3,763 research outputs found
sj-docx-1-whe-10.1177_17455057231190955 – Supplemental material for Severe acute respiratory syndrome coronavirus 2 seroprevalence and longitudinal antibody response following natural infection in pregnancy: A prospective cohort study
No full textSupplemental material, sj-docx-1-whe-10.1177_17455057231190955 for Severe acute respiratory syndrome coronavirus 2 seroprevalence and longitudinal antibody response following natural infection in pregnancy: A prospective cohort study by Alison L Drake, Jaclyn N Escudero, Morgan C Aurelio, Erica A Wetzler, Sascha R Ellington, Lauren B Zapata, Romeo R Galang, Margaret C Snead, Krissy Yamamoto, Carol C Salerno, Barbra A Richardson, Alexander L Greninger, Alisa B Kachikis, Janet A Englund and Sylvia M LaCourse in Women's Health</p
Human parainfluenza virus 3 field strains undergo extracellular fusion protein cleavage to activate entry
No full textABSTRACT Human parainfluenza virus 3 (HPIV3) infection is driven by the coordinated action of viral surface glycoproteins hemagglutinin-neuraminidase (HN) and fusion protein (F). Receptor-engaged HN activates F to insert into the target cell membrane and drive virion-cell membrane fusion. For F to mediate entry, its precursor (F0) must first be cleaved by host proteases. F0 cleavage has been thought to be executed during viral glycoprotein transit through the trans-Golgi network by the ubiquitously expressed furin because F0 proteins of laboratory-adapted viruses contain a furin recognition dibasic cleavage motif RXKR around residue 108. Here, we show that the F proteins of field strains have a different cleavage motif from laboratory-adapted strains and are cleaved by unidentified proteases expressed in only a narrow subset of cell types. We demonstrate that extracellular serine protease inhibitors block HPIV3 F0 cleavage for field strains, suggesting F0 cleavage occurs at the cell surface facilitated by transmembrane proteases. Candidate proteases that may process HPIV3 F in vivo were identified by a genome-wide CRISPRa screen in HEK293/dCas9-VP64 + MPH cells. The lung-expressed extracellular serine proteases TMPRSS2 and TMPRSS13 are both sufficient to cleave HPIV3 F and enable infectious virus release by otherwise non-permissive cells. Our findings support an alternative mechanism of F activation in vivo, reliant on extracellular membrane-bound serine proteases expressed in a narrow subset of cells. The proportion of HPIV3 F proteins cleaved and infectious virus release is determined by host cell expression of requisite proteases, allowing just-in-time activation of F and positioning F cleavage as another key regulator of HPIV3 spread.IMPORTANCEEnveloped viruses cause a wide range of diseases in humans. At the first step of infection, these viruses must fuse their envelope with a cell membrane to initiate infection. This fusion is mediated by viral proteins that require a critical activating cleavage event. It was previously thought that for parainfluenza virus 3, an important cause of respiratory disease and a representative of a group of important pathogens, this cleavage event was mediated by furin in the cell secretory pathways prior to formation of the virions. We show that this is only true for laboratory strain viruses, and that clinical viruses that infect humans utilize extracellular proteases that are only made by a small subset of cells. These results highlight the importance of studying authentic clinical viruses that infect human tissues for understanding natural infection
A checklist of New Jersey periodicals in the Special Collections Department, Rutgers University
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RAVA plots covering <i>in vitro</i> virus fitness tests.
No full textData can be found at https://github.com/greninger-lab/Lieber_IAV_4FIU_Supplemental_Data_1-4/tree/main/S2_Data/fitness_rava_plots. (ZIP)</p
RAVA plots covering virus populations isolated from infected mice.
No full textData can be found at https://github.com/greninger-lab/Lieber_IAV_4FIU_Supplemental_Data_1-4/tree/main/S3_Data/mouse_rava_plots. (ZIP)</p
Modeling Infection and Tropism of Human Parainfluenza Virus Type 3 in Ferrets
No full textHuman parainfluenza virus type 3 (HPIV-3) is a significant cause of lower respiratory tract infections, with the most severe disease in young infants, immunocompromised individuals, and the elderly. HPIV-3 infections are currently untreatable with licensed therapeutics, and prophylactic and therapeutic options are needed for patients at risk. To complement existing human airway models of HPIV-3 infection and develop an animal model to assess novel intervention strategies, we evaluated infection and transmission of HPIV-3 in ferrets. A well-characterized human clinical isolate (CI) of HPIV-3 engineered to express enhanced green fluorescent protein (rHPIV-3 CI-1-EGFP) was passaged on primary human airway epithelial cells (HAE) or airway organoids (AO) to avoid tissue culture adaptations. rHPIV3 CI-1-EGFP infection was assessed in vitro in ferret AO and in ferrets in vivo. Undifferentiated and differentiated ferret AO cultures supported rHPIV-3 CI-1-EGFP replication, but the ferret primary airway cells from AO were less susceptible and permissive than HAE. In vivo rHPIV-3 CI-1-EGFP replicated in the upper and lower airways of ferrets and targeted respiratory epithelial cells, olfactory epithelial cells, type I pneumocytes, and type II pneumocytes. The infection efficiently induced specific antibody responses. Taken together, ferrets are naturally susceptible to HPIV-3 infection; however, limited replication was observed that led to neither overt clinical signs nor ferret-to-ferret transmission. However, in combination with ferret AO, the ferret model of HPIV-3 infection, tissue tropism, and neutralizing antibodies complements human ex vivo lung models and can be used as a platform for prevention and treatment studies for this important respiratory pathogen. IMPORTANCE HPIV-3 is an important cause of pediatric disease and significantly impacts the elderly. Increasing numbers of immunocompromised patients suffer from HPIV-3 infections, often related to problems with viral clearance. There is a need to model HPIV-3 infections in vitro and in vivo to evaluate novel prophylaxis and treatment options. Currently existing animal models lack the potential for studying animal-to-animal transmission or the effect of immunosuppressive therapy. Here, we describe the use of the ferret model in combination with authentic clinical viruses to further complement human ex vivo models, providing a platform to study approaches to prevent and treat HPIV-3 infection. Although we did not detect ferret-to-ferret transmission in our studies, these studies lay the groundwork for further refinement of the ferret model to immunocompromised ferrets, allowing for studies of severe HPIV-3-associated disease. Such models for preclinical evaluation of prophylaxis and antivirals can contribute to reducing the global health burden of HPIV-3
Métricas de autor Alexander Sellamén-Garzón
No full textInforme de las métricas de autor del Dr. Alexander Sellamén-Garzón de las publicaciones indexadas en Google Académico cuyo objetivo es entregar un insumo para el fortalecimiento de las capacidades y potencialidades de los autores de la Universidad Santo Tomás en el posicionamiento y visibilidad de sus publicacionesReport of the author metrics Alexander Sellamén-Garzón of the publications indexed in Google Scholar whose objective is to provide an input for the strengthening of the capacities and potentialities of the authors of the Santo Tomás University in the positioning and visibility of their publicationshttp://unidadinvestigacion.usta.edu.c
RAVA plots covering virus populations isolated from infected ferrets.
No full textData can be found at https://github.com/greninger-lab/Lieber_IAV_4FIU_Supplemental_Data_1-4/tree/main/S4_Data/ferret_rava_plots. (ZIP)</p
RAVA plots covering virus adaptations.
No full textData can be found at https://github.com/greninger-lab/Lieber_IAV_4FIU_Supplemental_Data_1-4/tree/main/S1_Data/adaptation_rava_plots. (ZIP)</p
How a paramyxovirus fusion/entry complex adapts to escape a neutralizing antibody
No full textParamyxoviruses including measles, Nipah, and parainfluenza viruses are public health threats with pandemic potential. Human parainfluenza virus type 3 (HPIV3) is a leading cause of illness in pediatric, older, and immunocompromised populations. There are no approved vaccines or therapeutics for HPIV3. Neutralizing monoclonal antibodies (mAbs) that target viral fusion are a potential strategy for mitigating paramyxovirus infection, however their utility may be curtailed by viral evolution that leads to resistance. Paramyxoviruses enter cells by fusing with the cell membrane in a process mediated by a complex consisting of a receptor binding protein (HN) and a fusion protein (F). Existing atomic resolution structures fail to reveal physiologically relevant interactions during viral entry. We present cryo-ET structures of pre-fusion HN-F complexes in situ on surfaces of virions that evolved resistance to an anti-HPIV3 F neutralizing mAb. Single mutations in F abolish mAb binding and neutralization. In these complexes, the HN protein that normally restrains F triggering has shifted to uncap the F apex. These complexes are more readily triggered to fuse. These structures shed light on the adaptability of the pre-fusion HN-F complex and mechanisms of paramyxoviral resistance to mAbs, and help define potential barriers to resistance for the design of mAbs
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