Jaiprasath Sachithanandham, Julia Leep-Lazar, Jeffrey Quinn, Kenneth Bowden, Prasanthy Balasubramaniam, Kathleen Ward, Ruy M Ribeiro, Mark S Sulkowski, Ashwin Balagopal
Background Hepatitis C virus (HCV) infects nearly one-fourth of people with HIV (PWH). The role of direct-acting antivirals (DAAs) on immune activation in PWH and HCV is poorly understood. Methods We quantified plasma HCV RNA and CXCL10 in persons with HCV mono- versus HIV/HCV co-infection receiving Sofosbuvir-Velpatasvir. Single-cell laser capture was applied to liver biopsies obtained before and within 4-7 days of DAA initiation to estimate HCV clearance and changes in interferon stimulated genes (ISGs). Results We enrolled ten people with chronic genotype 1a HCV: five were PWH. Median (min-max) ages at enrollment were 55.5 (28-66) years, five were women, and eight were African American. At baseline, plasma HCV RNA levels were 6.36 (5.68-7.93) log10 IU/mL; all had transient elastography liver stiffness < 9 kPa. CD4+ T cell counts in PWH were 768 (244-1136) cells/µL. All had suppressed HIV viremia on antiretrovirals. First and second phase plasma HCV RNA kinetics were not different between groups. Median (min-max) proportions of infected hepatocytes at biopsy 1 were 0.06 (0.01-0.59) in HCV mono- and 0.21 (0.04-0.87) in HIV/HCV co-infection and did not differ. Participants had lower intracellular HCV RNA levels at biopsy 2, but not differentially by HIV status. CXCL10 levels declined in both groups but was higher in co- than in mono-infection even at the end of treatment. Proportion of cells expressing ISGs diminished in mono- but increased in co-infection. Conclusion Whereas DAAs rapidly cleared intrahepatic HCV in both groups, immune activation was slower to diminish in PWH. Residual immune activation in PWH warrants further exploration.
{"title":"Direct acting antivirals eradicate HCV from the liver quickly in people with HIV but do not fully reverse immune activation","authors":"Jaiprasath Sachithanandham, Julia Leep-Lazar, Jeffrey Quinn, Kenneth Bowden, Prasanthy Balasubramaniam, Kathleen Ward, Ruy M Ribeiro, Mark S Sulkowski, Ashwin Balagopal","doi":"10.1093/infdis/jiae598","DOIUrl":"https://doi.org/10.1093/infdis/jiae598","url":null,"abstract":"Background Hepatitis C virus (HCV) infects nearly one-fourth of people with HIV (PWH). The role of direct-acting antivirals (DAAs) on immune activation in PWH and HCV is poorly understood. Methods We quantified plasma HCV RNA and CXCL10 in persons with HCV mono- versus HIV/HCV co-infection receiving Sofosbuvir-Velpatasvir. Single-cell laser capture was applied to liver biopsies obtained before and within 4-7 days of DAA initiation to estimate HCV clearance and changes in interferon stimulated genes (ISGs). Results We enrolled ten people with chronic genotype 1a HCV: five were PWH. Median (min-max) ages at enrollment were 55.5 (28-66) years, five were women, and eight were African American. At baseline, plasma HCV RNA levels were 6.36 (5.68-7.93) log10 IU/mL; all had transient elastography liver stiffness &lt; 9 kPa. CD4+ T cell counts in PWH were 768 (244-1136) cells/µL. All had suppressed HIV viremia on antiretrovirals. First and second phase plasma HCV RNA kinetics were not different between groups. Median (min-max) proportions of infected hepatocytes at biopsy 1 were 0.06 (0.01-0.59) in HCV mono- and 0.21 (0.04-0.87) in HIV/HCV co-infection and did not differ. Participants had lower intracellular HCV RNA levels at biopsy 2, but not differentially by HIV status. CXCL10 levels declined in both groups but was higher in co- than in mono-infection even at the end of treatment. Proportion of cells expressing ISGs diminished in mono- but increased in co-infection. Conclusion Whereas DAAs rapidly cleared intrahepatic HCV in both groups, immune activation was slower to diminish in PWH. Residual immune activation in PWH warrants further exploration.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"228 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Samuel S Bailin, Siyuan Ma, Andrew S Perry, James G Terry, John Jeffrey Carr, Sangeeta Nair, Heidi J Silver, Mingjian Shi, Mona Mashayekhi, Jonathan A Kropski, Jane F Ferguson, Celestine N Wanjalla, Suman R Das, Ravi Shah, John R Koethe, Curtis L Gabriel
Background Persons with HIV (PWH) on contemporary antiretroviral therapy (ART) are at elevated risk for developing age-related cardiometabolic diseases. We hypothesized that integrative analysis of cross-tissue, multimodal data from PWH could provide insight into molecular programming that defines cardiometabolic phenotypes in this high-risk group. Methods We enrolled 93 PWH without diabetes who were virologically suppressed on contemporary ART and obtained measures of insulin resistance, glucose intolerance, and adiposity. We performed circulating lipidomics, proteomics, and metabolomics, as well as subcutaneous adipose tissue (SAT) bulk transcriptomics, and used multiomics factor analysis (MOFA) to perform integrative analyses of these datasets. Results The median age was 43 years, median body mass index 30.8 kg/m2, 81% were male, and 56% were self-identified non-Hispanic White. We identified a specific MOFA factor associated with visceral adipose tissue volume (ρ = −0.43), homeostasis model assessment 2 insulin resistance score (ρ = −0.52), liver density (ρ = 0.43), and other cardiometabolic risk factors, which explained more variance in the SAT transcriptome and circulating lipidome compared with the circulating proteome and metabolome. Gene set enrichment analysis of this factor showed extracellular matrix and inflammatory pathways that primarily mapped to SAT myeloid cells and adipose progenitor cells using single-cell deconvolution. Lipidomic analysis showed that this factor was significantly enriched for triacylglycerol and diacylglycerol species. Conclusions Our multiomic analysis demonstrated coordinated, multitissue molecular reprogramming in virologically suppressed PWH with elevated cardiometabolic disease risk. Longitudinal studies of PWH with assessments of adipose tissue and lipid handling are necessary to understand mechanisms of cardiometabolic disease in PWH. Clinical Trials Registration. NCT04451980.
{"title":"The Primacy of Adipose Tissue Gene Expression and Plasma Lipidome in Cardiometabolic Disease in Persons With HIV","authors":"Samuel S Bailin, Siyuan Ma, Andrew S Perry, James G Terry, John Jeffrey Carr, Sangeeta Nair, Heidi J Silver, Mingjian Shi, Mona Mashayekhi, Jonathan A Kropski, Jane F Ferguson, Celestine N Wanjalla, Suman R Das, Ravi Shah, John R Koethe, Curtis L Gabriel","doi":"10.1093/infdis/jiae532","DOIUrl":"https://doi.org/10.1093/infdis/jiae532","url":null,"abstract":"Background Persons with HIV (PWH) on contemporary antiretroviral therapy (ART) are at elevated risk for developing age-related cardiometabolic diseases. We hypothesized that integrative analysis of cross-tissue, multimodal data from PWH could provide insight into molecular programming that defines cardiometabolic phenotypes in this high-risk group. Methods We enrolled 93 PWH without diabetes who were virologically suppressed on contemporary ART and obtained measures of insulin resistance, glucose intolerance, and adiposity. We performed circulating lipidomics, proteomics, and metabolomics, as well as subcutaneous adipose tissue (SAT) bulk transcriptomics, and used multiomics factor analysis (MOFA) to perform integrative analyses of these datasets. Results The median age was 43 years, median body mass index 30.8 kg/m2, 81% were male, and 56% were self-identified non-Hispanic White. We identified a specific MOFA factor associated with visceral adipose tissue volume (ρ = −0.43), homeostasis model assessment 2 insulin resistance score (ρ = −0.52), liver density (ρ = 0.43), and other cardiometabolic risk factors, which explained more variance in the SAT transcriptome and circulating lipidome compared with the circulating proteome and metabolome. Gene set enrichment analysis of this factor showed extracellular matrix and inflammatory pathways that primarily mapped to SAT myeloid cells and adipose progenitor cells using single-cell deconvolution. Lipidomic analysis showed that this factor was significantly enriched for triacylglycerol and diacylglycerol species. Conclusions Our multiomic analysis demonstrated coordinated, multitissue molecular reprogramming in virologically suppressed PWH with elevated cardiometabolic disease risk. Longitudinal studies of PWH with assessments of adipose tissue and lipid handling are necessary to understand mechanisms of cardiometabolic disease in PWH. Clinical Trials Registration. NCT04451980.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"40 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jasmine Wang, Becky L Genberg, Kenneth Feder, Gregory D Kirk, Shruti H Mehta, Kyra Grantz, Amy Wesolowski
Background The COVID-19 pandemic may have disproportionally impacted vulnerable groups such as people who inject drugs (PWID) through reduced healthcare services as well as social changes from pandemic mitigation measures. Understanding how the COVID-19 pandemic and associated mitigation strategies subsequently changed the trajectory of hepatitis C virus (HCV) and HIV transmission is critical to estimating disease burdens, identifying outbreak risk, and developing informed intervention strategies. Methods Using behavioral data from the AIDS Linked to the IntraVenous Experience (ALIVE) study, an ongoing community-based cohort of PWID in Baltimore, USA, and an individual-based network model, we explored the impacts of service disruptions combined with changes in social networks and injecting behaviors of PWID on HCV and HIV transmission. Results Analyses of ALIVE data showed that during the pandemic, there was an acceleration in injection cessation trajectories overall, but those who continued injecting increased the frequency of injection; at the same time, individual drug-use networks became smaller and the probability of injecting with others decreased. Simulation results demonstrated that HCV and HIV prevalence increased from service disruptions alone, but these effects were mitigated when including observed behavior changes in addition. Conclusions Model results combined with rich individual behavioral data indicated that pandemic-induced behavioral changes of PWID that lasted longer than service disruptions could have offset the increasing disease burden caused by disrupted service access during the pandemic.
{"title":"Impact of pandemic-induced service disruptions and behavioral changes on HCV and HIV transmission amongst people who inject drugs: a modeling study","authors":"Jasmine Wang, Becky L Genberg, Kenneth Feder, Gregory D Kirk, Shruti H Mehta, Kyra Grantz, Amy Wesolowski","doi":"10.1093/infdis/jiae599","DOIUrl":"https://doi.org/10.1093/infdis/jiae599","url":null,"abstract":"Background The COVID-19 pandemic may have disproportionally impacted vulnerable groups such as people who inject drugs (PWID) through reduced healthcare services as well as social changes from pandemic mitigation measures. Understanding how the COVID-19 pandemic and associated mitigation strategies subsequently changed the trajectory of hepatitis C virus (HCV) and HIV transmission is critical to estimating disease burdens, identifying outbreak risk, and developing informed intervention strategies. Methods Using behavioral data from the AIDS Linked to the IntraVenous Experience (ALIVE) study, an ongoing community-based cohort of PWID in Baltimore, USA, and an individual-based network model, we explored the impacts of service disruptions combined with changes in social networks and injecting behaviors of PWID on HCV and HIV transmission. Results Analyses of ALIVE data showed that during the pandemic, there was an acceleration in injection cessation trajectories overall, but those who continued injecting increased the frequency of injection; at the same time, individual drug-use networks became smaller and the probability of injecting with others decreased. Simulation results demonstrated that HCV and HIV prevalence increased from service disruptions alone, but these effects were mitigated when including observed behavior changes in addition. Conclusions Model results combined with rich individual behavioral data indicated that pandemic-induced behavioral changes of PWID that lasted longer than service disruptions could have offset the increasing disease burden caused by disrupted service access during the pandemic.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"37 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Hyun Myung Kang, Hye-Jin Kim, Jiwon Jung, Jin Young Ahn, Kyoung-Ho Song, Jin Yang Baek, Ju-yeon Choi, Young Jae Lee, Hyeonji Jeong, Su-Hwan Kim, Soyoung Park, Hye Min Jang, Gi-eun Rhie, Eu Suk Kim, Jun Yong Choi, Sung-Han Kim, Eun-Suk Kang, Kyong Ran Peck, Hye Won Jeong, Jae-Hoon Ko
Background With the transition from the coronavirus disease 2019 (COVID-19) pandemic into endemicity, changes in group immunity and the effect of updated XBB.1.5 monovalent vaccine (MonoV) need to be investigated. Methods A multicenter vaccine cohort was followed for 3 years, and the investigation period was classified into the pre-Omicron, Omicron, and endemic eras. Thirteen sampling points were assessed, including pre- and post-MonoV administration. Specimens were classified as vaccinated, molecularly or serologically diagnosed breakthrough infection (BI), natural boosting (NB), or waned. Results A total of 327 healthcare workers contributed 2645 blood samples from March 2021 to December 2023. The log10 anti-spike protein antibody (SAb) levels, elevated by vaccination, declined linearly in the pre-Omicron era, were maintained during the Omicron era due to BIs, and increased in the endemic era (slope = 0.02, P = .02) without additional vaccination. NB cases increased significantly across the epidemiologic eras. The incidence rate ratios were 2.72 (P < .001) for Omicron/pre-Omicron and 3.39 (P < .001) for endemic/Omicron. Plaque reduction neutralization test (PRNT) titers against circulating strains (XBB.1.5 and XBB.1.9.1) in the NB group maintained previous levels, but ratios to wild-type PRNT and fold changes exhibited significantly enhanced activity. The XBB.1.5 MonoV increased PRNT by 5.8-fold against XBB.1.5 and 6.6-fold against JN.1, showing stronger enhancement against subsequent epidemic strains than the bivalent vaccine. Conclusions Group immunity in the COVID-19 endemic era exhibited maintained SAb levels and adjusted neutralizing activities through BI and NB. The XBB.1.5 MonoV significantly enhanced neutralizing activity against the vaccine strain and robust immunity against the subsequent epidemic JN.1 strain.
{"title":"Natural Boosting and the Immunogenicity of the XBB.1.5 Monovalent Vaccine in the Coronavirus Disease 2019 Endemic Era: A Longitudinal Observational Study","authors":"Hyun Myung Kang, Hye-Jin Kim, Jiwon Jung, Jin Young Ahn, Kyoung-Ho Song, Jin Yang Baek, Ju-yeon Choi, Young Jae Lee, Hyeonji Jeong, Su-Hwan Kim, Soyoung Park, Hye Min Jang, Gi-eun Rhie, Eu Suk Kim, Jun Yong Choi, Sung-Han Kim, Eun-Suk Kang, Kyong Ran Peck, Hye Won Jeong, Jae-Hoon Ko","doi":"10.1093/infdis/jiae536","DOIUrl":"https://doi.org/10.1093/infdis/jiae536","url":null,"abstract":"Background With the transition from the coronavirus disease 2019 (COVID-19) pandemic into endemicity, changes in group immunity and the effect of updated XBB.1.5 monovalent vaccine (MonoV) need to be investigated. Methods A multicenter vaccine cohort was followed for 3 years, and the investigation period was classified into the pre-Omicron, Omicron, and endemic eras. Thirteen sampling points were assessed, including pre- and post-MonoV administration. Specimens were classified as vaccinated, molecularly or serologically diagnosed breakthrough infection (BI), natural boosting (NB), or waned. Results A total of 327 healthcare workers contributed 2645 blood samples from March 2021 to December 2023. The log10 anti-spike protein antibody (SAb) levels, elevated by vaccination, declined linearly in the pre-Omicron era, were maintained during the Omicron era due to BIs, and increased in the endemic era (slope = 0.02, P = .02) without additional vaccination. NB cases increased significantly across the epidemiologic eras. The incidence rate ratios were 2.72 (P &lt; .001) for Omicron/pre-Omicron and 3.39 (P &lt; .001) for endemic/Omicron. Plaque reduction neutralization test (PRNT) titers against circulating strains (XBB.1.5 and XBB.1.9.1) in the NB group maintained previous levels, but ratios to wild-type PRNT and fold changes exhibited significantly enhanced activity. The XBB.1.5 MonoV increased PRNT by 5.8-fold against XBB.1.5 and 6.6-fold against JN.1, showing stronger enhancement against subsequent epidemic strains than the bivalent vaccine. Conclusions Group immunity in the COVID-19 endemic era exhibited maintained SAb levels and adjusted neutralizing activities through BI and NB. The XBB.1.5 MonoV significantly enhanced neutralizing activity against the vaccine strain and robust immunity against the subsequent epidemic JN.1 strain.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"68 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142752865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Nithya Thambi, Jia Yao Phuah, Ryan P Staupe, Lori M Tobias, Yu Cao, Troy McKelvey, Radha A Railkar, Antonios O Aliprantis, Carmen Sofia Arriola, Brian M Maas, Kalpit A Vora
Background Clesrovimab is a human half-life extended mAb in phase 3 evaluation for the prevention of RSV disease in infants. ADA were observed at late time points in a phase 1b/2a study where clesrovimab was well tolerated with an extended half-life of ∼45 days. Methods Serum samples at days 150, 365 and 545 post-dose were assayed for ADA titers. Samples with high ADA titers were characterized for their binding specificity to the Fab or the YTE portion of clesrovimab. RSV serum neutralization (SNA) titers were also measured on ADA+ and ADA- infants. Additionally, a D25 (site Ø) competitive ELISA was performed on ADA+ available samples to determine RSV exposure. Local surveillance data was used to ascertain RSV circulation during the trial. Results High ADA titers were observed in a minority of infants at days 365 and 545 for all doses tested. Additionally, all high titer ADA+ infants had ADA directed towards the YTE epitope of clesrovimab. Moreover, these infants demonstrated robust RSV-SNA and had D25 competitive antibodies suggesting an RSV exposure after day 150, coinciding with the epidemiological data. Conclusion RSV exposure in infants beyond day 150 after dosing is associated with ADA development and high RSV-SNA titers with no impact on pharmacokinetics.
{"title":"Development of high titer anti-drug antibodies in a Phase 1b/2a infant clesrovimab trial are associated with RSV exposure beyond day 150","authors":"Nithya Thambi, Jia Yao Phuah, Ryan P Staupe, Lori M Tobias, Yu Cao, Troy McKelvey, Radha A Railkar, Antonios O Aliprantis, Carmen Sofia Arriola, Brian M Maas, Kalpit A Vora","doi":"10.1093/infdis/jiae582","DOIUrl":"https://doi.org/10.1093/infdis/jiae582","url":null,"abstract":"Background Clesrovimab is a human half-life extended mAb in phase 3 evaluation for the prevention of RSV disease in infants. ADA were observed at late time points in a phase 1b/2a study where clesrovimab was well tolerated with an extended half-life of ∼45 days. Methods Serum samples at days 150, 365 and 545 post-dose were assayed for ADA titers. Samples with high ADA titers were characterized for their binding specificity to the Fab or the YTE portion of clesrovimab. RSV serum neutralization (SNA) titers were also measured on ADA+ and ADA- infants. Additionally, a D25 (site Ø) competitive ELISA was performed on ADA+ available samples to determine RSV exposure. Local surveillance data was used to ascertain RSV circulation during the trial. Results High ADA titers were observed in a minority of infants at days 365 and 545 for all doses tested. Additionally, all high titer ADA+ infants had ADA directed towards the YTE epitope of clesrovimab. Moreover, these infants demonstrated robust RSV-SNA and had D25 competitive antibodies suggesting an RSV exposure after day 150, coinciding with the epidemiological data. Conclusion RSV exposure in infants beyond day 150 after dosing is associated with ADA development and high RSV-SNA titers with no impact on pharmacokinetics.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"257 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142718311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ana Isabel Fernandes, Alexandre Jorge Pinto, Diogo Silvério, Ulrike Zedler, Carolina Ferreira, Iola F Duarte, Ricardo Silvestre, Anca Dorhoi, Margarida Saraiva
The diversity of Mycobacterium tuberculosis (Mtb) impacts the outcome of tuberculosis. We previously showed that Mtb isolates obtained from patients with severe disease induced low inflammasome activation and IL-1β production by infected macrophages. Here we questioned whether this differential modulation of macrophages by Mtb isolates depended on distinct metabolic reprogramming. We found that the macrophage metabolic landscape was similar regardless of the infecting Mtb isolate. Paralleling single-TLR activated macrophages, glycolysis inhibition during infection impaired IL-1β secretion. However, departing from TLR based models, in infected macrophages, IL-1β secretion was independent of mitochondrial metabolic changes and HIF-1α. Additionally, we found an unappreciated impact of a host metabolic inhibitor on the pathogen, and show that inflammasome activation and IL-1β production by macrophages require metabolically active bacteria. Our study highlights the potential confounding effect of host metabolic inhibitors on the pathogen and uncouples Mtb-inflammasome modulation from the host metabolic reprogramming.
{"title":"Genetically diverse Mycobacterium tuberculosis isolates manipulate inflammasome activation and IL-1β secretion independently of macrophage metabolic rewiring","authors":"Ana Isabel Fernandes, Alexandre Jorge Pinto, Diogo Silvério, Ulrike Zedler, Carolina Ferreira, Iola F Duarte, Ricardo Silvestre, Anca Dorhoi, Margarida Saraiva","doi":"10.1093/infdis/jiae583","DOIUrl":"https://doi.org/10.1093/infdis/jiae583","url":null,"abstract":"The diversity of Mycobacterium tuberculosis (Mtb) impacts the outcome of tuberculosis. We previously showed that Mtb isolates obtained from patients with severe disease induced low inflammasome activation and IL-1β production by infected macrophages. Here we questioned whether this differential modulation of macrophages by Mtb isolates depended on distinct metabolic reprogramming. We found that the macrophage metabolic landscape was similar regardless of the infecting Mtb isolate. Paralleling single-TLR activated macrophages, glycolysis inhibition during infection impaired IL-1β secretion. However, departing from TLR based models, in infected macrophages, IL-1β secretion was independent of mitochondrial metabolic changes and HIF-1α. Additionally, we found an unappreciated impact of a host metabolic inhibitor on the pathogen, and show that inflammasome activation and IL-1β production by macrophages require metabolically active bacteria. Our study highlights the potential confounding effect of host metabolic inhibitors on the pathogen and uncouples Mtb-inflammasome modulation from the host metabolic reprogramming.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142684282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ranjini Sankaranarayanan, Binh Ha, Heying Sun, Katie Liu, Samadhan Jadhao, Laila Hussaini, Courtney McCracken, Theda Gibson, Inci Yildirim, Jumi Yi, Kathy Stephens, Chelsea Korski, Carol Kao, Christina A Rostad, Evan J Anderson, Larry J Anderson
Background Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory infections in children <2 years of age. Prior infection in a child is usually determined by RSV antibodies; however, in young children, persisting maternal immunoglobulin G antibodies can incorrectly indicate past RSV infection. We developed and evaluated 4 immunoglobulin A (IgA) antibody enzyme immunoassays (EIAs) with the RSV F, subgroup G (Ga or Gb proteins) or RSV lysate antigens to distinguish infection induced from persisting maternal RSV antibodies. Methods We tested the EIAs against 62 cord blood specimens (group A), 39 plasma specimens from infants not exposed to an RSV season (group B), 102 plasma specimens from infants with a documented RSV infection (group C), and 124 plasma specimens from infants exposed to their first RSV season but without a documented RSV infection (group D). Results Among the 2 negative control groups, no group A specimens and 1 of the group B specimens were positive in all 4 IgA EIAs, giving a specificity of 100% and 97%, respectively. The sensitivity of the F, Ga, Gb, and Lysate IgA EIAs were 88%, 31%, 26%, and 61%, respectively, for group C specimens. Forty-four percent of the 124 specimens in group D were positive in the RSV-F IgA EIA. Conclusions The RSV-F protein IgA EIA exhibited a high level of sensitivity and specificity for detecting previous RSV infections in the presence of maternal antibodies and can help in RSV clinical trials and epidemiologic studies in young children.
背景 呼吸道合胞病毒（RSV）是导致 2 岁儿童急性下呼吸道感染的主要原因。通常通过 RSV 抗体来确定儿童是否曾感染过 RSV；然而，在幼儿中，持续存在的母体免疫球蛋白 G 抗体可能会错误地提示儿童曾感染过 RSV。我们用 RSV F、G 亚群（Ga 或 Gb 蛋白）或 RSV 裂解抗原开发并评估了 4 种免疫球蛋白 A (IgA) 抗体酶联免疫测定 (EIA)，以区分感染诱导的母体 RSV 抗体和持续存在的母体 RSV 抗体。方法 我们对 62 份脐带血标本（A 组）、39 份未暴露于 RSV 季节的婴儿血浆标本（B 组）、102 份有 RSV 感染记录的婴儿血浆标本（C 组）和 124 份暴露于第一个 RSV 季节但无 RSV 感染记录的婴儿血浆标本（D 组）进行了 EIA 检测。结果 在 2 个阴性对照组中，没有 A 组标本和 1 个 B 组标本在所有 4 种 IgA EIA 中均呈阳性，特异性分别为 100%和 97%。对于 C 组标本，F、Ga、Gb 和裂解液 IgA EIA 的灵敏度分别为 88%、31%、26% 和 61%。在 D 组的 124 份标本中，44% 的标本在 RSV-F IgA EIA 中呈阳性。结论 RSV-F 蛋白 IgA EIA 在检测存在母体抗体的既往 RSV 感染方面具有很高的灵敏度和特异性，有助于幼儿 RSV 临床试验和流行病学研究。
{"title":"Evaluation of Immunoglobulin A Enzyme Immunoassays to Detect Primary Respiratory Syncytial Virus Infection in Infants and Young Children","authors":"Ranjini Sankaranarayanan, Binh Ha, Heying Sun, Katie Liu, Samadhan Jadhao, Laila Hussaini, Courtney McCracken, Theda Gibson, Inci Yildirim, Jumi Yi, Kathy Stephens, Chelsea Korski, Carol Kao, Christina A Rostad, Evan J Anderson, Larry J Anderson","doi":"10.1093/infdis/jiae514","DOIUrl":"https://doi.org/10.1093/infdis/jiae514","url":null,"abstract":"Background Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory infections in children &lt;2 years of age. Prior infection in a child is usually determined by RSV antibodies; however, in young children, persisting maternal immunoglobulin G antibodies can incorrectly indicate past RSV infection. We developed and evaluated 4 immunoglobulin A (IgA) antibody enzyme immunoassays (EIAs) with the RSV F, subgroup G (Ga or Gb proteins) or RSV lysate antigens to distinguish infection induced from persisting maternal RSV antibodies. Methods We tested the EIAs against 62 cord blood specimens (group A), 39 plasma specimens from infants not exposed to an RSV season (group B), 102 plasma specimens from infants with a documented RSV infection (group C), and 124 plasma specimens from infants exposed to their first RSV season but without a documented RSV infection (group D). Results Among the 2 negative control groups, no group A specimens and 1 of the group B specimens were positive in all 4 IgA EIAs, giving a specificity of 100% and 97%, respectively. The sensitivity of the F, Ga, Gb, and Lysate IgA EIAs were 88%, 31%, 26%, and 61%, respectively, for group C specimens. Forty-four percent of the 124 specimens in group D were positive in the RSV-F IgA EIA. Conclusions The RSV-F protein IgA EIA exhibited a high level of sensitivity and specificity for detecting previous RSV infections in the presence of maternal antibodies and can help in RSV clinical trials and epidemiologic studies in young children.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"63 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142684287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chlamydia psittaci is a zoonotic pathogen known to cause respiratory diseases in humans. Chlamydia infections are closely associated with apoptosis, in which miRNAs play regulatory roles. Herein, we demonstrated that C. psittaci infection induces apoptosis in human bronchial epithelial (HBE) cells and investigated regulatory mechanism involving miR-124-3p and the PI3K/AKT signaling pathway. Following C. psittaci infection in HBE cells, we observed an elevated of HBE cells apoptosis, accompanied by upregulation of miR-124-3p levels. Mechanistically, we identified EIF3B as a novel target gene of miR-124-3p, supported by the inverse correlation of their mRNA expressions. MiR-124-3p inhibitors reduced apoptosis induced by C. psittaci, increased the replication of C. psittaci and inhibited the PI3K/AKT activated, whereas miR-124-3p mimics produced opposite effects, and transfection with EIF3B siRNA reversed the effects of miR-124-3p inhibitors. Our findings suggest that miR-124-3p targeting EIF3B promotes apoptosis in C. psittaci-infected HBE cells through the activation of PI3K/AKT signaling pathway.
{"title":"MiR-124-3p/EIF3B regulates host cell apoptosis induced by Chlamydia psittaci through PI3K/AKT signaling pathway","authors":"Ting Tong, Yunfei Li, You Zhou, Xindian Zeng, Cui Xiao, Saihong Cao, Chuan Wang, Zhongyu Li, Zhou zhou, Qinqin Bai, Shenghua Chen, Shuwu Yan, Lili Chen","doi":"10.1093/infdis/jiae573","DOIUrl":"https://doi.org/10.1093/infdis/jiae573","url":null,"abstract":"Chlamydia psittaci is a zoonotic pathogen known to cause respiratory diseases in humans. Chlamydia infections are closely associated with apoptosis, in which miRNAs play regulatory roles. Herein, we demonstrated that C. psittaci infection induces apoptosis in human bronchial epithelial (HBE) cells and investigated regulatory mechanism involving miR-124-3p and the PI3K/AKT signaling pathway. Following C. psittaci infection in HBE cells, we observed an elevated of HBE cells apoptosis, accompanied by upregulation of miR-124-3p levels. Mechanistically, we identified EIF3B as a novel target gene of miR-124-3p, supported by the inverse correlation of their mRNA expressions. MiR-124-3p inhibitors reduced apoptosis induced by C. psittaci, increased the replication of C. psittaci and inhibited the PI3K/AKT activated, whereas miR-124-3p mimics produced opposite effects, and transfection with EIF3B siRNA reversed the effects of miR-124-3p inhibitors. Our findings suggest that miR-124-3p targeting EIF3B promotes apoptosis in C. psittaci-infected HBE cells through the activation of PI3K/AKT signaling pathway.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"250 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142672913","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Camille Vellas, Dorine Martres, Mary Requena, Manon Nayrac, Nived Collercandy, Justine Latour, Karl Barange, Laurent Alric, Guillaume Martin-Blondel, Jacques Izopet, Bernard Lagane, Pierre Delobel
Background The persistence of latently infected cells prevents a cure of HIV. The intestinal mucosa contains numerous target cells, and high levels of HIV-1 DNA persist in this compartment under ART. While CD4+ T cells are the best characterized reservoir of HIV-1, the role of long-lived intestinal macrophages in HIV-1 persistence on ART remains controversial. Methods We collected duodenal and colonic biopsies from 12 people living with HIV (PLWH) on suppressive ART, enrolled in the ARNS EP61 GALT study. Total, integrated, intact and defective HIV-1 proviruses were quantified from sorted T cells and monocytes/macrophages. HIV-1 env quasispecies were analyzed by single-molecule next-generation sequencing and env-pseudotyped viruses were constructed to assess macrophage versus T-tropism. Results Total HIV-1 DNA levels in intestinal T cells were significantly higher than those in monocytes/macrophages (P<0.0001). Unintegrated HIV-1 DNA was detected in one-third of T-cell and monocyte/macrophage-positive samples. Intact HIV-1 proviruses were detected using the intact proviral DNA assay in 4/16 T-cell samples and 1/6 monocyte/macrophage samples with detectable HIV-1 DNA. HIV-1 sequences were compartmentalized between intestinal monocytes/macrophages and T cells in some subjects. Phenotypic analysis of pseudotyped viruses expressing HIV-1 envelopes from colonic monocytes/macrophages revealed T-tropism rather than M-tropism. Conclusions Our results show that monocytes/macrophages from the intestinal mucosa of PLWH on ART can contain HIV-1 DNA, including intact or unintegrated forms, but at much lower levels than those found in T cells, and with some compartmentalization although they do not exhibit a specific macrophage tropism, raising the question of the mechanisms of infection involved.
背景潜伏感染细胞的持续存在阻碍了艾滋病毒的治愈。肠道粘膜含有大量靶细胞，在抗逆转录病毒疗法的作用下，高水平的 HIV-1 DNA 会持续存在于这一区域。CD4+ T 细胞是特征最明显的 HIV-1 储存库，而长效肠巨噬细胞在抗逆转录病毒疗法中持续存在 HIV-1 的作用仍存在争议。方法 我们收集了参加 ARNS EP61 GALT 研究的 12 名接受抑制性抗逆转录病毒疗法的 HIV 感染者（PLWH）的十二指肠和结肠活检组织。我们对分选的 T 细胞和单核细胞/巨噬细胞中的 HIV-1 总病毒、整合病毒、完整病毒和缺陷病毒进行了定量分析。通过单分子下一代测序分析了 HIV-1 env quasispecies，并构建了 env 假型病毒，以评估巨噬细胞与 T 细胞之间的相互影响。结果 肠道 T 细胞中的 HIV-1 DNA 总含量明显高于单核细胞/巨噬细胞（P<0.0001）。三分之一的 T 细胞和单核细胞/巨噬细胞阳性样本中检测到未整合的 HIV-1 DNA。在 4/16 份 T 细胞样本和 1/6 份可检测到 HIV-1 DNA 的单核细胞/巨噬细胞样本中，使用完整前病毒 DNA 检测法检测到了完整的 HIV-1 前病毒。一些受试者的肠道单核细胞/巨噬细胞和 T 细胞之间存在 HIV-1 序列分区。对结肠单核细胞/巨噬细胞中表达 HIV-1 包膜的伪型病毒进行表型分析，发现其具有 T 向性而非 M 向性。结论 我们的研究结果表明，接受抗逆转录病毒疗法的 PLWH 肠粘膜单核细胞/巨噬细胞可含有 HIV-1 DNA，包括完整或未整合的形式，但其含量远低于在 T 细胞中发现的含量，而且具有一定的区隔性，尽管它们并不表现出特定的巨噬细胞滋养性，这就提出了相关感染机制的问题。
{"title":"Compartmentalized HIV-1 reservoir in intestinal monocytes/macrophages on antiretroviral therapy","authors":"Camille Vellas, Dorine Martres, Mary Requena, Manon Nayrac, Nived Collercandy, Justine Latour, Karl Barange, Laurent Alric, Guillaume Martin-Blondel, Jacques Izopet, Bernard Lagane, Pierre Delobel","doi":"10.1093/infdis/jiae557","DOIUrl":"https://doi.org/10.1093/infdis/jiae557","url":null,"abstract":"Background The persistence of latently infected cells prevents a cure of HIV. The intestinal mucosa contains numerous target cells, and high levels of HIV-1 DNA persist in this compartment under ART. While CD4+ T cells are the best characterized reservoir of HIV-1, the role of long-lived intestinal macrophages in HIV-1 persistence on ART remains controversial. Methods We collected duodenal and colonic biopsies from 12 people living with HIV (PLWH) on suppressive ART, enrolled in the ARNS EP61 GALT study. Total, integrated, intact and defective HIV-1 proviruses were quantified from sorted T cells and monocytes/macrophages. HIV-1 env quasispecies were analyzed by single-molecule next-generation sequencing and env-pseudotyped viruses were constructed to assess macrophage versus T-tropism. Results Total HIV-1 DNA levels in intestinal T cells were significantly higher than those in monocytes/macrophages (P&lt;0.0001). Unintegrated HIV-1 DNA was detected in one-third of T-cell and monocyte/macrophage-positive samples. Intact HIV-1 proviruses were detected using the intact proviral DNA assay in 4/16 T-cell samples and 1/6 monocyte/macrophage samples with detectable HIV-1 DNA. HIV-1 sequences were compartmentalized between intestinal monocytes/macrophages and T cells in some subjects. Phenotypic analysis of pseudotyped viruses expressing HIV-1 envelopes from colonic monocytes/macrophages revealed T-tropism rather than M-tropism. Conclusions Our results show that monocytes/macrophages from the intestinal mucosa of PLWH on ART can contain HIV-1 DNA, including intact or unintegrated forms, but at much lower levels than those found in T cells, and with some compartmentalization although they do not exhibit a specific macrophage tropism, raising the question of the mechanisms of infection involved.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142672987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Deng B Madut, Matthew P Rubach, Kathryn J Allan, Kate M Thomas, William A de Glanville, Jo E B Halliday, Cristina Costales, Manuela Carugati, Robert J Rolfe, John P Bonnewell, Michael J Maze, Alex R Mremi, Patrick T Amsi, Nathaniel H Kalengo, Furaha Lyamuya, Grace D Kinabo, Ronald Mbwasi, Kajiru G Kilonzo, Venance P Maro, Blandina T Mmbaga, Bingileki Lwezaula, Calvin Mosha, Annette Marandu, Tito J Kibona, Feng Zhu, Tanu Chawla, Wan Ni Chia, Danielle E Anderson, Lin-Fa Wang, Jie Liu, Eric R Houpt, Roosecelis B Martines, Sherif R Zaki, Austin Leach, Aridth Gibbons, Cheng-Feng Chiang, Ketan Patel, John D Klena, Sarah Cleaveland, John A Crump
Background A peri-urban outbreak of Rift Valley fever virus (RVFV) among dairy cattle from May through August 2018 in northern Tanzania was detected through testing samples from prospective livestock abortion surveillance. We sought to identify concurrent human infections, their phylogeny, and epidemiologic characteristics in a cohort of febrile patients enrolled from 2016-2019 at hospitals serving the epizootic area. Methods From September 2016 through May 2019, we conducted a prospective cohort study that enrolled febrile patients hospitalized at two hospitals in Moshi, Tanzania. Archived serum, plasma, or whole blood samples were retrospectively tested for RVFV by PCR. Human samples positive for RVFV were sequenced and compared to RVFV sequences obtained from cattle through a prospective livestock abortion study. Phylogenetic analysis was performed on complete RVFV genomes. Results Among 656 human participants, we detected RVFV RNA in four (0.6%), including one death with hepatic necrosis and other end-organ damage at autopsy. Humans infected with RVFV were enrolled from June through August 2018, and all resided in or near urban areas. Phylogenetic analysis of human and cattle RVFV sequences demonstrated that most clustered to lineage B, a lineage previously described in East Africa. A lineage E strain clustering with lineages in Angola was also identified in cattle. Conclusion We provide evidence that an apparently small RVFV outbreak among dairy cattle in northern Tanzania was associated with concurrent severe and fatal infections among humans. Our findings highlight the unidentified scale and diversity of inter-epizootic RVFV transmission, including near and within an urban area.
{"title":"Epidemiologic and genomic characterization of an outbreak of Rift Valley fever among humans and dairy cattle in northern Tanzania","authors":"Deng B Madut, Matthew P Rubach, Kathryn J Allan, Kate M Thomas, William A de Glanville, Jo E B Halliday, Cristina Costales, Manuela Carugati, Robert J Rolfe, John P Bonnewell, Michael J Maze, Alex R Mremi, Patrick T Amsi, Nathaniel H Kalengo, Furaha Lyamuya, Grace D Kinabo, Ronald Mbwasi, Kajiru G Kilonzo, Venance P Maro, Blandina T Mmbaga, Bingileki Lwezaula, Calvin Mosha, Annette Marandu, Tito J Kibona, Feng Zhu, Tanu Chawla, Wan Ni Chia, Danielle E Anderson, Lin-Fa Wang, Jie Liu, Eric R Houpt, Roosecelis B Martines, Sherif R Zaki, Austin Leach, Aridth Gibbons, Cheng-Feng Chiang, Ketan Patel, John D Klena, Sarah Cleaveland, John A Crump","doi":"10.1093/infdis/jiae562","DOIUrl":"https://doi.org/10.1093/infdis/jiae562","url":null,"abstract":"Background A peri-urban outbreak of Rift Valley fever virus (RVFV) among dairy cattle from May through August 2018 in northern Tanzania was detected through testing samples from prospective livestock abortion surveillance. We sought to identify concurrent human infections, their phylogeny, and epidemiologic characteristics in a cohort of febrile patients enrolled from 2016-2019 at hospitals serving the epizootic area. Methods From September 2016 through May 2019, we conducted a prospective cohort study that enrolled febrile patients hospitalized at two hospitals in Moshi, Tanzania. Archived serum, plasma, or whole blood samples were retrospectively tested for RVFV by PCR. Human samples positive for RVFV were sequenced and compared to RVFV sequences obtained from cattle through a prospective livestock abortion study. Phylogenetic analysis was performed on complete RVFV genomes. Results Among 656 human participants, we detected RVFV RNA in four (0.6%), including one death with hepatic necrosis and other end-organ damage at autopsy. Humans infected with RVFV were enrolled from June through August 2018, and all resided in or near urban areas. Phylogenetic analysis of human and cattle RVFV sequences demonstrated that most clustered to lineage B, a lineage previously described in East Africa. A lineage E strain clustering with lineages in Angola was also identified in cattle. Conclusion We provide evidence that an apparently small RVFV outbreak among dairy cattle in northern Tanzania was associated with concurrent severe and fatal infections among humans. Our findings highlight the unidentified scale and diversity of inter-epizootic RVFV transmission, including near and within an urban area.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142610066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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