemicity in a secondary animal reservoir outside of Asia or acquire adaptations that result in new variants with the ability to evade the immune response and reinfect the human population. Previous work has shown that North American deer mice (Peromyscus maniculatus) are susceptible and can transmit SARS-CoV-2 to naive conspecifics, indicating its potential to serve as a wildlife reservoir for SARS-CoV-2 in North America. In this study, we report experimental SARS-CoV-2 susceptibility of two additional subspecies of the North American deer mouse and two additional deer mouse species, with infectious virus and viral RNA present in oral swabs and lung tissue of infected deer mice and neutralizing antibodies present at 15 days post-challenge. Moreover, some of one species, the California mouse (P. californicus) developed clinical disease, including one that required humane euthanasia. California mice often develop spontaneous liver disease, which may serve as a comorbidity for SARS-CoV-2 severity. The results of this study suggest broad susceptibility of rodents in the genus Peromyscus and further emphasize the potential of SARS-CoV-2 to infect a wide array of North American rodents. ImportanceA significant concern is the spillback of SARS-CoV-2 into North American wildlife species. We have determined that several species of peromyscine rodents, the most abundant mammals in North America, are susceptible to SARS-CoV-2 and that infection is likely long enough that the virus may be able to establish persistence in local rodent populations. Strikingly, some California mice developed clinical disease that suggests this species may be useful for the study of human co-morbidities often associated with severe and fatal COVID-19 disease.

microbiology↗

bioRxiv2022

Viral diversity and zoonotic risk in endangered species

A growing body of evidence links zoonotic disease risk, including pandemic threats, to biodiversity loss and other upstream anthropogenic impacts on ecosystem health. However, there is little current research assessing viral diversity in endangered species. Here, combining IUCN Red List data on 5,876 mammal species with data on host-virus associations for a subset of 1,273 extant species, we examine the relationship between endangered species status and viral diversity, including the subset of viruses that can infect humans (zoonotic viruses). We show that fewer total viruses and fewer zoonotic viruses are known to infect more threatened species. After correcting for sampling effort, zoonotic virus diversity is mostly independent of threat status, but endangered species--despite a higher apparent research effort--have a significantly lower diversity of viruses, a property that is not explained by collinearity with host phylogeography or life history variation. Although this pattern could be generated by real biological processes, we suspect instead that endangered species may be subject to additional sampling biases not captured by the total volume of scientific literature (e.g., lower rates of invasive sampling may decrease viral discovery). Overall, our findings suggest that endangered species are no more or less likely to host viruses that pose a threat to humans, but future zoonotic threats might remain undiscovered in these species. This may be concerning, given that drivers of endangered species vulnerability such as habitat disturbance, wildlife trade, or climate vulnerability may increase virus prevalence in reservoirs and risk of spillover into humans.

ecology↗

bioRxiv2022

Sampling strategies and pre-pandemic surveillance gaps for bat coronaviruses

The emergence of SARS-CoV-2, and the challenge of pinpointing its ecological and evolutionary context, has highlighted the importance of evidence-based strategies for monitoring viral dynamics in bat reservoir hosts. Here, we compiled the results of 93,877 samples collected from bats across 111 studies between 1996 and 2018, and used these to develop an unprecedented open database, with over 2,400 estimates of coronavirus infection prevalence or seroprevalence at the finest methodological, spatiotemporal, and phylogenetic level of detail possible from public records. These data revealed a high degree of heterogeneity in viral prevalence, reflecting both real spatiotemporal variation in viral dynamics and the effect of variation in sampling design. Phylogenetically controlled meta-analysis revealed that the most significant determinant of successful viral detection was repeat sampling (i.e., returning to the same site multiple times); however, fewer than one in five studies longitudinally collected and reported data. Viral detection was also more successful in some seasons and from certain tissues, but was not improved by the use of euthanasia, indicating that viral detection may not be improved by terminal sampling. Finally, we found that prior to the pandemic, sampling effort was highly concentrated in ways that reflected concerns about zoonotic risk, leaving several broad geographic regions (e.g., South Asia, Latin America and the Caribbean, and most of Sub-Saharan Africa) and bat subfamilies (e.g., Stenodermatinae and Pteropodinae) measurably undersampled. These gaps constitute a notable vulnerability for global health security and will likely be a future barrier to contextualizing the origin of novel zoonotic coronaviruses.

ecology↗

bioRxiv2022

Exploring the mosquito-arbovirus network: a survey of vector competence experiments

Arboviruses receive heightened research attention during major outbreaks, or when they cause unusual or severe clinical disease, but are otherwise under-characterized. Global change is also accelerating the emergence and spread of arboviral diseases, leading to time sensitive questions about potential interactions between viruses and novel vectors. Vector competence experiments help determine the susceptibility of certain arthropods to a given arbovirus, but these experiments are often conducted in real-time during outbreaks, rather than with preparedness in mind. We conducted a systematic review of reported mosquito-arbovirus competence experiments, screening 570 abstracts to arrive at 265 studies testing in vivo arboviral competence. We found that over 90% of potential mosquito-virus combinations are untested in experimental settings, and that entire regions and their corresponding vectors and viruses are undersampled. These knowledge gaps stymie outbreak response, and limit attempts to both build and validate predictive models of the vector-virus network.

ecology↗

bioRxiv2021

The Global Virome in One Network (VIRION): an atlas of vertebrate-virus associations

Data cataloguing viral diversity on Earth have been fragmented across sources, disciplines, formats, and various degrees of open collation, posing challenges for research on macroecology, evolution, and public health. Here, we solve this problem by establishing a dynamically-maintained database of vertebrate-virus associations, called The Global Virome in One Network (VIRION). The VIRION database has been assembled through both reconciliation of static datasets and integration of dynamically-updated databases. These data sources are all harmonized against one taxonomic backbone, including metadata on host and virus taxonomic validity and higher classification; additional metadata on sampling methodology and evidence strength are also available in a harmonized format. In total, the VIRION database is the largest open-source, open-access database of its kind, with roughly half a million unique records that include 9,521 resolved virus "species" (of which 1,661 are ICTV ratified), 3,692 resolved vertebrate host species, and 23,147 unique interactions between taxonomically-valid organisms. Together, these data cover roughly a quarter of mammal diversity, a tenth of bird diversity, and ~6% of the estimated total diversity of vertebrates, and a much larger proportion of their virome than any previous database. We show how these data can be used to test hypotheses about microbiology, ecology, and evolution, and make suggestions for best practices that address the unique mix of evidence that coexists in these data.

microbiology↗

bioRxiv2021

A novel glucocorticoid and androgen receptor modulator reduces viral entry and innate immune inflammatory responses in the Syrian Hamster model of SARS-CoV-2

Since its initial discovery in late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of COVID19, has spread worldwide and despite significant research efforts, treatment options remain limited. Replication of SARS-CoV-2 in lung is associated with marked infiltration of macrophages and activation of innate immune inflammatory responses triggered, in part, by heightened production of interleukin-6 (IL-6) that recruits lymphocytes to the site of infection that amplify tissue injury. Antagonists of the glucocorticoid and androgen receptors have shown promise in experimental models of COVID19 and in clinical studies, because cell surface proteins required for viral entry, angiotensin converting enzyme 2 (ACE2) and the transmembrane serine protease 2 (TMPRSS2), are transcriptionally regulated by these receptors. We therefore postulated that the glucocorticoid (GR) and androgen receptor (AR) antagonist, PT150, would reduce infectivity of SARS-CoV-2 and prevent inflammatory lung injury in the Syrian golden hamster model of COVID19. Animals were infected intranasally with 2.5 x 104 TCID50/ml equivalents of SARS-CoV-2 (strain 2019-nCoV/USA-WA1/ 2020) and PT150 was administered by oral gavage at 30 and 100 mg/Kg/day for a total of 7 days. Animals were then examined at days 3, 5 and 7 post-infection (DPI) for lung histopathology, viral load and production of proteins regulating the initiation and progression of SARS-CoV-2 infection. Results of these studies indicated that oral administration of PT150 decreased replication of SARS-CoV-2 in lung, as well as expression of ACE2 and TMPRSS2 protein. Hypercellularity and inflammatory cell infiltration driven by macrophage responses were dramatically decreased in PT150-treated animals, as was tissue damage and expression of IL-6. Molecular modeling suggested that PT150 binds to the co-activator interface of the ligand binding domain of both AR and GR and thereby acts as an allosteric modulator and transcriptional repressor of these receptors. Phylogenetic analysis of AR and GR across multiple species permissive to SARS-CoV-2 infection revealed a high degree of sequence identity maintained across species, including human, suggesting that the mechanism of action and therapeutic efficacy observed in Syrian hamsters would likely be predictive of positive outcomes in patients. PT150 is therefore a strong candidate for further clinical development for the treatment of COVID19 across variants of SARS-CoV-2.

immunology↗