Autophagy-Inducing Protein Beclin-1 in Dendritic Cells Regulates CD4 T Cell Responses and Disease Severity during Respiratory Syncytial Virus Infection

Reed, Michelle; Morris, Susan H.; Jang, Sihyug; Mukherjee, Sumanta; Yue, Zhenyu; Lukacs, Nicholas W.

doi:10.4049/jimmunol.1300477

Cited by 64 publications

(75 citation statements)

References 55 publications

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“…In contrast to other situations in which autophagy supports antigen presentation by DCs (Cooney et al, 2010; Jagannath et al, 2009; Ma et al, 2012; Reed et al, 2013; Romao et al, 2013), we found a major immuno-suppressive function of Atg16L1 in this cell type. This discrepancy likely reflects the pathophysiology of GVHD, which does not necessarily rely on the proper trafficking of one particular antigen, and can be driven by either MHC class I or II molecules.…”

Section: Discussioncontrasting

confidence: 99%

Autophagy Gene Atg16l1 Prevents Lethal T Cell Alloreactivity Mediated by Dendritic Cells

et al. 2014

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SUMMARY Atg16L1 mediates the cellular degradative process of autophagy and is considered a critical regulator of inflammation based on its genetic association with inflammatory bowel disease. Here we find that Atg16L1 deficiency leads to an exacerbated graft-versus-host disease (GVHD) in a mouse model of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Atg16L1-deficient allo-HSCT recipients with GVHD displayed increased T cell proliferation due to increased dendritic cell (DC) numbers and co-stimulatory molecule expression. Reduced autophagy within DCs was associated with lysosomal abnormalities and decreased amounts of A20, a negative regulator of DC activation. These results broaden the function of Atg16L1 and the autophagy pathway to include a role in limiting a DC-mediated response during inflammatory disease, such as GVHD.

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Section: Discussioncontrasting

confidence: 99%

Autophagy Gene Atg16l1 Prevents Lethal T Cell Alloreactivity Mediated by Dendritic Cells

et al. 2014

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“…RSV strain line 19-induced airway mucin expression in mice has been shown to be modulated by immune regulators, such as CXCR2 (38), IL-12 (39), Toll-like receptor 3 (TLR3) (40), CCR1 (41), MyD88 (42), IL-25 (43), and Beclin-1 (44). In our study, compared to A2-line19F, the hypofusogenic A2-line19F-M79I/R191K had lower early viral loads, recovered to a peak viral load equivalent to that of A2-line19F, and induced slightly but significantly more airway mucin expression than A2-line19F.…”

Section: Discussionmentioning

confidence: 99%

Identification of Residues in the Human Respiratory Syncytial Virus Fusion Protein That Modulate Fusion Activity and Pathogenesis

Hotard

Lee

Currier

et al. 2015

J Virol

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Human respiratory syncytial virus (RSV) lower respiratory tract infection can result in inflammation and mucus plugging of airways. RSV strain A2-line19F induces relatively high viral load and mucus in mice. The line 19 fusion (F) protein harbors five unique residues compared to the non-mucus-inducing strains A2 and Long, at positions 79, 191, 357, 371, and 557. We hypothesized that differential fusion activity is a determinant of pathogenesis. In a cell-cell fusion assay, line 19 F was more fusogenic than Long F. We changed the residues unique to line 19 F to the corresponding residues in Long F and identified residues 79 and 191 together as responsible for high fusion activity. Surprisingly, mutation of residues 357 or 357 with 371 resulted in gain of fusion activity. Thus, we generated RSV F mutants with a range of defined fusion activity and engineered these into recombinant viruses. We found a clear, positive correlation between fusion activity and early viral load in mice; however, we did not detect a correlation between viral loads and levels of airway mucin expression. The F mutant with the highest fusion activity, A2-line19F-K357T/Y371N, induced high viral loads, severe lung histopathology, and weight loss but did not induce high levels of airway mucin expression. We defined residues 79/191 as critical for line 19 F fusion activity and 357/371 as playing a role in A2-line19F mucus induction. Defining the molecular basis of the role of RSV F in pathogenesis may aid vaccine and therapeutic strategies aimed at this protein. IMPORTANCEHuman respiratory syncytial virus (RSV) is the most important lower respiratory tract pathogen of infants for which there is no vaccine. Elucidating mechanisms of RSV pathogenesis is important for rational vaccine and drug design. We defined specific amino acids in the fusion (F) protein of RSV strain line 19 critical for fusion activity and elucidated a correlation between fusion activity and viral load in mice. Further, we identified two distinct amino acids in F as contributing to the mucogenic phenotype of the A2-line19F virus. Taken together, these results illustrate a role for RSV F in virulence.H uman respiratory syncytial virus (hRSV according to the International Committee on Taxonomy of Viruses; often abbreviated RSV) is a negative-sense, nonsegmented, and singlestranded RNA virus in the Paramyxoviridae family. RSV is the most important viral lower respiratory tract pathogen for infants, causing 16 times more hospitalizations than influenza virus in children under 1 year old (1). There is currently no vaccine licensed to prevent RSV infections; there is also a need for additional therapies, and further knowledge of RSV pathogenesis will enhance efforts toward these goals.Strains of RSV exhibit differential pathogenesis in the BALB/c mouse model of RSV disease (2-4). A strain called line 19 was originally isolated in 1967 and then passaged in primary chick kidney cells, as well as primary chick lung cells, prior to 72 passages in human MRC-5 fibroblast cells (...

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“…Autophagy (self-eating) is known as a process through which cytoplasmic macromolecules or organelles are delivered to lysosomes for degradation to maintain the energy balance in the cell. Previous studies have indicated that the induction of autophagy exerts a protective effect against tissue and cell injury (32)(33)(34). Studies have demonstrated the protective effects of autophagy against liver injury (1,6,11); however, the mechanisms through which autophagy prevents liver injury are not yet completely understood.…”

Section: Discussionmentioning

confidence: 99%

ZnPP reduces autophagy and induces apoptosis, thus aggravating liver ischemia/reperfusion injury in vitro

Wang

Xiong

Guo

et al. 2014

International Journal of Molecular Medicine

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Abstract. There is growing evidence indicating that autophagy plays a protective role in liver ischemia/reperfusion (IR) injury. Heme oxygenase-1 (HO-1) can also prevent liver IR injury by limiting inflammation and inducing an anti-apoptotic response. Autophagy also plays a crucial role in liver IR injury. The aim of the present study was to investigate the role of HO-1 in liver IR injury and the association between HO-1, autophagy and apoptotic pathways. IR simulation was performed using buffalo rat liver (BRL) cells, and HO-1 activity was either induced by hemin (HIR group) or inhibited by zinc protoporphyrin (ZnPP) (ZIR group). In the HIR and ZIR group, the expression of HO-1 and autophagy-related genes [light chain 3-Ⅱ (LC3-Ⅱ)] was assessed by RT-qPCR and the protein expression of caspases, autophagy-related genes and genes associated with apoptotic pathways (Bax) was detected by western blot anlaysis. The results of RT-PCR revealed the genetically decreased expression of HO-1 and autophagy-related genes in the ZIR group. Similar results were obtained by western blot analysis and immunofluorescence. An ultrastructural analysis revealed a lower number of autophagosomes in the ZIR group; in the HIR group, the number of autophagosomes was increased. The expression of Bax and cytosolic cytochrome c was increased, while that of Bcl-2 was decreased following treatment of the cells with ZnPP prior to IR simulation; the oppostie occurred in the HIR group. Cleaved caspase-3, caspase-9 and poly(ADPribose) polymerase (PARP) protein were activated in the IR and ZIR groups. The disruption of mitochondrial membrane potential was also observed in the ZIR group. In general, the downregulation of HO-1 reduced autophagy and activated the mitochondrial apoptotic pathway.

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Autophagy-Inducing Protein Beclin-1 in Dendritic Cells Regulates CD4 T Cell Responses and Disease Severity during Respiratory Syncytial Virus Infection

Cited by 64 publications

References 55 publications

Autophagy Gene Atg16l1 Prevents Lethal T Cell Alloreactivity Mediated by Dendritic Cells

Autophagy Gene Atg16l1 Prevents Lethal T Cell Alloreactivity Mediated by Dendritic Cells

Identification of Residues in the Human Respiratory Syncytial Virus Fusion Protein That Modulate Fusion Activity and Pathogenesis

ZnPP reduces autophagy and induces apoptosis, thus aggravating liver ischemia/reperfusion injury in vitro

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