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Port, J. R.

Publications and source records attributed to Port, J. R..

13 recordsLinked to original sources
bioRxiv2026

Jamaican fruit bats are susceptible to henipaviruses but rapidly control infection

Henipaviruses (HNV), Hendra (HeV) and Nipah (NiV) virus, cause severe pulmonary and neurologic disease in humans and other mammals. Bats in the genus Pteropus naturally host HeV and NiV, but their feasibility in experimental studies is limited due to their large size, low fertility rate, and unavailability outside of their native range. Understanding bat-henipavirus interactions that regulate shedding and replication could improve mitigation of spillover events and illuminate the factors that differentiate severe and controlled HNV infection. Here, we assessed the suitability of the Jamaican fruit bat (JFB) (Artibeus jamaicensis) to model HNV infection in vitro and in vivo. JFB primary kidney cells were permissive to HNVs, and HeV and NiV antagonized the induction of the innate antiviral response. JFBs were inoculated via the intranasal and oral routes (IN/PO) with HeV or NiV or intravenously (IV) with HeV and monitored for 7 days. Following IN/PO exposure, infection was quenched rapidly and limited HeV RNA was detected in oral swabs and tissues while NiV RNA was found in only one oral swab. HeV IV inoculation resulted in robust, disseminated infection and viral RNA was detected in oral, rectal, and environmental swabs. Overall, these results support that JFBs are susceptible to both viruses, but replication is quenched rapidly in vivo following IN/PO exposure. Future studies will optimize the in vivo model to leverage the JFB to further our understanding of bat-henipavirus interactions. Author SummaryHenipaviruses (HNV) spillover from pteropid bat species and cause severe diseases in humans. Many gaps limit our understanding of HNV-bat interactions that influence spillover and effective control of infection. Here, we evaluate the Jamaican fruit bat (JFB) as a henipavirus model. We demonstrate that JFB cells are permissive all HNVs evaluated, and that JFBs support Hendra virus replication and shedding without signs of clinical disease.

microbiology↗
bioRxiv2023

A bivalent Adenovirus-Vectored Vaccine induces a measurable humoral response, but does not protect cynomolgus macaques against a lethal challenge with Sudan virus

The most recent Sudan virus (SUDV) outbreak in Uganda was first detected in September 2022 and resulted in 164 laboratory-confirmed cases and 77 deaths. Currently, there are no approved vaccines or therapeutics against SUDV. In the current study, we investigated the protective efficacy of ChAdOx1-biEBOV in cynomolgus macaques using a prime or a prime-boost regimen. ChAdOx1-biEBOV is a replication-deficient simian adenovirus vector encoding SUDV and Ebola virus (EBOV) glycoproteins (GPs) at the E1 and E4 loci, respectively. Intramuscular vaccination induced SUDV and EBOV GP-specific IgG responses and neutralizing antibodies. Upon challenge with SUDV, vaccinated animals, regardless of vaccination scheme, showed signs of disease like those observed in control animals, and no difference in survival outcomes were measured among all three groups. Viral load in blood samples and in tissue samples obtained after necropsy were not significantly different between groups. Overall, this study highlights the importance of evaluating vaccines in multiple animal models, including nonhuman primates, and demonstrates the importance of understanding protective efficacy in both animal models and human hosts.

microbiology↗
bioRxiv2023

Stability of mpox (monkeypox) virus in bodily fluids and wastewater

ImportanceSince May 2022, human monkeypox (mpox) infections have spread rapidly outside endemic countries. On July 23, 2023, WHO declared a Public Health Emergency of international Concern because of the unprecedented global spread of mpox. Whereas there is an incomplete understanding of transmission routes, the spread of monkeypox virus (MPXV) through sexual contact networks of men who have sex with men (MSM) highlights the potential of transmission during sexual activity, either via bodily fluids or via direct contact. This research assesses the potential for MPXV to remain infectious in the environment on surfaces and in fluids under different environmental conditions. ObjectiveTo investigate the stability of MPXV on various surfaces, at different environmental conditions and in different bodily fluids (human blood, semen, serum, saliva, urine, and feces), and to assess decontamination of MPXV-contaminated wastewater via chlorination. Design, Setting, and ExposuresAll experiments involving viable MPXV were performed at the Rocky Mountains Laboratory under high containment conditions using MPXV strain hMPXV/USA/MA001. Infectious MPXV was quantified via plaque assay. Environmental decay rates were estimated using a Bayesian statistical model, with a Poisson likelihood for plaque counts. ResultsMPXV showed surface dependent stability, with faster decay at higher temperatures. Decay rates varied considerably depending on the medium in which virus was suspended, both overall MPXV displayed considerable environmental stability in bodily fluids and in particular proteinaceous fluids, such as blood and semen, lead to greater persistence. Wastewater chlorination was an effective decontamination technique. Conclusions and RelevanceMPXV retains its infectivity in the environment when it is deposited in blood, semen, and serum; environmental decay is more rapid in less proteinaceous fluids, particularly once residual liquid has evaporated. The observed persistence of MPXV implies environmental contamination in healthcare setting, could serve as vehicles of transmission and dissemination in these environments. Chlorination was effective in decontamination of wastewater. Key findings and public health implications; these results suggest that MPXV can have prolonged stability in the environment and are therefore directly relevant for hospital hygiene practices to prevent nosocomial transmission.

microbiology↗
bioRxiv2023

Rectal and vaginal challenge with mpox virus increases virus dissemination and contact transmission compared to skin challenge in the multimammate rat (Mastomys natalensis)

The 2022 mpox virus outbreak was sustained by efficient human-to-human transmission and spread predominantly through sexual networks of men who have sex with men (MSM). It is currently unclear what combination of factors resulted in the enhanced transmission. To investigate this, we established the peridomestic African rodent Mastomys natalensis as a new rodent model susceptible to infection after intraperitoneal, rectal, vaginal, and transdermal inoculation with an early 2022 human outbreak isolate (Clade IIb). Route-dependent shedding and tissue replication occurred in the presence of self-resolving localized skin, reproductive tract, or rectal lesions. Mucosal inoculation via both the rectal and vaginal route led to increased shedding compared to skin inoculation, and increased replication and a proinflammatory T-cell profile. Contact transmission was higher in rectally inoculated animals. This suggests that the spread in MSM communities may have been enhanced by increased susceptibility of the anal and genital mucosae for infection and subsequent virus release.

microbiology↗
bioRxiv2022

Host and viral determinants of airborne transmission of SARS-CoV-2 in the Syrian hamster

It remains poorly understood how SARS-CoV-2 infection influences the physiological host factors important for aerosol transmission. We assessed breathing pattern, exhaled droplets, and infectious virus after infection with Alpha and Delta variants of concern (VOC) in the Syrian hamster. Both VOCs displayed a confined window of detectable airborne virus (24-48 h), shorter than compared to oropharyngeal swabs. The loss of airborne shedding was linked to airway constriction resulting in a decrease of fine aerosols (1-10{micro}m) produced, which are suspected to be the major driver of airborne transmission. Male sex was associated with increased viral replication and virus shedding in the air. Next, we compared the transmission efficiency of both variants and found no significant differences. Transmission efficiency varied mostly among donors, 0-100% (including a superspreading event), and aerosol transmission over multiple chain links was representative of natural heterogeneity of exposure dose and downstream viral kinetics. Co-infection with VOCs only occurred when both viruses were shed by the same donor during an increased exposure timeframe (24-48 h). This highlights that assessment of host and virus factors resulting in a differential exhaled particle profile is critical for understanding airborne transmission.

microbiology↗
bioRxiv2022

Infection- or vaccine mediated immunity reduces SARS-CoV-2 transmission, but increases competitiveness of Omicron in hamsters

Omicron has demonstrated a competitive advantage over Delta in vaccinated people. To understand this, we designed a transmission chain experiment using naive, intranasally (IN) or intramuscularly (IM) vaccinated, and previously infected (PI) hamsters. Vaccination and previous infection protected animals from disease and virus replication after Delta and Omicron dual challenge. A gradient in transmission blockage was observed: IM vaccination displayed moderate transmission blockage potential over three airborne chains (approx. 70%), whereas, IN vaccination and PI blocked airborne transmission in >90%. In naive hamsters, Delta completely outcompeted Omicron within and between hosts after dual infection in onward transmission. Although Delta also outcompeted Omicron in the vaccinated and PI transmission chains, an increase in Omicron competitiveness was observed in these groups. This correlated with the increase in the strength of the humoral response against Delta, with the strongest response seen in PI animals. These data highlight the continuous need to assess the emergence and spread of novel variants in populations with pre-existing immunity and address the additional evolutionary pressure this may exert on the virus.

microbiology↗
bioRxiv2022

Severe acute respiratory disease in American mink (Neovison vison) experimentally infected with SARS-CoV-2

An animal model that fully recapitulates severe COVID-19 presentation in humans has been a top priority since the discovery of SARS-CoV-2 in 2019. Although multiple animal models are available for mild to moderate clinical disease, a non-transgenic model that develops severe acute respiratory disease has not been described. Mink experimentally infected with SARS-CoV-2 developed severe acute respiratory disease, as evident by clinical respiratory disease, radiological, and histological changes. Virus was detected in nasal, oral, rectal, and fur swabs. Deep sequencing of SARS-CoV-2 from oral swabs and lung tissue samples showed repeated enrichment for a mutation in the gene encoding for nonstructural protein 6 in open reading frame 1a/1ab. Together, these data indicate that American mink develop clinical features characteristic of severe COVID19 and as such, are uniquely suited to test viral countermeasures. One Sentence SummarySARS-CoV-2 infected mink develop severe respiratory disease that recapitulates some components of severe acute respiratory disease, including ARDS.

microbiology↗
bioRxiv2021

Age-related differences in immune dynamics during SARS-CoV-2 infection in rhesus macaques

Advanced age is a key predictor of severe COVID-19. To gain insight into this relationship, particularly with respect to immune responses, we utilized the rhesus macaque model of SARS-CoV-2 infection. Two cohorts of eight older (16-23 years) and eight younger (3-5 years) rhesus macaques were inoculated with SARS-CoV-2. Animals were evaluated using viral RNA quantification, clinical observations, thoracic radiographs, single-cell transcriptomics, multiparameter flow cytometry, multiplex immunohistochemistry, cytokine detection, and lipidomics analysis at pre-defined timepoints in various tissues. Differences in clinical signs, pulmonary infiltrates, and virus replication dynamics were limited between age cohorts. Transcriptional signatures of inflammation-associated genes in cells isolated from bronchoalveolar lavage fluid at 3 dpi revealed efficient mounting of innate immune defenses in both younger and older animals. These findings suggested that age did not substantially skew major facets of acute disease in this model. However, age-specific divergence of immune responses emerged during the post-acute phase of infection (7-21 dpi). Older animals exhibited sustained local inflammatory innate responses while local effector T-cell responses were induced earlier in the younger animals. Circulating lipid mediator and cytokine levels highlighted increased repair-associated signals in the younger animals, in contrast to persistent pro-inflammatory responses in the older animals. In summary, despite similar disease outcomes, multi-omics profiling in SARS-CoV-2-infected rhesus macaques suggests that age may delay or impair the induction of anti-viral cellular immune responses and delay efficient return to immune homeostasis following acute infection.

immunology↗
bioRxiv2021

The B.1.427/1.429 (epsilon) SARS-CoV-2 variants are more virulent than ancestral B.1 (614G) in Syrian hamsters

As novel SARS-CoV-2 variants continue to emerge, it is critical that their potential to cause severe disease and evade vaccine-induced immunity is rapidly assessed in humans and studied in animal models. In early January 2021, a novel variant of concern (VOC) designated B.1.429 comprising 2 lineages, B.1.427 and B.1.429, was originally detected in California (CA) and shown to enhance infectivity in vitro and decrease antibody neutralization by plasma from convalescent patients and vaccine recipients. Here we examine the virulence, transmissibility, and susceptibility to pre-existing immunity for B 1.427 and B 1.429 in the Syrian hamster model. We find that both strains exhibit enhanced virulence as measured by increased body weight loss compared to hamsters infected with ancestral B.1 (614G), with B.1.429 causing the most body weight loss among all 3 lineages. Faster dissemination from airways to parenchyma and more severe lung pathology at both early and late stages were also observed with B.1.429 infections relative to B.1. (614G) and B.1.427 infections. In addition, subgenomic viral RNA (sgRNA) levels were highest in oral swabs of hamsters infected with B.1.429, however sgRNA levels in lungs were similar in all three strains. This demonstrates that B.1.429 replicates to higher levels than ancestral B.1 (614G) or B.1.427 in the upper respiratory tract (URT) but not in the lungs. In multi-virus in-vivo competition experiments, we found that epsilon (B.1.427/B.1.429) and gamma (P.1) dramatically outcompete alpha (B.1.1.7), beta (B.1.351) and zeta (P.2) in the lungs. In the URT gamma, and epsilon dominate, but the highly infectious alpha variant also maintains a moderate size niche. We did not observe significant differences in airborne transmission efficiency among the B.1.427, B.1.429 and ancestral B.1 (614G) variants in hamsters. These results demonstrate enhanced virulence and high relative fitness of the epsilon (B.1.427/B.1.429) variant in Syrian hamsters compared to an ancestral B.1 (614G) strain. Author SummaryIn the last 12 months new variants of SARS-CoV-2 have arisen in the UK, South Africa, Brazil, India, and California. New SARS-CoV-2 variants will continue to emerge for the foreseeable future in the human population and the potential for these new variants to produce severe disease and evade vaccines needs to be understood. In this study, we used the hamster model to determine the epsilon (B.1.427/429) SARS-CoV-2 strains that emerged in California in late 2020 cause more severe disease and infected hamsters have higher viral loads in the upper respiratory tract compared to the prior B.1 (614G) strain. These findings are consistent with human clinical data and help explain the emergence and rapid spread of this strain in early 2021.

microbiology↗
bioRxiv2021

Western diet increases COVID-19 disease severity in the Syrian hamster

Pre-existing comorbidities such as obesity or metabolic diseases can adversely affect the clinical outcome of COVID-19. Chronic metabolic disorders are globally on the rise and often a consequence of an unhealthy diet, referred to as a Western Diet. For the first time in the Syrian hamster model, we demonstrate the detrimental impact of a continuous high-fat high-sugar diet on COVID-19 outcome. We observed increased weight loss and lung pathology, such as exudate, vasculitis, hemorrhage, fibrin, and edema, delayed viral clearance and functional lung recovery, and prolonged viral shedding. This was accompanied by an increased trend of systemic IL-10 and IL-6, as well as a dysregulated serum lipid response dominated by polyunsaturated fatty acid-containing phosphatidylethanolamine, recapitulating cytokine and lipid responses associated with severe human COVID-19. Our data support the hamster model for testing restrictive or targeted diets and immunomodulatory therapies to mediate the adverse effects of metabolic disease on COVID-19.

microbiology↗
bioRxiv2020

SARS-CoV-2 disease severity and transmission efficiency is increased for airborne but not fomite exposure in Syrian hamsters

Transmission of SARS-CoV-2 is driven by contact, fomite, and airborne transmission. The relative contribution of different transmission routes remains subject to debate. Here, we show Syrian hamsters are susceptible to SARS-CoV-2 infection through intranasal, aerosol and fomite exposure. Different routes of exposure presented with distinct disease manifestations. Intranasal and aerosol inoculation caused more severe respiratory pathology, higher virus loads and increased weight loss. Fomite exposure led to milder disease manifestation characterized by an anti-inflammatory immune state and delayed shedding pattern. Whereas the overall magnitude of respiratory virus shedding was not linked to disease severity, the onset of shedding was. Early shedding was linked to an increase in disease severity. Airborne transmission was more efficient than fomite transmission and dependent on the direction of the airflow. Carefully characterized of SARS-CoV-2 transmission models will be crucial to assess potential changes in transmission and pathogenic potential in the light of the ongoing SARS-CoV-2 evolution.

microbiology↗
bioRxiv2020

K18-hACE2 mice develop respiratory disease resembling severe COVID-19

SARS-CoV-2 emerged in late 2019 and resulted in the ongoing COVID-19 pandemic. Several animal models have been rapidly developed that recapitulate the asymptomatic to moderate disease spectrum. Now, there is a direct need for additional small animal models to study the pathogenesis of severe COVID-19 and for fast-tracked medical countermeasure development. Here, we show that transgenic mice expressing the human SARS-CoV-2 receptor (angiotensin-converting enzyme 2 [hACE2]) under a cytokeratin 18 promoter (K18) are susceptible to SARS-CoV-2 and that infection resulted in a dose-dependent lethal disease course. After inoculation with either 104 TCID50 or 105 TCID50, the SARS-CoV-2 infection resulted in rapid weight loss in both groups and uniform lethality in the 105 TCID50 group. High levels of viral RNA shedding were observed from the upper and lower respiratory tract and intermittent shedding was observed from the intestinal tract. Inoculation with SARS-CoV-2 resulted in upper and lower respiratory tract infection with high infectious virus titers in nasal turbinates, trachea and lungs. The observed interstitial pneumonia and pulmonary pathology, with SARS-CoV-2 replication evident in pneumocytes, were similar to that reported in severe cases of COVID-19. SARS-CoV-2 infection resulted in macrophage and lymphocyte infiltration in the lungs and upregulation of Th1 and proinflammatory cytokines/chemokines. Extrapulmonary replication of SARS-CoV-2 was observed in the cerebral cortex and hippocampus of several animals at 7 DPI but not at 3 DPI. The rapid inflammatory response and observed pathology bears resemblance to COVID-19. Taken together, this suggests that this mouse model can be useful for studies of pathogenesis and medical countermeasure development. Authors SummaryThe disease manifestation of COVID-19 in humans range from asymptomatic to severe. While several mild to moderate disease models have been developed, there is still a need for animal models that recapitulate the severe and fatal progression observed in a subset of patients. Here, we show that humanized transgenic mice developed dose-dependent disease when inoculated with SARS-CoV-2, the etiological agent of COVID-19. The mice developed upper and lower respiratory tract infection, with virus replication also in the brain after day 3 post inoculation. The pathological and immunological diseases manifestation observed in these mice bears resemblance to human COVID-19, suggesting increased usefulness of this model for elucidating COVID-19 pathogenesis further and testing of countermeasures, both of which are urgently needed.

microbiology↗