The Importance of Physiologically Relevant Cell Lines for Studying Virus–Host Interactions

Hare, David; Collins, Susan E.; Cuddington, Breanne; Mossman, Karen

doi:10.3390/v8110297

Cited by 30 publications

(20 citation statements)

References 82 publications

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“…The lipase 1-mediated phenotype was observed only in primary fibroblast cells, and it is possible that the lipids modified by lipase 1 are not present or are differentially regulated in immortalized cells. Indeed, immortalized cells have been reported to have numerous attenuations affecting innate intracellular immunity (42) and the lipid composition of membranes (43). This is consistent with the differences in proviral activity between lipase 1 and lipase 2, which have been shown to have different substrate preferences (5,18).…”

Section: Discussionsupporting

confidence: 61%

Staphylococcus aureus Lipase 1 Enhances Influenza A Virus Replication

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et al. 2020

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ABSTRACT Influenza A virus (IAV) causes annual epidemics of respiratory disease in humans, often complicated by secondary coinfection with bacterial pathogens such as Staphylococcus aureus. Here, we report that the S. aureus secreted protein lipase 1 enhances IAV replication in vitro in primary cells, including human lung fibroblasts. The proviral activity of lipase 1 is dependent on its enzymatic function, acts late in the viral life cycle, and results in increased infectivity through positive modulation of virus budding. Furthermore, the proviral effect of lipase 1 on IAV is exhibited during in vivo infection of embryonated hen’s eggs and, importantly, increases the yield of a vaccine strain of IAV by approximately 5-fold. Thus, we have identified the first S. aureus protein to enhance IAV replication, suggesting a potential role in coinfection. Importantly, this activity may be harnessed to address global shortages of influenza vaccines. IMPORTANCE Influenza A virus (IAV) causes annual epidemics and sporadic pandemics of respiratory disease. Secondary bacterial coinfection by organisms such as Staphylococcus aureus is the most common complication of primary IAV infection and is associated with high levels of morbidity and mortality. Here, we report the first identified S. aureus factor (lipase 1) that enhances IAV replication during infection via positive modulation of virus budding. The effect is observed in vivo in embryonated hen’s eggs and greatly enhances the yield of a vaccine strain, a finding that could be applied to address global shortages of influenza vaccines.

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Section: Discussionsupporting

confidence: 61%

Staphylococcus aureus Lipase 1 Enhances Influenza A Virus Replication

Goncheva

Conceicao

Tuffs

et al. 2020

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“…Taken together, these data confirmed the induction of a strong antiviral IFN response in multiple HIE lines at the transcriptional and protein level upon VA1 infection. Caco-2 cells, on the other hand, exhibited dysregulated IFN signaling responses, a finding common to many transformed cell lines [35]. Regardless of the strength of the antiviral IFN response, VA-1 replicated robustly in either culture system.…”

Section: Hie But Not Caco-2 Cells Mount Strong Type I and Iii Ifn Rmentioning

confidence: 96%

Astrovirus replication in human intestinal enteroids reveals multi-cellular tropism and an intricate host innate immune landscape

et al. 2019

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Human astroviruses (HAstV) are understudied positive-strand RNA viruses that cause gastroenteritis mostly in children and the elderly. Three clades of astroviruses, classic, MLBtype and VA-type have been reported in humans. One limitation towards a better understanding of these viruses has been the lack of a physiologically relevant cell culture model that supports growth of all clades of HAstV. Herein, we demonstrate infection of HAstV strains belonging to all three clades in epithelium-only human intestinal enteroids (HIE) isolated from biopsy-derived intestinal crypts. A detailed investigation of infection of VA1, a member of the non-canonical HAstV-VA/HMO clade, showed robust replication in HIE derived from different patients and from different intestinal regions independent of the cellular differentiation status. Flow cytometry and immunofluorescence analysis revealed that VA1 infects several cell types, including intestinal progenitor cells and mature enterocytes, in HIE cultures. RNA profiling of VA1-infected HIE uncovered that the host response to infection is dominated by interferon (IFN)-mediated innate immune responses. A comparison of the antiviral host response in non-transformed HIE and transformed human colon carcinoma Caco-2 cells highlighted significant differences between these cells, including an increased magnitude of the response in HIE. Additional studies confirmed the sensitivity of VA1 to exogenous IFNs, and indicated that the endogenous IFN response of HIE to curtail the growth of strains from all three clades. Genotypic variation in the permissiveness of different HIE lines to HAstV could be overcome by pharmacologic inhibition of JAK/STAT PLOS Pathogens | https://doi.and ALSAC to SSC.; NIH R21 NS101371 to DW; Wellcome Trust: Ref 207498/Z/ signaling. Collectively, our data identify HIE as a universal infection model for HAstV and an improved model of the intestinal epithelium to investigate enteric virus-host interactions. Author summaryHuman astroviruses (HAstV) are understudied positive-strand RNA viruses that typically cause gastroenteritis mostly in children and the elderly, but more recent studies also implicate them in neurological disease in immunocompromised patients. To better understand these viruses, a physiologically relevant cell culture model that supports growth of all clades of HAstV would be highly beneficial. Herein, we demonstrated robust infection of HAstV strains belonging to all three clades in epithelium-only human intestinal enteroids (HIE) isolated from biopsy-derived intestinal crypts from different patients and intestinal regions, making HIE a valuable model to study HAstV biology. Using this system, we identify for the first time that VA1 infects several cell types, including intestinal progenitor cells and mature enterocytes. Analysis of the antiviral host response to infection demonstrated that HIE respond to infection with a type I and III interferon response. This response reduced HAstV replication and when blocked resulted in increased infection. Establis...

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“…Nevertheless, immortalization and transformation of primary cells may affect cellular antiviral signaling, possibly resulting in misrepresentation of in vivo innate immune responses. In fact, a number of cellular pathways regulating IFN-stimulated genes and antiviral defense are closely linked to cellular tumor suppression activity, including anti-proliferative, pro-apoptotic, and pro-inflammatory responses (75). Accordingly, the antiviral responses observed in immortalized IEC or IPEC cells, despite being of porcine intestinal epithelial cell origin, should be further compared to those in primary IECs.…”

Section: In Vitro Models For Pedv and Pdcov Infection: Cell Lines Andmentioning

confidence: 99%

PEDV and PDCoV Pathogenesis: The Interplay Between Host Innate Immune Responses and Porcine Enteric Coronaviruses

et al. 2019

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Enteropathogenic porcine epidemic diarrhea virus (PEDV) and porcine deltacoronavirus (PDCoV), members of the coronavirus family, account for the majority of lethal watery diarrhea in neonatal pigs in the past decade. These two viruses pose significant economic and public health burdens, even as both continue to emerge and reemerge worldwide. The ability to evade, circumvent or subvert the host’s first line of defense, namely the innate immune system, is the key determinant for pathogen virulence, survival, and the establishment of successful infection. Unfortunately, we have only started to unravel the underlying viral mechanisms used to manipulate host innate immune responses. In this review, we gather current knowledge concerning the interplay between these viruses and components of host innate immunity, focusing on type I interferon induction and signaling in particular, and the mechanisms by which virus-encoded gene products antagonize and subvert host innate immune responses. Finally, we provide some perspectives on the advantages gained from a better understanding of host-pathogen interactions. This includes their implications for the future development of PEDV and PDCoV vaccines and how we can further our knowledge of the molecular mechanisms underlying virus pathogenesis, virulence, and host coevolution.

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The Importance of Physiologically Relevant Cell Lines for Studying Virus–Host Interactions

Cited by 30 publications

References 82 publications

Staphylococcus aureus Lipase 1 Enhances Influenza A Virus Replication

Staphylococcus aureus Lipase 1 Enhances Influenza A Virus Replication

Astrovirus replication in human intestinal enteroids reveals multi-cellular tropism and an intricate host innate immune landscape

PEDV and PDCoV Pathogenesis: The Interplay Between Host Innate Immune Responses and Porcine Enteric Coronaviruses

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