The effects of free chlorine disinfection of tap water and wastewater effluents on the infectivity, gene integrity and surface antigens of rotaviruses were evaluated by a bench-scale chlorine disinfection experiments....The effects of free chlorine disinfection of tap water and wastewater effluents on the infectivity, gene integrity and surface antigens of rotaviruses were evaluated by a bench-scale chlorine disinfection experiments. Plaque assays, integrated cell culture-quantitative RT- PCR （ICC-RT-qPCR）, RT-qPCR, and enzyme-linked immunosorbent assays （ELISA）, respectively, were used to assess the influence of the disinfectant on virus infectivity as well as genetic and antigenic integrity of simian rotavirus SA11 as a surrogate for human rotaviruses. The ICC-RT-qPCR was able to detect rotaviruses survival from chlorine disinfection at chlorine dose up to 20 mg/L （60 min contact）, which suggested a required chlorine dose of 5 folds （from 1 to 5 mg/L） higher than that indicated by the plaque assay to achieve 1.8 log10 reductions in tap water with 60 rain exposing. The VP7 gene was more resistant than the infectivity and existed at chlorine dose up to 20 mg/L （60 min contact）, while the antigencity was undetectable with chlorine dose more than 5 mg/L （60 min contact）. The water quality also impacted the inactivation efficiencies, and rotaviruses have a relatively higher resistant in secondary effluents than in the tap water under the same chlorine disinfection treatments. This study indicated that rotaviruses have a higher infectivity, gene and antigencity resistance to chlorine than that previously indicated by plaque assay only, which seemed to underestimate the resistance of rotaviruses to chlorine and the risk of rotaviruses in environments. Present results also suggested that re-evaluation of resistance of other waterborne viruses after disinfections by more sensitive infectivity detection method （such as ICC-RT-qPCR） may be necessary, to determine the adequate disinfectant doses required for the inactivation of waterborne viruses.展开更多
This is the first country-wide surveillance of bat-borne viruses in Kenya spanning from 2012-2015 covering sites perceived to have medium to high level bat-human interaction. The objective of this surveillance study w...This is the first country-wide surveillance of bat-borne viruses in Kenya spanning from 2012-2015 covering sites perceived to have medium to high level bat-human interaction. The objective of this surveillance study was to apply a non-invasive approach using fresh feces to detect viruses circulating within the diverse species of Kenyan bats. We screened for both DNA and RNA viruses; specifically, astroviruses （AstVs）, adenoviruses （ADVs）, caliciviruses （CalVs）, coronaviruses （CoVs）, flaviviruses, filoviruses, paramyxoviruses （PMVs）, polyomaviruses （PYVs） and rotaviruses. We used family-specific primers, amplicon sequencing and further characterization by phyloge- netic analysis. Except for filoviruses, eight virus families were detected with varying distributions and positive rates across the five regions （former provinces） studied. AstVs （12.83%）, CoVs （3.97%）, PMV （2.4%）, ADV （2.26%）, PYV （1.65%）, CalVs （0.29%）, rotavirus （0.19%） and flavivirus （0.19%）. Novel CalVs were detected in Rousettus aegyptiacus and Mops condylurus while novel Rotavirus-A-related viruses were detected in Taphozous bats and R. aegyptiacus. The two Rotavirus A （RVA） strains detected were highly related to human strains with VP6 genotypes 12 and 116. Genotype 116 has previously been assigned to human RVA-strain B10 from Kenya only, which raises public health concern, particularly considering increased human-bat interaction. Additionally, 229E-like bat CoVs were detected in samples originating from Hipposideros bats roosting in sites with high human activity. Our findings confirm the presence of diverse viruses in Kenyan bats while providing extended knowledge on bat virus distribution. The detection of viruses highly related to human strains and hence of public health concern, underscores the importance of continuous surveillance.展开更多
Rotaviruses are non-enveloped double-stranded RNA virus that causes acute diarrheal diseases in children(<5 years).More than 90%of the global rotavirus infection in humans was caused by Rotavirus group A.Rotavirus ...Rotaviruses are non-enveloped double-stranded RNA virus that causes acute diarrheal diseases in children(<5 years).More than 90%of the global rotavirus infection in humans was caused by Rotavirus group A.Rotavirus infection has caused more than 200000 deaths annually and predominantly occurs in the low-income countries.Rotavirus evolution is indicated by the strain dynamics or the emergence of the unprecedented strain.The major factors that drive the rotavirus evolution include the genetic shift that is caused by the reassortment mechanism,either in the intra-or the inter-genogroup.However,other factors are also known to have an impact on rotavirus evolution.This review discusses the structure and types,epidemiology,and evolution of rotaviruses.This article also reviews other supplemental factors of rotavirus evolution,such as genetic reassortment,mutation rate,glycan specificity,vaccine introduction,the host immune respo-nses,and antiviral drugs.展开更多
The oral hexavalent live human-bovine reassortant rotavirus vaccine(RV6)developed by Wuhan Institute of Biological Products Co.,Ltd(WIBP)has finished a randomized,placebo-controlled phase III clinical trial in four pr...The oral hexavalent live human-bovine reassortant rotavirus vaccine(RV6)developed by Wuhan Institute of Biological Products Co.,Ltd(WIBP)has finished a randomized,placebo-controlled phase III clinical trial in four provinces of China in 2021.The trail demonstrated that RV6 has a high vaccine efficacy against the prevalent strains and is safe for use in infants.During the phase III clinical trial(2019–2021),200 rotavirus-positive fecal samples from children with RV gastroenteritis(RVGE)were further studied.Using reverse transcription-polymerase chain reaction and high-throughput sequencing,VP7 and VP4 sequences were obtained and their genetic characteristics,as well as the differences in antigenic epitopes of VP7,were analyzed in detail.Seven rotavirus genotypes were identified.The predominant rotavirus genotype was G9P[8](77.0%),followed by prevalent strains G8P[8](8.0%),G3P[8](3.5%),G3P[9](1.5%),G1P[8](1.0%),G2P[4](1.0%),and G4P[6](1.0%).The amino acid sequence identities of G1,G2,G3,G4,G8,and G9 genotypes of isolates compared to the vaccine strains were 98.8%,98.2%–99.7%,88.4%–99.4%,98.2%,94.2%–100%,and 93.9%–100%,respectively.Notably,the vaccine strains exhibited high similarity in amino acid sequence,with only minor differences in antigenic epitopes compared to the Chinese endemic strains.This supports the potential application of the vaccine in preventing diseases caused by rotaviruses.展开更多
Rotavirus infections cause severe gastroenteritis and dehydration in young children and animals worldwide,leading to high rates of morbidity and mortality,predominantly in low-and middleincome countries.In the past de...Rotavirus infections cause severe gastroenteritis and dehydration in young children and animals worldwide,leading to high rates of morbidity and mortality,predominantly in low-and middleincome countries.In the past decade,substantial progress has been made in the development and implementation of rotavirus vaccines,which have been essential in alleviating the global burden of this disease,not only in human being but also in livestock species like calves and piglets,where these infections can cause significant economic losses.By synthesizing the latest research and real-world evidence,this review article is designated to provide deep insights into the current state of rotavirus vaccine technology and its global implementation as well as the application of rotavirus vaccines in veterinary settings and their importance in controlling zoonotic transmission and maintaining food security.展开更多
The original version of Figure 2 contained the following inaccuracies:Rotarix was incorrectly shown as a 3-dose vaccine instead of a 2-dose vaccine;RotaTeq and Rotasiil were incorrectly shown as 2-dose vaccines instea...The original version of Figure 2 contained the following inaccuracies:Rotarix was incorrectly shown as a 3-dose vaccine instead of a 2-dose vaccine;RotaTeq and Rotasiil were incorrectly shown as 2-dose vaccines instead of 3-dose vaccines;Polyvac was incorrectly shown as a 3-dose vaccine instead of a 2-dose regimen;and the LLR vaccine should have been indicated as a single primary dose followed by annual boosters between 2 months and 3 years of age.展开更多
As an emerging genotype,the G9 genotype rotaviruses(RVs)are widespread among humans and pigs,and have been reported in many countries and regions in the recent years.Moreover,porcine G9 strains could cross the intersp...As an emerging genotype,the G9 genotype rotaviruses(RVs)are widespread among humans and pigs,and have been reported in many countries and regions in the recent years.Moreover,porcine G9 strains could cross the interspecies barrier to infect human.To investigate the epidemic trends of porcine G9 strains as well as the cross-immunoreactivity among different isolates,an epidemiological investigation about porcine G9 genotype RVs(PoRVs)was performed during the period 2020-2023 in multiple provinces of China.A total of nine representative strains were identified.The phylogenetic analysis based on viral VP7 gene showed that these strains mainly clustered with lineages Ⅲ and Ⅵ,which revealed the predominant G9 PoRVs in China.Moreover,a new lineage,lineage Ⅶ,was identified,and strains of this lineage were found to be circulating in Guangdong and Taiwan.Except lineages Ⅰ and Ⅳ,some isolates from other lineages could co-circulate in pigs and humans.Three G9 strains,namely 923H,923E,and 923X,which belonged to the largest sub-lineage Ⅲ,were isolated.Then,the significant cross-reactivity was observed among strains of the same or different lineages.This study is the first to systematically investigate the genetic and immunogenetic characteristics of porcine G9 genotype rotavirus in China,as well as the potential cross-species transmission between pigs and humans,providing a valuable direction for the effective prevention of porcine rotavirus.展开更多
Objective The objective of our study was to evaluate the vaccine effectiveness(VE)of the pentavalent rotavirus vaccine(RV5)among<5-year-old children in three provinces of China during 2020-2024 via a propensity sco...Objective The objective of our study was to evaluate the vaccine effectiveness(VE)of the pentavalent rotavirus vaccine(RV5)among<5-year-old children in three provinces of China during 2020-2024 via a propensity score-matched test-negative case-control study.Methods Electronic health records and immunization information systems were used to obtain data on acute gastroenteritis(AGE)cases tested for rotavirus(RV)infection.RV-positive cases were propensity score matched with RV-negative controls for age,visit month,and province.Results The study included 27,472 children with AGE aged 8 weeks to 4 years at the time of AGE diagnosis;7.98%(2,192)were RV-positive.The VE(95%confidence interval,CI)of 1-2 and 3 doses of RV5 against any medically attended RV infection(inpatient or outpatient)was 57.6%(39.8%,70.2%)and 67.2%(60.3%,72.9%),respectively.Among children who received the 3rd dose before turning 5 months of age,3-dose VE decreased from 70.4%(53.9%,81.1%)(<5 months since the 3rd dose)to 63.0%(49.1%,73.0%)(≥1 year since the 3rd dose).The three-dose VE rate was 69.4%(41.3%,84.0%)for RVGE hospitalization and 57.5%(38.9%,70.5%)for outpatient-only medically attended RVGE.Conclusion Three-dose RV5 VE against rotavirus gastroenteritis(RVGE)in children aged<5 years was higher than 1-2-dose VE.Three-dose VE decreased with time since the 3rd dose in children who received the 3rd dose before turning five months of age,but remained above 60%for at least one year.VE was higher for RVGE hospitalizations than for medically attended outpatient visits.展开更多
BACKGROUND Rotavirus(RV),a primary cause of diarrhea-related mortality in 2021,has been shown to damage intestinal epithelial cells while upregulating intestinal stem cells(ISCs)activities.ISCs within the crypt niche ...BACKGROUND Rotavirus(RV),a primary cause of diarrhea-related mortality in 2021,has been shown to damage intestinal epithelial cells while upregulating intestinal stem cells(ISCs)activities.ISCs within the crypt niche drive the continuous self-renewal of intestinal epithelium,preserving its barrier functions.Paneth cells secrete antimicrobial peptide and signaling molecules within the intestine crypt,thereby playing a crucial role in intestinal immune defense and providing ISCs functional support.However,the regulatory function of Paneth cells under pathological conditions,such as RV infection,remains unclear.AIM To determine the impact of RV infection on Paneth cells and how Paneth cells regulate ISCs during intestinal injury repair.METHODS We constructed a reference genome for the RV enteric cytopathogenic human orphan virus strain and reanalyzed published single-cell RNA sequencing data to investigate Paneth cell responses to RV-induced intestinal injury.We derived Paneth-ISC communication networks using CellChat,tracked ISC differentiation with pseudotime analysis,and validated our findings in leucine-rich repeat-containing G protein-coupled receptor 5-enhanced green fluorescent protein-internal ribosomal entry site-Cre recombinase estrogen receptor variant 2 mice and organoids via immunofluorescence,flow cytometry,and reverse transcription quantitative polymerase chain reaction.RESULTS We found that RV directly infects Paneth cells,leading to a reduction in mature Paneth cells and an increase in kallikrein 1-high immature Paneth cells.Paneth-ISC communication was significantly enhanced.In particular,the bone morphogenic protein 7(BMP7)-activin A receptor type 2B/BMP receptor type 1A-Smad pathway was upregulated post-infection,suggesting that Paneth cells suppress excessive ISC proliferation.Functional validation confirmed activation of this pathway.CONCLUSION Paneth cells regulate ISC proliferation during RV infection by activating BMP7 signaling,limiting excessive stem cell expansion and preserving crypt homeostasis for effective epithelial repair.展开更多
Rotaviruses are the single leading cause of life-threatening diarrhea affecting children under 5 years of age. Rotavirus entry into the host cell seems to occur by sequential interactions between virion proteins and v...Rotaviruses are the single leading cause of life-threatening diarrhea affecting children under 5 years of age. Rotavirus entry into the host cell seems to occur by sequential interactions between virion proteins and various cell surface molecules. The entry mechanisms seem to involve the contribution of cellular molecules having binding, chaperoning and oxido-reducing activities. It appears to be that the receptor usage and tropism of rotaviruses is determined by the species, cell line and rotavirus strain. Rotaviruses have evolved functions which can antagonize the host innate immune response, whereas are able to induce endoplasmic reticulum(ER) stress, oxidative stress and inflammatory signaling. A networking between ER stress, inflammation and oxidative stress is suggested, in which release of calcium from the ER increases the generation of mitochondrial reactive oxygen species(ROS) leading to toxic accumulation of ROS within ER and mitochondria. Sustained ER stress potentially stimulates inflammatory response through unfolded protein response pathways. However, the detailed characterization of the molecular mechanisms underpinning these rotavirus-induced stressful conditions is still lacking. The signaling events triggered by host recognition of virusassociated molecular patterns offers an opportunity for the development of novel therapeutic strategies aimed at interfering with rotavirus infection. The use of N-acetylcysteine, non-steroidal anti-inflammatory drugs and PPARγ agonists to inhibit rotavirus infection opens a new way for treating the rotavirus-induced diarrhea and complementing vaccines.展开更多
基金supported by the Special Fund of State Key Joint Laboratory of Environment Simulation and Pollution Control of China (No. 10Y04ESPCT)the National Natural Science Fundation of China (No. 51178242)the Major Science and Technology Program for Water Pollution Control and Treatment of China (No. 2008ZX07313-007)
文摘The effects of free chlorine disinfection of tap water and wastewater effluents on the infectivity, gene integrity and surface antigens of rotaviruses were evaluated by a bench-scale chlorine disinfection experiments. Plaque assays, integrated cell culture-quantitative RT- PCR （ICC-RT-qPCR）, RT-qPCR, and enzyme-linked immunosorbent assays （ELISA）, respectively, were used to assess the influence of the disinfectant on virus infectivity as well as genetic and antigenic integrity of simian rotavirus SA11 as a surrogate for human rotaviruses. The ICC-RT-qPCR was able to detect rotaviruses survival from chlorine disinfection at chlorine dose up to 20 mg/L （60 min contact）, which suggested a required chlorine dose of 5 folds （from 1 to 5 mg/L） higher than that indicated by the plaque assay to achieve 1.8 log10 reductions in tap water with 60 rain exposing. The VP7 gene was more resistant than the infectivity and existed at chlorine dose up to 20 mg/L （60 min contact）, while the antigencity was undetectable with chlorine dose more than 5 mg/L （60 min contact）. The water quality also impacted the inactivation efficiencies, and rotaviruses have a relatively higher resistant in secondary effluents than in the tap water under the same chlorine disinfection treatments. This study indicated that rotaviruses have a higher infectivity, gene and antigencity resistance to chlorine than that previously indicated by plaque assay only, which seemed to underestimate the resistance of rotaviruses to chlorine and the risk of rotaviruses in environments. Present results also suggested that re-evaluation of resistance of other waterborne viruses after disinfections by more sensitive infectivity detection method （such as ICC-RT-qPCR） may be necessary, to determine the adequate disinfectant doses required for the inactivation of waterborne viruses.
基金funded by SinoAfrica Joint Research Center (SAJC201313 and SAJC 201605)
文摘This is the first country-wide surveillance of bat-borne viruses in Kenya spanning from 2012-2015 covering sites perceived to have medium to high level bat-human interaction. The objective of this surveillance study was to apply a non-invasive approach using fresh feces to detect viruses circulating within the diverse species of Kenyan bats. We screened for both DNA and RNA viruses; specifically, astroviruses （AstVs）, adenoviruses （ADVs）, caliciviruses （CalVs）, coronaviruses （CoVs）, flaviviruses, filoviruses, paramyxoviruses （PMVs）, polyomaviruses （PYVs） and rotaviruses. We used family-specific primers, amplicon sequencing and further characterization by phyloge- netic analysis. Except for filoviruses, eight virus families were detected with varying distributions and positive rates across the five regions （former provinces） studied. AstVs （12.83%）, CoVs （3.97%）, PMV （2.4%）, ADV （2.26%）, PYV （1.65%）, CalVs （0.29%）, rotavirus （0.19%） and flavivirus （0.19%）. Novel CalVs were detected in Rousettus aegyptiacus and Mops condylurus while novel Rotavirus-A-related viruses were detected in Taphozous bats and R. aegyptiacus. The two Rotavirus A （RVA） strains detected were highly related to human strains with VP6 genotypes 12 and 116. Genotype 116 has previously been assigned to human RVA-strain B10 from Kenya only, which raises public health concern, particularly considering increased human-bat interaction. Additionally, 229E-like bat CoVs were detected in samples originating from Hipposideros bats roosting in sites with high human activity. Our findings confirm the presence of diverse viruses in Kenyan bats while providing extended knowledge on bat virus distribution. The detection of viruses highly related to human strains and hence of public health concern, underscores the importance of continuous surveillance.
文摘Rotaviruses are non-enveloped double-stranded RNA virus that causes acute diarrheal diseases in children(<5 years).More than 90%of the global rotavirus infection in humans was caused by Rotavirus group A.Rotavirus infection has caused more than 200000 deaths annually and predominantly occurs in the low-income countries.Rotavirus evolution is indicated by the strain dynamics or the emergence of the unprecedented strain.The major factors that drive the rotavirus evolution include the genetic shift that is caused by the reassortment mechanism,either in the intra-or the inter-genogroup.However,other factors are also known to have an impact on rotavirus evolution.This review discusses the structure and types,epidemiology,and evolution of rotaviruses.This article also reviews other supplemental factors of rotavirus evolution,such as genetic reassortment,mutation rate,glycan specificity,vaccine introduction,the host immune respo-nses,and antiviral drugs.
基金the National Health Committee of the People's Republic of China(grant number:2019ZX09302059).
文摘The oral hexavalent live human-bovine reassortant rotavirus vaccine(RV6)developed by Wuhan Institute of Biological Products Co.,Ltd(WIBP)has finished a randomized,placebo-controlled phase III clinical trial in four provinces of China in 2021.The trail demonstrated that RV6 has a high vaccine efficacy against the prevalent strains and is safe for use in infants.During the phase III clinical trial(2019–2021),200 rotavirus-positive fecal samples from children with RV gastroenteritis(RVGE)were further studied.Using reverse transcription-polymerase chain reaction and high-throughput sequencing,VP7 and VP4 sequences were obtained and their genetic characteristics,as well as the differences in antigenic epitopes of VP7,were analyzed in detail.Seven rotavirus genotypes were identified.The predominant rotavirus genotype was G9P[8](77.0%),followed by prevalent strains G8P[8](8.0%),G3P[8](3.5%),G3P[9](1.5%),G1P[8](1.0%),G2P[4](1.0%),and G4P[6](1.0%).The amino acid sequence identities of G1,G2,G3,G4,G8,and G9 genotypes of isolates compared to the vaccine strains were 98.8%,98.2%–99.7%,88.4%–99.4%,98.2%,94.2%–100%,and 93.9%–100%,respectively.Notably,the vaccine strains exhibited high similarity in amino acid sequence,with only minor differences in antigenic epitopes compared to the Chinese endemic strains.This supports the potential application of the vaccine in preventing diseases caused by rotaviruses.
基金supported by the National Key Laboratory of Agricultural Microbiology(AML2023A02)the Fundamental Research Funds for the Central Universities(2662023DKPY004).
文摘Rotavirus infections cause severe gastroenteritis and dehydration in young children and animals worldwide,leading to high rates of morbidity and mortality,predominantly in low-and middleincome countries.In the past decade,substantial progress has been made in the development and implementation of rotavirus vaccines,which have been essential in alleviating the global burden of this disease,not only in human being but also in livestock species like calves and piglets,where these infections can cause significant economic losses.By synthesizing the latest research and real-world evidence,this review article is designated to provide deep insights into the current state of rotavirus vaccine technology and its global implementation as well as the application of rotavirus vaccines in veterinary settings and their importance in controlling zoonotic transmission and maintaining food security.
文摘The original version of Figure 2 contained the following inaccuracies:Rotarix was incorrectly shown as a 3-dose vaccine instead of a 2-dose vaccine;RotaTeq and Rotasiil were incorrectly shown as 2-dose vaccines instead of 3-dose vaccines;Polyvac was incorrectly shown as a 3-dose vaccine instead of a 2-dose regimen;and the LLR vaccine should have been indicated as a single primary dose followed by annual boosters between 2 months and 3 years of age.
基金supported by the National Natural Science Foundation of China(Grant no.32402927).
文摘As an emerging genotype,the G9 genotype rotaviruses(RVs)are widespread among humans and pigs,and have been reported in many countries and regions in the recent years.Moreover,porcine G9 strains could cross the interspecies barrier to infect human.To investigate the epidemic trends of porcine G9 strains as well as the cross-immunoreactivity among different isolates,an epidemiological investigation about porcine G9 genotype RVs(PoRVs)was performed during the period 2020-2023 in multiple provinces of China.A total of nine representative strains were identified.The phylogenetic analysis based on viral VP7 gene showed that these strains mainly clustered with lineages Ⅲ and Ⅵ,which revealed the predominant G9 PoRVs in China.Moreover,a new lineage,lineage Ⅶ,was identified,and strains of this lineage were found to be circulating in Guangdong and Taiwan.Except lineages Ⅰ and Ⅳ,some isolates from other lineages could co-circulate in pigs and humans.Three G9 strains,namely 923H,923E,and 923X,which belonged to the largest sub-lineage Ⅲ,were isolated.Then,the significant cross-reactivity was observed among strains of the same or different lineages.This study is the first to systematically investigate the genetic and immunogenetic characteristics of porcine G9 genotype rotavirus in China,as well as the potential cross-species transmission between pigs and humans,providing a valuable direction for the effective prevention of porcine rotavirus.
基金the Study on Vaccine Application Evaluation Strategies and Capacity Building (INV-006373)the National Key R&D Program of China(2024YFC2310604)
文摘Objective The objective of our study was to evaluate the vaccine effectiveness(VE)of the pentavalent rotavirus vaccine(RV5)among<5-year-old children in three provinces of China during 2020-2024 via a propensity score-matched test-negative case-control study.Methods Electronic health records and immunization information systems were used to obtain data on acute gastroenteritis(AGE)cases tested for rotavirus(RV)infection.RV-positive cases were propensity score matched with RV-negative controls for age,visit month,and province.Results The study included 27,472 children with AGE aged 8 weeks to 4 years at the time of AGE diagnosis;7.98%(2,192)were RV-positive.The VE(95%confidence interval,CI)of 1-2 and 3 doses of RV5 against any medically attended RV infection(inpatient or outpatient)was 57.6%(39.8%,70.2%)and 67.2%(60.3%,72.9%),respectively.Among children who received the 3rd dose before turning 5 months of age,3-dose VE decreased from 70.4%(53.9%,81.1%)(<5 months since the 3rd dose)to 63.0%(49.1%,73.0%)(≥1 year since the 3rd dose).The three-dose VE rate was 69.4%(41.3%,84.0%)for RVGE hospitalization and 57.5%(38.9%,70.5%)for outpatient-only medically attended RVGE.Conclusion Three-dose RV5 VE against rotavirus gastroenteritis(RVGE)in children aged<5 years was higher than 1-2-dose VE.Three-dose VE decreased with time since the 3rd dose in children who received the 3rd dose before turning five months of age,but remained above 60%for at least one year.VE was higher for RVGE hospitalizations than for medically attended outpatient visits.
文摘BACKGROUND Rotavirus(RV),a primary cause of diarrhea-related mortality in 2021,has been shown to damage intestinal epithelial cells while upregulating intestinal stem cells(ISCs)activities.ISCs within the crypt niche drive the continuous self-renewal of intestinal epithelium,preserving its barrier functions.Paneth cells secrete antimicrobial peptide and signaling molecules within the intestine crypt,thereby playing a crucial role in intestinal immune defense and providing ISCs functional support.However,the regulatory function of Paneth cells under pathological conditions,such as RV infection,remains unclear.AIM To determine the impact of RV infection on Paneth cells and how Paneth cells regulate ISCs during intestinal injury repair.METHODS We constructed a reference genome for the RV enteric cytopathogenic human orphan virus strain and reanalyzed published single-cell RNA sequencing data to investigate Paneth cell responses to RV-induced intestinal injury.We derived Paneth-ISC communication networks using CellChat,tracked ISC differentiation with pseudotime analysis,and validated our findings in leucine-rich repeat-containing G protein-coupled receptor 5-enhanced green fluorescent protein-internal ribosomal entry site-Cre recombinase estrogen receptor variant 2 mice and organoids via immunofluorescence,flow cytometry,and reverse transcription quantitative polymerase chain reaction.RESULTS We found that RV directly infects Paneth cells,leading to a reduction in mature Paneth cells and an increase in kallikrein 1-high immature Paneth cells.Paneth-ISC communication was significantly enhanced.In particular,the bone morphogenic protein 7(BMP7)-activin A receptor type 2B/BMP receptor type 1A-Smad pathway was upregulated post-infection,suggesting that Paneth cells suppress excessive ISC proliferation.Functional validation confirmed activation of this pathway.CONCLUSION Paneth cells regulate ISC proliferation during RV infection by activating BMP7 signaling,limiting excessive stem cell expansion and preserving crypt homeostasis for effective epithelial repair.
文摘Rotaviruses are the single leading cause of life-threatening diarrhea affecting children under 5 years of age. Rotavirus entry into the host cell seems to occur by sequential interactions between virion proteins and various cell surface molecules. The entry mechanisms seem to involve the contribution of cellular molecules having binding, chaperoning and oxido-reducing activities. It appears to be that the receptor usage and tropism of rotaviruses is determined by the species, cell line and rotavirus strain. Rotaviruses have evolved functions which can antagonize the host innate immune response, whereas are able to induce endoplasmic reticulum(ER) stress, oxidative stress and inflammatory signaling. A networking between ER stress, inflammation and oxidative stress is suggested, in which release of calcium from the ER increases the generation of mitochondrial reactive oxygen species(ROS) leading to toxic accumulation of ROS within ER and mitochondria. Sustained ER stress potentially stimulates inflammatory response through unfolded protein response pathways. However, the detailed characterization of the molecular mechanisms underpinning these rotavirus-induced stressful conditions is still lacking. The signaling events triggered by host recognition of virusassociated molecular patterns offers an opportunity for the development of novel therapeutic strategies aimed at interfering with rotavirus infection. The use of N-acetylcysteine, non-steroidal anti-inflammatory drugs and PPARγ agonists to inhibit rotavirus infection opens a new way for treating the rotavirus-induced diarrhea and complementing vaccines.
