Opposite Effects of Apoptotic and Necroptotic Cellular Pathways on Rotavirus Replication

doi:10.1128/JVI.01222-21

. 2022 Jan 12;96(1):e0122221.

doi: 10.1128/JVI.01222-21. Epub 2021 Oct 20.

Opposite Effects of Apoptotic and Necroptotic Cellular Pathways on Rotavirus Replication

Mahmoud Soliman^#^{1

2}, Ja-Young Seo^#^{1

3}, Yeong-Bin Baek^#¹, Jun-Gyu Park¹, Mun-Il Kang¹, Kyoung-Oh Cho¹, Sang-Ik Park¹

Affiliations

¹ Laboratory of Veterinary Pathology, College of Veterinary Medicine, Chonnam National Universitygrid.14005.30, Gwangju, Republic of Korea.
² Department of Pathology & Clinical Pathology, Faculty of Veterinary Medicine, Assiut University, Assiut, Egypt.
³ Jeonnam Bioindustry Foundation Biopharmaceutical Research Center, Hwasun-gun, Jeollanamdo, Republic of Korea.

^# Contributed equally.

PMID: 34668777
PMCID: PMC8754216
DOI: 10.1128/JVI.01222-21

Opposite Effects of Apoptotic and Necroptotic Cellular Pathways on Rotavirus Replication

Mahmoud Soliman et al. J Virol. 2022.

. 2022 Jan 12;96(1):e0122221.

doi: 10.1128/JVI.01222-21. Epub 2021 Oct 20.

Authors

Mahmoud Soliman^#^{1

2}, Ja-Young Seo^#^{1

3}, Yeong-Bin Baek^#¹, Jun-Gyu Park¹, Mun-Il Kang¹, Kyoung-Oh Cho¹, Sang-Ik Park¹

Affiliations

¹ Laboratory of Veterinary Pathology, College of Veterinary Medicine, Chonnam National Universitygrid.14005.30, Gwangju, Republic of Korea.
² Department of Pathology & Clinical Pathology, Faculty of Veterinary Medicine, Assiut University, Assiut, Egypt.
³ Jeonnam Bioindustry Foundation Biopharmaceutical Research Center, Hwasun-gun, Jeollanamdo, Republic of Korea.

^# Contributed equally.

PMID: 34668777
PMCID: PMC8754216
DOI: 10.1128/JVI.01222-21

Abstract

Group A rotavirus (RVA), one of the leading pathogens causing severe acute gastroenteritis in children and a wide variety of young animals worldwide, induces apoptosis upon infecting cells. Though RVA-induced apoptosis mediated via the dual modulation of its NSP4 and NSP1 proteins is relatively well studied, the nature and signaling pathway(s) involved in RVA-induced necroptosis are yet to be fully elucidated. Here, we demonstrate the nature of RVA-induced necroptosis, the signaling cascade involved, and correlation with RVA-induced apoptosis. Infection with the bovine NCDV and human DS-1 RVA strains was shown to activate receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed-lineage kinase domain-like protein (MLKL), the key necroptosis molecules in virus-infected cells. Using an immunoprecipitation assay, RIPK1 was found to bind phosphorylated RIPK3 (pRIPK3) and pMLKL. pMLKL, the major executioner molecule in the necroptotic pathway, was translocated to the plasma membrane of RVA-infected cells to puncture the cell membrane. Interestingly, transfection of RVA NSP4 also induced necroptosis through the RIPK1/RIPK3/MLKL necroptosis pathway. Blockage of each key necroptosis molecule in the RVA-infected or NSP4-transfected cells resulted in decreased necroptosis but increased cell viability and apoptosis, thereby resulting in decreased viral yields in the RVA-infected cells. In contrast, suppression of RVA-induced apoptosis increased necroptosis and virus yields. Our findings suggest that RVA NSP4 also induces necroptosis via the RIPK1/RIPK3/MLKL necroptosis pathway. Moreover, necroptosis and apoptosis-which have proviral and antiviral effects, respectively-exhibited cross talk in RVA-infected cells. These findings significantly increase our understanding of the nature of RVA-induced necroptosis and the cross talk between RVA-induced necroptosis and apoptosis. IMPORTANCE Viral infection usually culminates in cell death through apoptosis, necroptosis, and, rarely, pyroptosis. Necroptosis is a form of programmed necrosis that is mediated by signaling complexes of the receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed-lineage kinase domain-like protein (MLKL). Although apoptosis induction by rotavirus and its NSP4 protein is well known, rotavirus-induced necroptosis is not fully understood. Here, we demonstrate that rotavirus and also its NSP4 protein can induce necroptosis in cultured cells through activation of the RIPK1/RIPK3/MLKL necroptosis pathway. Moreover, rotavirus-induced necroptosis and apoptosis have opposite effects on viral yield, i.e., they function as proviral and antiviral processes, respectively, and counterbalance each other in rotavirus-infected cells. Our findings provide important insights for understanding the nature of rotavirus-induced necroptosis and the development of novel therapeutic strategies against infection with rotavirus and other RNA viruses.

Keywords: NSP4; RIPK1/RIPK3/MLKL; apoptosis; necroptosis; rotavirus.

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Figures

**FIG 1**
RVA-induced activation of key necroptosis-related molecules in MA104 cells. (A and B) The viability of MA104 cells treated with trypsin or infected with trypsin-activated RVA strain NCDV (A) or DS-1 (B) (MOI = 1) at the indicated time points was evaluated using the MTT assay on an ELISA reader (optical density at 570 nm [OD₅₇₀]). The results are expressed as the mean percentages of viable cells for three independent experiments. (C and D) MA104 cells were treated with trypsin or infected with trypsin-activated RVA strain NCDV (C) or DS-1 (D) (MOI = 1) for the indicated times. The cell lysates were subjected to Western blotting to evaluate the expression of the indicated proteins. GAPDH was used as the loading control. All experiments were performed in triplicate. The relative expression of phosphorylated receptor-interacting protein kinase 1 (pRIPK1), pRIPK3, and mixed-lineage kinase domain-like protein (pMLKL) in virus-infected cells was determined via densitometric analysis and is shown in graphs below each Western blot. The data in panels A to D represent the means ± standard errors of the means from three independent experiments. Differences were evaluated using one-way ANOVA. **, *P <* 0.001; ***, *P <* 0.0001.

**FIG 2**
RVA-induced activation of key necroptosis-related molecules in Caco-2 cells. (A and B) The viability of Caco-2 cells treated with trypsin or infected with trypsin-activated RVA strain NCDV (A) or DS-1 (B) (MOI = 1) at the indicated time points was evaluated using the MTT assay on an ELISA reader (OD₅₇₀). The results are expressed as the mean percentages of viable cells for three independent experiments. (C and D) Caco-2 cells were treated with trypsin or infected with trypsin-activated RVA strain NCDV (C) or DS-1 (D) (MOI = 1) for the indicated times. The cell lysates were subjected to Western blotting to evaluate the expression of the indicated proteins. GAPDH was used as the loading control. All experiments were performed in triplicate. The relative expression of pRIPK1, pRIPK3, and pMLKL in virus-infected cells was determined via densitometric analysis and is shown in graphs below each Western blot. The data in panels A to D represent the means ± standard errors of the means from three independent experiments. Differences were evaluated using one-way ANOVA. *, *P <* 0.01; **, *P <* 0.001; ***, *P <* 0.0001.

**FIG 3**
RVA-induced necroptosis and apoptosis. MA104 cells were treated with trypsin or infected with trypsin-activated RVA strain NCDV (MOI = 1) at the indicated time points. (A to C) The cells were harvested at the indicated time points and analyzed using flow cytometry to quantify the number of apoptotic cells using TUNEL staining (A) or necroptotic cells using pMLKL antibody (B) in response to RVA infection. (C) Graphical representation of each apoptotic and necroptotic cell population in response to RVA infection. (D to F) The harvested cells at the indicated time points under the above condition were colabeled for the viral antigen (using VP6 antibody) and either TUNEL or pMLKL antibody and analyzed using flow cytometry to quantify whether RVA-positive cells were apoptotic (D) or necroptotic (E). (F) Graphical representation of RVA VP6-positive and TUNEL-positive apoptotic cells or RVA VP6-positive and pMLKL-positive necroptotic cells at the different time points. Data are shown as the percentage of apoptotic or necrotic cells in RVA-infected cells. The data in panels C and F represent the means ± standard errors of the means from three independent experiments.

**FIG 4**
Examination of RVA-induced necroptosis and apoptosis by confocal microscopy. (A and B) MA104 cells treated with trypsin for the indicated times were processed for the TUNEL assay to detect apoptotic cells (A) or for immunofluorescence (IF) to detect necroptotic cells (using an antibody against pMLKL) (B). (C and D) MA104 cells infected with trypsin-activated RVA strain NCDV (MOI = 1) for the indicated times were processed for IF and TUNEL assays to detect the RVA VP6 protein and apoptotic cells (C) and IF to detect the RVA VP6 protein and necroptotic cells (D). The nuclei were stained with DAPI, and all images shown are representative of experiments performed in triplicate. (E and F) The percentages of RVA antigen-positive apoptotic (E) and RVA antigen-positive necroptotic (F) cells were evaluated by counting the cells stained by TUNEL or pMLKL, respectively, as mentioned in Materials and Methods. The data in panels E and F represent the means ± standard errors of the means from three independent experiments. Differences were evaluated using one-way ANOVA. ***, *P <* 0.0001. Scale bars = 10 μm.

**FIG 5**
RVA-induced necrosome formation consisting of RIPK1, RIPK3, and MLKL complex. (A and B) MA104 cells were mock infected or infected with RVA strain NCDV (A) or DS-1 (B) (MOI = 1) for the indicated times. The cells were then harvested, and the cell lysates were immunoprecipitated (IP) using an antibody against pRIPK1. Coimmunoprecipitated proteins were analyzed using Western blotting (WB) to detect pRIPK3 and pMLKL using relevant antibodies. All experiments were performed in triplicate, and representative images of different gels from each group are presented.

**FIG 6**
Determination of the cytotoxicity of chemicals using MTT assay. MA104 cells grown in 96-well plates were incubated with various concentrations of the indicated chemicals in triplicate for 24 h at 37°C. Then cell viability was evaluated using the MTT assay on an ELISA reader (OD₅₇₀). The results represent the means ± standard errors of the means from three independent experiments. Differences were evaluated using one-way ANOVA. *, *P <* 0.05; **, *P <* 0.001; ***, *P <* 0.0001.

**FIG 7**
Inhibition of replication of bovine NCDV strain by blocking of necrosome formation in MA104 cells. MA104 cells were infected with bovine RVA strain NCDV (MOI = 1) for 1 h and then incubated with a maintenance medium containing 1 μg/mL trypsin and 30 μM necrostatin-1 (Nec-1; RIPK1 inhibitor), 10 μM GSK’872 (RIPK3 inhibitor), 10 μM necrosulfonamide (NSA; MLKL inhibitor), or 20 μM Z-VAD-FMK (pan-caspase inhibitor). (A to D) The cells harvested at 16 hpi were subjected to Western blotting to determine their target phosphorylated forms of pRIPK1, pRIPK3, pMLKL, and cleaved caspase-3, respectively. GAPDH was used as the loading control. (E) The harvested cells at the indicated time points were subjected to Western blotting to determine RVA VP6 protein using an antibody against the VP6 protein. GAPDH was used as the loading control. (F) Using densitometric analysis, the relative expression of the RVA VP6 protein in cells treated with each necroptosis and apoptosis inhibitor was compared with that in the mock-treated and virus-infected cells. (G) The viral titer under each of the above-described experimental conditions was determined using the median tissue culture infective dose (TCID₅₀) assay and compared with that in the mock-treated and virus-infected cells. The data in panels F and G represent the means ± standards error of the means from three independent experiments. Differences were evaluated using one-way ANOVA. *, *P <* 0.05; **, *P <* 0.001; ***, *P <* 0.0001.

**FIG 8**
Inhibition of replication of human strain DS-1 by blocking necrosome formation in MA104 cells. MA104 cells were infected with human RVA strain DS-1 (MOI = 1) for 1 h and then incubated with a maintenance medium containing 1 μg/mL trypsin and 30 μM Nec-1 (RIPK1 inhibitor), 10 μM GSK’872 (RIPK3 inhibitor), 10 μM NSA (MLKL inhibitor), or 20 μM Z-VAD-FMK (pan-caspase inhibitor). (A to D) The cells harvested at 16 hpi were subjected to Western blotting to determine their target phosphorylated forms of pRIPK1, pRIPK3, pMLKL, and cleaved caspase-3, respectively. GAPDH was used as the loading control. (E) The harvested cells at the indicated time points were subjected to Western blotting to determine RVA VP6 protein using an antibody against the VP6 protein. GAPDH was used as the loading control. (F) Using densitometric analysis, the relative expression of the RVA VP6 protein in cells treated with each necroptosis and apoptosis inhibitor was compared with that in the mock-treated and virus-infected cells. (G) The viral titer under each of the above-described experimental conditions was determined using the TCID₅₀ assay and compared with that in the mock-treated and virus-infected cells. The data in panels F and G represent the means ± standard errors of the means from three independent experiments. Differences were evaluated using one-way ANOVA. *, *P <* 0.05; **, *P <* 0.001; ***, *P <* 0.0001.

**FIG 9**
Inhibition of replication of the bovine NCDV and human DS-1 strains by blocking necrosome formation in Caco-2 cells. Caco-2 cells were infected with either bovine RVA NCDV or human RVA DS-1 (MOI = 1) for 1 h and then incubated with a maintenance medium containing 1 μg/mL trypsin and 30 μM Nec-1 (RIPK1 inhibitor), 10 μM GSK’872 (RIPK3 inhibitor), 10 μM NSA (MLKL inhibitor), or 20 μM Z-VAD-FMK (pan-caspase inhibitor). (A and D) The cells harvested at 16 hpi were subjected to Western blotting to determine RVA VP6 protein using an antibody against the VP6 protein. GAPDH was used as the loading control. (B and E) Using densitometric analysis, the relative expression of the RVA VP6 protein in cells treated with each necroptosis and apoptosis inhibitor was compared with that in the mock-treated and virus-infected cells. (C and F). The viral titer under each of the above-described experimental conditions was determined using the TCID₅₀ assay and compared with that in the mock-treated and virus-infected cells. The data in panels B, C, E, and F represent the means ± standard error of the mean from three independent experiments. Differences were evaluated using one-way ANOVA. *, *P <* 0.05; **, *P <* 0.001; ***, *P <* 0.0001.

**FIG 10**
Inhibition of replication of the RVA strains NCDV and DS-1 via the silencing necroptosis molecules. (A to C) Mock-infected MA104 cells were transfected with either scrambled siRNA or siRNAs against RIPK1 (A), RIPK3 (B), or MLKL (C) and harvested at 24 and 48 h posttransfection. Knockdown of RIPK1, RIPK3, or MLKL protein levels was evaluated via Western blot analysis. GAPDH was used as the loading control. (D to F) The transfected cells with either scrambled siRNA or siRNAs against RIPK1, RIPK3, or MLKL were infected with NCDV or DS-1 and harvested at 16 hpi. The cell lysates were subjected to Western blotting to determine their target phosphorylated forms, pRIPK1, pRIPK3, and pMLKL, respectively. GAPDH was used as the loading control. (G to L) MA104 cells were transfected with either scrambled siRNA or siRNAs against RIPK1, RIPK3, or MLKL and incubated for 48 h. Afterward, cells were infected with RVA strain NCDV (G to I) or DS-1 (J to L) at an MOI of 1 and incubated for 16 h. The cells were then processed for Western blotting to check viral protein synthesis (G and J) and relative viral VP6 protein using densitometric analysis (H and K) and for TCID₅₀ assay to count progeny virus production (I and L). The data in panels H, I, K, and L were obtained by comparing the results of RVA infection after transfection with the scrambled siRNA and the results of RVA infection after transfection with each siRNA against RIPK1, RIPK3, or MLKL and represent the means ± standard errors of the means from three independent experiments. Differences were evaluated using one-way ANOVA. *, *P <* 0.05; **, *P <* 0.001; ***, *P <* 0.0001.

**FIG 11**
Inhibition of necroptosis or apoptosis reduces RVA-induced cell death. MA104 cells were infected with RVA strain NCDV (MOI = 1) at the indicated time points and posttreated with different concentrations of Nec-1 (A), GSK’872 (B), NSA (C), and Z-VAD-FMK (D) for RIPK1, RIPK3, MLKL, and pan-caspase inhibition. Cell viability at each time point in panels A to D was compared with that in the mock-treated and virus-infected cells. All experiments were performed in triplicate, and the data represent the means ± standard errors of the means. Differences were evaluated using one-way ANOVA. *, *P <* 0.05; **, *P <* 0.001; ***, *P <* 0.0001.

**FIG 12**
Inhibition of necroptosis converted RVA-induced cell death into apoptosis and vice versa. MA104 cells were infected with RVA strain NCDV (MOI = 1) and then mock treated or treated with 30 μM RIPK1 inhibitor Nec-1 (A), 10 μM RIPK3 inhibitor GSK’872 (B), 10 μM MLKL inhibitor NSA (C), or 20 μM pan-caspase inhibitor Z-VAD-FMK (D). The cells were then harvested at the indicated time points. Double staining was performed for detecting both viral VP6 antigen and necroptosis molecule pMLKL or for detecting both viral VP6 antigen using IF and apoptotic DNA fragments using TUNEL assay and analyzed using flow cytometry to quantify dually positive cells for the RVA VP6 protein with TUNEL-positive signal or pMLKL-positive signal. The data are shown as the percentage of apoptotic or necrotic cells in RVA-infected cells at each time point and compared with those in the mock-treated and virus-infected cells. All experiments were performed in triplicate, and the data represent the means ± standard errors of the means. Differences were evaluated using one-way ANOVA. *, *P <* 0.05; **, *P <* 0.001; ***, *P <* 0.0001.

**FIG 13**
Induction of both apoptosis and necroptosis by the RVA NSP4 protein. (A) MA104 cells transfected with the control pcDNA or pcDNSP4 encoding RVA NSP4 (pcDNSP4) were harvested at the indicated time points and subjected to Western blot analysis to check the expression level of NSP4. GAPDH was used as a loading control. The expression of NSP4 relative to GAPDH was determined using densitometric analysis. MFC, mean fold change. (B) The viability of MA104 cells transfected with the control pcDNA or pcDNSP4 was evaluated using WST assay with an ELISA reader (OD₄₅₀). The results are expressed as the mean percentages of viable cells for three independent experiments. (C) The transfected cells under the above condition were stained with a hyperimmune rabbit serum against NSP4, and the transfection efficiency was analyzed by flow cytometry. (D) The cell lysates under the above-described experimental conditions were subjected to Western blotting to evaluate the expression of the indicated proteins. GAPDH was used as the loading control. The expression levels of pRIPK1, pRIPK3, and pMLKL relative to GAPDH were determined using densitometric analysis. (E) MA104 cells transfected with the control pcDNA or pcDNSP4 were processed for determining both the NSP4 protein and apoptotic DNA fragment using IF and TUNEL assays or for determining both the NSP4 protein and pMLKL using IF assays. The nuclei were stained with DAPI. Scale bars = 10 μm. (F) MA104 cells transfected with the control pcDNA or pcDNSP4 were treated with the 30 μM Nec-1 (RIPK1 inhibitor), 10 μM GSK’872 (RIPK3 inhibitor), 10 μM NSA (MLKL inhibitor), or 20 μM Z-VAD-FMK (pan-caspase inhibitor) 6 h after transfection, harvested at 36 h, and analyzed using flow cytometry to quantify the number of apoptotic (using TUNEL staining) or necroptotic (using pMLKL antibody) cells. The data are shown as the percentage of apoptotic or necroptotic cells from the total tested and compared with those in the pcDNSP4-transfected cells without any treatment. All experiments were performed in triplicate, and the data in panels B and F represent the means ± standard errors of the means. Differences were evaluated using one-way ANOVA. *, *P <* 0.05; **, *P <* 0.001; ***, *P <* 0.0001.

**FIG 14**
Schematic summary of RVA-induced cell mortality. *In vitro* RVA infection induces both proviral necroptosis and antiviral apoptosis. Inhibition of necrosome molecules, RIPK1, RIPK3, and MLKL, by treatment with chemicals (RIPK1 inhibitor Nec-1, RIPK3 inhibitor GSK’872, MLKL inhibitor NSA) or transfection with each corresponding siRNA converts RVA-induced necroptotic cells partially to apoptotic cells, resulting in suppression of viral replication. In contrast, suppression of RVA-induced apoptosis by treatment with pan-caspase inhibitor (Z-VAD-FMK) switches apoptotic cells partially to necroptotic cells, leading to an increase in viral replication.

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References

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1. Galluzzi L, Vitale I, Abrams JM, Alnemri ES, Baehrecke EH, Blagosklonny MV, Dawson TM, Dawson VL, El-Deiry WS, Fulda S, Gottlieb E, Green DR, Hengartner MO, Kepp O, Knight RA, Kumar S, Lipton SA, Lu X, Madeo F, Malorni W, Mehlen P, Nunez G, Peter ME, Piacentini M, Rubinsztein DC, Shi Y, Simon HU, Vandenabeele P, White E, Yuan J, Zhivotovsky B, Melino G, Kroemer G. 2012. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ 19:107–120. 10.1038/cdd.2011.96. - DOI - PMC - PubMed
1. Danthi P. 2016. Viruses and the diversity of cell death. Annu Rev Virol 3:533–553. 10.1146/annurev-virology-110615-042435. - DOI - PubMed
1. Lennemann NJ, Coyne CB. 2015. Catch me if you can: the link between autophagy and viruses. PLoS Pathog 11:e1004685. 10.1371/journal.ppat.1004685. - DOI - PMC - PubMed
1. Clarke P, Tyler KL. 2009. Apoptosis in animal models of virus-induced disease. Nat Rev Microbiol 7:144–155. 10.1038/nrmicro2071. - DOI - PMC - PubMed

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[1] Sridharan H, Upton JW. 2014. Programmed necrosis in microbial pathogenesis. Trends Microbiol 22:199–207. 10.1016/j.tim.2014.01.005. - DOI - PubMed

[2] Sridharan H, Upton JW. 2014. Programmed necrosis in microbial pathogenesis. Trends Microbiol 22:199–207. 10.1016/j.tim.2014.01.005. - DOI - PubMed

[3] Galluzzi L, Vitale I, Abrams JM, Alnemri ES, Baehrecke EH, Blagosklonny MV, Dawson TM, Dawson VL, El-Deiry WS, Fulda S, Gottlieb E, Green DR, Hengartner MO, Kepp O, Knight RA, Kumar S, Lipton SA, Lu X, Madeo F, Malorni W, Mehlen P, Nunez G, Peter ME, Piacentini M, Rubinsztein DC, Shi Y, Simon HU, Vandenabeele P, White E, Yuan J, Zhivotovsky B, Melino G, Kroemer G. 2012. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ 19:107–120. 10.1038/cdd.2011.96. - DOI - PMC - PubMed

[4] Galluzzi L, Vitale I, Abrams JM, Alnemri ES, Baehrecke EH, Blagosklonny MV, Dawson TM, Dawson VL, El-Deiry WS, Fulda S, Gottlieb E, Green DR, Hengartner MO, Kepp O, Knight RA, Kumar S, Lipton SA, Lu X, Madeo F, Malorni W, Mehlen P, Nunez G, Peter ME, Piacentini M, Rubinsztein DC, Shi Y, Simon HU, Vandenabeele P, White E, Yuan J, Zhivotovsky B, Melino G, Kroemer G. 2012. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ 19:107–120. 10.1038/cdd.2011.96. - DOI - PMC - PubMed

[5] Danthi P. 2016. Viruses and the diversity of cell death. Annu Rev Virol 3:533–553. 10.1146/annurev-virology-110615-042435. - DOI - PubMed

[6] Danthi P. 2016. Viruses and the diversity of cell death. Annu Rev Virol 3:533–553. 10.1146/annurev-virology-110615-042435. - DOI - PubMed

[7] Lennemann NJ, Coyne CB. 2015. Catch me if you can: the link between autophagy and viruses. PLoS Pathog 11:e1004685. 10.1371/journal.ppat.1004685. - DOI - PMC - PubMed

[8] Lennemann NJ, Coyne CB. 2015. Catch me if you can: the link between autophagy and viruses. PLoS Pathog 11:e1004685. 10.1371/journal.ppat.1004685. - DOI - PMC - PubMed

[9] Clarke P, Tyler KL. 2009. Apoptosis in animal models of virus-induced disease. Nat Rev Microbiol 7:144–155. 10.1038/nrmicro2071. - DOI - PMC - PubMed

[10] Clarke P, Tyler KL. 2009. Apoptosis in animal models of virus-induced disease. Nat Rev Microbiol 7:144–155. 10.1038/nrmicro2071. - DOI - PMC - PubMed

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Opposite Effects of Apoptotic and Necroptotic Cellular Pathways on Rotavirus Replication

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Opposite Effects of Apoptotic and Necroptotic Cellular Pathways on Rotavirus Replication

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