Pub Date : 2024-06-25eCollection Date: 2024-01-01DOI: 10.20411/pai.v9i2.705
Nika Zielinski, Dragos Baiceanu, Antonela Dragomir, Jan Heyckendorf, Elmira Ibraim, Niklas Köhler, Christoph Leschczyk, Cristina Popa, Andrea Rachow, Jens Sachsenweger, Patricia Sanchez Carballo, Dagmar Schaub, Hajo Zeeb, Begna Tulu, Andrew R DiNardo, Christoph Lange, Maja Reimann
Background: Neuropathic adverse events occur frequently in linezolid-containing regimens, some of which remain irreversible after drug discontinuation.
Objective: We aimed to identify and validate a host RNA-based biomarker that can predict linezolid-associated neuropathy before multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) treatment initiation and to identify genes and pathways that are associated with linezolid-associated neuropathy.
Methods: Adult patients initiating MDR/RR-TB treatment including linezolid were prospectively enrolled in 3 independent cohorts in Germany. Clinical data and whole blood RNA for transcriptomic analysis were collected. The primary outcome was linezolid-associated optic and/or peripheral neuropathy. A random forest algorithm was used for biomarker identification. The biomarker was validated in an additional fourth cohort of patients with MDR/RR-TB from Romania.
Results: A total of 52 patients from the 3 identification cohorts received linezolid treatment. Of those, 24 (46.2%) developed peripheral and/or optic neuropathies during linezolid treatment. The majority (59.3%) of the episodes were of moderate (grade 2) severity. In total, the expression of 1,479 genes differed significantly at baseline of treatment. Suprabasin (SBSN) was identified as a potential biomarker to predict linezolid-associated neuropathy. In the validation cohort, 10 of 42 (23.8%) patients developed grade ≥3 neuropathies. The area under the curve for the biomarker algorithm prediction of grade ≥3 neuropathies was 0.63 (poor; 95% confidence interval: 0.42 - 0.84).
Conclusions: We identified and preliminarily validated a potential clinical biomarker to predict linezolid-associated neuropathies before the initiation of MDR/RR-TB therapy. Larger studies of the SBSN biomarker in more diverse populations are warranted.
{"title":"A Transcriptomic Biomarker Predicting Linezolid-Associated Neuropathy During Treatment of Drug-Resistant Tuberculosis.","authors":"Nika Zielinski, Dragos Baiceanu, Antonela Dragomir, Jan Heyckendorf, Elmira Ibraim, Niklas Köhler, Christoph Leschczyk, Cristina Popa, Andrea Rachow, Jens Sachsenweger, Patricia Sanchez Carballo, Dagmar Schaub, Hajo Zeeb, Begna Tulu, Andrew R DiNardo, Christoph Lange, Maja Reimann","doi":"10.20411/pai.v9i2.705","DOIUrl":"10.20411/pai.v9i2.705","url":null,"abstract":"<p><strong>Background: </strong>Neuropathic adverse events occur frequently in linezolid-containing regimens, some of which remain irreversible after drug discontinuation.</p><p><strong>Objective: </strong>We aimed to identify and validate a host RNA-based biomarker that can predict linezolid-associated neuropathy before multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) treatment initiation and to identify genes and pathways that are associated with linezolid-associated neuropathy.</p><p><strong>Methods: </strong>Adult patients initiating MDR/RR-TB treatment including linezolid were prospectively enrolled in 3 independent cohorts in Germany. Clinical data and whole blood RNA for transcriptomic analysis were collected. The primary outcome was linezolid-associated optic and/or peripheral neuropathy. A random forest algorithm was used for biomarker identification. The biomarker was validated in an additional fourth cohort of patients with MDR/RR-TB from Romania.</p><p><strong>Results: </strong>A total of 52 patients from the 3 identification cohorts received linezolid treatment. Of those, 24 (46.2%) developed peripheral and/or optic neuropathies during linezolid treatment. The majority (59.3%) of the episodes were of moderate (grade 2) severity. In total, the expression of 1,479 genes differed significantly at baseline of treatment. Suprabasin (<i>SBSN</i>) was identified as a potential biomarker to predict linezolid-associated neuropathy. In the validation cohort, 10 of 42 (23.8%) patients developed grade ≥3 neuropathies. The area under the curve for the biomarker algorithm prediction of grade ≥3 neuropathies was 0.63 (poor; 95% confidence interval: 0.42 - 0.84).</p><p><strong>Conclusions: </strong>We identified and preliminarily validated a potential clinical biomarker to predict linezolid-associated neuropathies before the initiation of MDR/RR-TB therapy. Larger studies of the <i>SBSN</i> biomarker in more diverse populations are warranted.</p>","PeriodicalId":36419,"journal":{"name":"Pathogens and Immunity","volume":"9 2","pages":"25-42"},"PeriodicalIF":0.0,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11210591/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141471245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-18eCollection Date: 2024-01-01DOI: 10.20411/pai.v9i2.679
Ruth I Connor, Mrunal Sakharkar, C Garrett Rappazzo, Chengzi I Kaku, Nicholas C Curtis, Seungmin Shin, Wendy F Wieland-Alter, Jordan Wentworth, Daniel W Mielcarz, Joshua A Weiner, Margaret E Ackerman, Laura M Walker, Jiwon Lee, Peter F Wright
Background: Fcγ-receptor (FcγR)-independent enhancement of SARS-CoV-2 infection mediated by N-terminal domain (NTD)-binding monoclonal antibodies (mAbs) has been observed in vitro, but the functional significance of these antibodies in vivo is less clear.
Methods: We characterized 1,213 SARS-CoV-2 spike (S)-binding mAbs derived from COVID-19 convalescent patients for binding specificity to the SARS-CoV-2 S protein, VH germ-line usage, and affinity maturation. Infection enhancement in a vesicular stomatitis virus (VSV)-SARS-CoV-2 S pseudovirus (PV) assay was characterized in respiratory and intestinal epithelial cell lines, and against SARS-CoV-2 variants of concern (VOC). Proteomic deconvolution of the serum antibody repertoire was used to determine functional attributes of secreted NTD-binding mAbs.
Results: We identified 72/1213 (5.9%) mAbs that enhanced SARS-CoV-2 infection in a PV assay. The majority (68%) of these mAbs recognized the NTD, were identified in patients with mild and severe disease, and persisted for at least 5 months post-infection. Infection enhancement by NTD-binding mAbs was not observed in intestinal and respiratory epithelial cell lines and was diminished or lost against SARS-CoV-2 VOC. Proteomic deconvolution of the serum antibody repertoire from 2 of the convalescent patients identified, for the first time, NTD-binding, infection-enhancing mAbs among the circulating immunoglobulins directly isolated from serum. Functional analysis of these mAbs demonstrated robust activation of FcγRIIIa associated with antibody binding to recombinant S proteins.
Conclusions: Functionally active NTD-specific mAbs arise frequently during natural infection and can last as major serum clonotypes during convalescence. These antibodies display functional attributes that include FcγR activation, and may be selected against by mutations in NTD associated with SARS-CoV-2 VOC.
{"title":"Characteristics and Functions of Infection-enhancing Antibodies to the N-terminal Domain of SARS-CoV-2.","authors":"Ruth I Connor, Mrunal Sakharkar, C Garrett Rappazzo, Chengzi I Kaku, Nicholas C Curtis, Seungmin Shin, Wendy F Wieland-Alter, Jordan Wentworth, Daniel W Mielcarz, Joshua A Weiner, Margaret E Ackerman, Laura M Walker, Jiwon Lee, Peter F Wright","doi":"10.20411/pai.v9i2.679","DOIUrl":"10.20411/pai.v9i2.679","url":null,"abstract":"<p><strong>Background: </strong>Fcγ-receptor (FcγR)-independent enhancement of SARS-CoV-2 infection mediated by N-terminal domain (NTD)-binding monoclonal antibodies (mAbs) has been observed <i>in vitro</i>, but the functional significance of these antibodies <i>in vivo</i> is less clear.</p><p><strong>Methods: </strong>We characterized 1,213 SARS-CoV-2 spike (S)-binding mAbs derived from COVID-19 convalescent patients for binding specificity to the SARS-CoV-2 S protein, VH germ-line usage, and affinity maturation. Infection enhancement in a vesicular stomatitis virus (VSV)-SARS-CoV-2 S pseudovirus (PV) assay was characterized in respiratory and intestinal epithelial cell lines, and against SARS-CoV-2 variants of concern (VOC). Proteomic deconvolution of the serum antibody repertoire was used to determine functional attributes of secreted NTD-binding mAbs.</p><p><strong>Results: </strong>We identified 72/1213 (5.9%) mAbs that enhanced SARS-CoV-2 infection in a PV assay. The majority (68%) of these mAbs recognized the NTD, were identified in patients with mild and severe disease, and persisted for at least 5 months post-infection. Infection enhancement by NTD-binding mAbs was not observed in intestinal and respiratory epithelial cell lines and was diminished or lost against SARS-CoV-2 VOC. Proteomic deconvolution of the serum antibody repertoire from 2 of the convalescent patients identified, for the first time, NTD-binding, infection-enhancing mAbs among the circulating immunoglobulins directly isolated from serum. Functional analysis of these mAbs demonstrated robust activation of FcγRIIIa associated with antibody binding to recombinant S proteins.</p><p><strong>Conclusions: </strong>Functionally active NTD-specific mAbs arise frequently during natural infection and can last as major serum clonotypes during convalescence. These antibodies display functional attributes that include FcγR activation, and may be selected against by mutations in NTD associated with SARS-CoV-2 VOC.</p>","PeriodicalId":36419,"journal":{"name":"Pathogens and Immunity","volume":"9 2","pages":"1-24"},"PeriodicalIF":0.0,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11197847/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141459756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
It is widely acknowledged that HIV infection results in disruption of the gut’s mucosal integrity partly due a profound loss of gastrointestinal CD4+ T cells that are targets of the virus. In addition, systemic inflammation and immune activation that drive disease pathogenesis are reduced but not normalized by antiretroviral therapy (ART). It has long been postulated that through the process of microbial translocation, the gut microbiome acts as a key driver of systemic inflammation and immune recovery in HIV infection. As such, many studies have aimed at characterizing the gut microbiota in order to unravel its influence in people with HIV and have reported an association between various bacterial taxa and inflammation. This review assesses both contradictory and consistent findings among several studies in order to clarify the overall mechanisms by which the gut microbiota in adults may influence immune recovery in HIV infection. Independently of the gut microbiome, observations made from analysis of microbial products in the blood provide direct insight into how the translocated microbiome may drive immune recovery. To help better understand strengths and limitations of the findings reported, this review also highlights the numerous factors that can influence microbiome studies, be they experimental methodologies, and host-intrinsic or host-extrinsic factors. Altogether, a fuller understanding of the interplay between the gut microbiome and immunity in HIV infection may contribute to preventive and therapeutic approaches.
人们普遍认为，艾滋病病毒感染会破坏肠道粘膜的完整性，部分原因是作为病毒攻击目标的胃肠道 CD4+ T 细胞大量丧失。此外，抗逆转录病毒疗法（ART）可减轻但无法恢复正常的全身炎症和免疫激活，而这正是疾病发病机制的驱动因素。长期以来，人们一直推测肠道微生物组通过微生物转运过程，在艾滋病病毒感染中扮演着全身炎症和免疫恢复的关键驱动角色。因此，许多研究旨在描述肠道微生物群的特征，以揭示其对艾滋病病毒感染者的影响，并报告了各种细菌类群与炎症之间的关联。本综述评估了几项研究中相互矛盾和一致的发现，以阐明成人肠道微生物群可能影响艾滋病病毒感染者免疫恢复的总体机制。与肠道微生物群无关，通过对血液中微生物产物的分析观察，可以直接了解转运微生物群如何推动免疫恢复。为了帮助更好地理解所报道研究结果的优势和局限性，本综述还强调了可能影响微生物组研究的众多因素，无论是实验方法、宿主内在因素还是宿主外在因素。总之，更全面地了解艾滋病毒感染中肠道微生物组与免疫之间的相互作用可能有助于预防和治疗方法。
{"title":"The Gut and the Translocated Microbiomes in HIV Infection: Current Concepts and Future Avenues","authors":"Krystelle Nganou-Makamdop, Daniel C. Douek","doi":"10.20411/pai.v9i1.693","DOIUrl":"https://doi.org/10.20411/pai.v9i1.693","url":null,"abstract":"It is widely acknowledged that HIV infection results in disruption of the gut’s mucosal integrity partly due a profound loss of gastrointestinal CD4+ T cells that are targets of the virus. In addition, systemic inflammation and immune activation that drive disease pathogenesis are reduced but not normalized by antiretroviral therapy (ART). It has long been postulated that through the process of microbial translocation, the gut microbiome acts as a key driver of systemic inflammation and immune recovery in HIV infection. As such, many studies have aimed at characterizing the gut microbiota in order to unravel its influence in people with HIV and have reported an association between various bacterial taxa and inflammation. This review assesses both contradictory and consistent findings among several studies in order to clarify the overall mechanisms by which the gut microbiota in adults may influence immune recovery in HIV infection. Independently of the gut microbiome, observations made from analysis of microbial products in the blood provide direct insight into how the translocated microbiome may drive immune recovery. To help better understand strengths and limitations of the findings reported, this review also highlights the numerous factors that can influence microbiome studies, be they experimental methodologies, and host-intrinsic or host-extrinsic factors. Altogether, a fuller understanding of the interplay between the gut microbiome and immunity in HIV infection may contribute to preventive and therapeutic approaches.","PeriodicalId":36419,"journal":{"name":"Pathogens and Immunity","volume":"90 12","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141100960","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}
Samir Memic, Claire Kaple, Jennifer Cadnum, Curtis Donskey
Background: Technologies that provides safe and effective decontamination of surfaces and equipment between episodes of manual cleaning could be an important advance in efforts to prevent transmission of the emerging fungal pathogen Candida auris. Methods: We tested the efficacy of a novel wall-mounted far ultraviolet-C (UV-C) light technology that delivers far UV-C, when people are not detected within the field of illumination, against C. auris isolates from clades I, II, III, and IV using a quantitative disk carrier test method. In an equipment room, we examined the efficacy of the technology in reducing an isolate of C. auris from clade IV inoculated on multiple sites on portable devices. Results: The far UV-C technology reduced isolates from all 4 clades of C. auris by >3 log10 colony-forming units (CFU) after an 8-hour exposure on steel disks. For the clade IV isolate, similar reductions were achieved on glass and plastic carriers. In the equipment room, the technology reduced C. auris inoculated on multiple sites on portable equipment by >2 log10 CFU in 4 hours. Conclusions: The far UV-C technology could be useful for decontamination of surfaces and equipment between episodes of manual cleaning. Additional studies are needed to evaluate the use of the technology in clinical settings.
背景：在两次人工清洁之间对表面和设备进行安全有效净化的技术，是防止新出现的真菌病原体念珠菌传播的重要进步：我们测试了一种新型壁挂式远紫外-C (UV-C) 光技术的功效，该技术可在照明范围内检测不到人的情况下提供远紫外-C 光，并采用定量盘载体测试方法来检测 I、II、III 和 IV 支系的白色念珠菌分离物。我们在一间设备房中检验了该技术在减少接种于便携式设备多个部位的 IV 支系球孢子菌分离株方面的功效。结果显示在钢盘上暴露 8 小时后，远紫外线-C 技术可将所有 4 个支系的球孢子菌分离物减少 >3 log10 菌落总数 (CFU)。对于 IV 支系的分离物，在玻璃和塑料载体上也实现了类似的减少。在设备间，该技术可在 4 小时内将多处接种在便携式设备上的 C. auris 减少 >2 log10 CFU。结论：远紫外线-C 技术可用于在人工清洁间隙对表面和设备进行净化。需要进行更多的研究来评估该技术在临床环境中的应用。
{"title":"Evaluation of an Automated Wall-mounted Far Ultraviolet-C Light Technology for Continuous or Intermittent Decontamination of Candida auris on Surfaces","authors":"Samir Memic, Claire Kaple, Jennifer Cadnum, Curtis Donskey","doi":"10.20411/pai.v9i1.683","DOIUrl":"https://doi.org/10.20411/pai.v9i1.683","url":null,"abstract":"Background: Technologies that provides safe and effective decontamination of surfaces and equipment between episodes of manual cleaning could be an important advance in efforts to prevent transmission of the emerging fungal pathogen Candida auris.\u0000Methods: We tested the efficacy of a novel wall-mounted far ultraviolet-C (UV-C) light technology that delivers far UV-C, when people are not detected within the field of illumination, against C. auris isolates from clades I, II, III, and IV using a quantitative disk carrier test method. In an equipment room, we examined the efficacy of the technology in reducing an isolate of C. auris from clade IV inoculated on multiple sites on portable devices. \u0000Results: The far UV-C technology reduced isolates from all 4 clades of C. auris by >3 log10 colony-forming units (CFU) after an 8-hour exposure on steel disks. For the clade IV isolate, similar reductions were achieved on glass and plastic carriers. In the equipment room, the technology reduced C. auris inoculated on multiple sites on portable equipment by >2 log10 CFU in 4 hours. \u0000Conclusions: The far UV-C technology could be useful for decontamination of surfaces and equipment between episodes of manual cleaning. Additional studies are needed to evaluate the use of the technology in clinical settings. ","PeriodicalId":36419,"journal":{"name":"Pathogens and Immunity","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140962534","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}
Pub Date : 2024-05-06eCollection Date: 2024-01-01DOI: 10.20411/pai.v9i1.660
Katya C Corado, Kara W Chew, Mark J Giganti, Ying Mu, Courtney V Fletcher, Judith S Currier, Eric S Daar, David A Wohl, Jonathan Z Li, Carlee B Moser, Justin Ritz, Arzhang Cyrus Javan, Gene Neytman, Marina Caskey, Michael D Hughes, Davey M Smith, Joseph J Eron
Background: Outpatient COVID-19 monoclonal antibody (mAb) treatment via subcutaneous delivery, if effective, overcomes the logistical burdens of intravenous administration.
Methods: ACTIV-2/A5401 was a randomized, masked placebo-controlled platform trial where participants with COVID-19 at low risk for progression were randomized 1:1 to subcutaneously administered BMS-986414 (C135-LS) 200 mg, plus BMS-986413 (C144-LS) 200 mg, (BMS mAbs), or placebo. Coprimary outcomes were time to symptom improvement through 28 days; nasopharyngeal SARS-CoV-2 RNA below the lower limit of quantification (LLoQ) on days 3, 7, or 14; and treatment-emergent grade 3 or higher adverse events (TEAEs) through 28 days.
Results: A total of 211 participants (105 BMS mAbs and 106 placebo) initiated study product. Time to symptom improvement favored the active therapy but was not significant (median 8 vs 10 days, P=0.19). There was no significant difference in the proportion with SARS-CoV-2 RNA
Conclusions: While safe, the BMS mAbs delivered subcutaneously were not effective at treating COVID-19 at low risk for progression. The lack of clinically significant activity may relate to the pharmacokinetics of subcutaneous administration of mAbs.
{"title":"Safety, Efficacy, and Pharmacokinetics of Combination SARS-CoV-2 Neutralizing Monoclonal Antibodies BMS-986414 (C135-LS) and BMS-986413 (C144-LS) Administered Subcutaneously in Non-Hospitalized Persons with COVID-19 in a Phase 2 Trial.","authors":"Katya C Corado, Kara W Chew, Mark J Giganti, Ying Mu, Courtney V Fletcher, Judith S Currier, Eric S Daar, David A Wohl, Jonathan Z Li, Carlee B Moser, Justin Ritz, Arzhang Cyrus Javan, Gene Neytman, Marina Caskey, Michael D Hughes, Davey M Smith, Joseph J Eron","doi":"10.20411/pai.v9i1.660","DOIUrl":"10.20411/pai.v9i1.660","url":null,"abstract":"<p><strong>Background: </strong>Outpatient COVID-19 monoclonal antibody (mAb) treatment via subcutaneous delivery, if effective, overcomes the logistical burdens of intravenous administration.</p><p><strong>Methods: </strong>ACTIV-2/A5401 was a randomized, masked placebo-controlled platform trial where participants with COVID-19 at low risk for progression were randomized 1:1 to subcutaneously administered BMS-986414 (C135-LS) 200 mg, plus BMS-986413 (C144-LS) 200 mg, (BMS mAbs), or placebo. Coprimary outcomes were time to symptom improvement through 28 days; nasopharyngeal SARS-CoV-2 RNA below the lower limit of quantification (LLoQ) on days 3, 7, or 14; and treatment-emergent grade 3 or higher adverse events (TEAEs) through 28 days.</p><p><strong>Results: </strong>A total of 211 participants (105 BMS mAbs and 106 placebo) initiated study product. Time to symptom improvement favored the active therapy but was not significant (median 8 vs 10 days, <i>P</i>=0.19). There was no significant difference in the proportion with SARS-CoV-2 RNA <LLoQ at day 3 (risk ratio [RR] for BMS mAbs versus placebo: 1.03; 95%CI: 0.80, 1.32), at day 7 (RR: 1.04; 95%CI: 0.94, 1.15), or at day 14 (RR: 1.00; 95%CI: 0.90, 1.12). Fewer grade 3 TEAEs were reported for the BMS mAbs arm than placebo (RR: 0.58 [95%CI: 0.25, 1.32]). Through day 28, there were no deaths, and there were 4 hospitalizations in the BMS mAbs arm versus 3 in the placebo arm. Higher early plasma mAb concentrations were associated with more favorable outcomes.</p><p><strong>Conclusions: </strong>While safe, the BMS mAbs delivered subcutaneously were not effective at treating COVID-19 at low risk for progression. The lack of clinically significant activity may relate to the pharmacokinetics of subcutaneous administration of mAbs.</p>","PeriodicalId":36419,"journal":{"name":"Pathogens and Immunity","volume":"9 1","pages":"138-155"},"PeriodicalIF":0.0,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11093219/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140923213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Dimapasoc, Jose Moran, Steve Cole, Alok Ranjan, Rami Hourani, Jocelyn Kim, Paul A Wender, Matthew Marsden, Jerome Zack
Background: Latency reversing agents (LRAs) such as protein kinase C (PKC) modulators can reduce rebound-competent HIV reservoirs in small animal models. Furthermore, administration of natural killer (NK) cells following LRA treatment improves this reservoir reduction. It is currently unknown why the combination of a PKC modulator and NK cells is so potent and whether exposure to PKC modulators may augment NK cell function in some way. Methods: Primary human NK cells were treated with PKC modulators (bryostatin-1, prostratin, or the designed, synthetic bryostatin-1 analog SUW133), and evaluated by examining expression of activation markers by flow cytometry, analyzing transcriptomic profiles by RNA sequencing, measuring cytotoxicity by co-culturing with K562 cells, assessing cytokine production by Luminex assay, and examining the ability of cytokines and secreted factors to independently reverse HIV latency by co-culturing with Jurkat-Latency (J-Lat) cells. Results: PKC modulators increased expression of proteins involved in NK cell activation. Transcriptomic profiles from PKC-treated NK cells displayed signatures of cellular activation and enrichment of genes associated with the NFκB pathway. NK cell cytotoxicity was unaffected by prostratin but significantly decreased by bryostatin-1 and SUW133. Cytokines from PKC-stimulated NK cells did not induce latency reversal in J-Lat cell lines. Conclusions: Although PKC modulators have some significant effects on NK cells, their contribution in “kick and kill” strategies is likely due to upregulating HIV expression in CD4+ T cells, not directly enhancing the effector functions of NK cells. This suggests that PKC modulators are primarily augmenting the “kick” rather than the “kill” arm of this HIV cure approach.
背景：蛋白激酶 C（PKC）调节剂等潜伏期逆转剂（LRA）可减少小动物模型中具有反弹能力的艾滋病毒储库。此外，在 LRA 治疗后施用自然杀伤（NK）细胞也能改善储库的减少。目前还不清楚为什么 PKC 调节剂和 NK 细胞的结合会如此有效，也不知道接触 PKC 调节剂是否会以某种方式增强 NK 细胞的功能：用PKC调节剂（bryostatin-1、prostatin或设计合成的bryostatin-1类似物SUW133）处理原代人类NK细胞，并通过流式细胞术检测活化标志物的表达，用RNA测序分析转录组图谱、通过与 K562 细胞共培养测定细胞毒性，通过 Luminex 检测法评估细胞因子的产生，以及通过与 Jurkat-Latency (J-Lat) 细胞共培养检测细胞因子和分泌因子独立逆转 HIV 潜伏期的能力。结果显示PKC 调节剂增加了参与 NK 细胞活化的蛋白质的表达。经 PKC 处理的 NK 细胞的转录组图谱显示了细胞活化的特征，并富集了与 NFκB 通路相关的基因。NK细胞的细胞毒性不受prostratin的影响，但受bryostatin-1和SUW133的影响则明显降低。来自 PKC 刺激的 NK 细胞的细胞因子不能诱导 J-Lat 细胞系的潜伏逆转。结论虽然 PKC 调节剂对 NK 细胞有一些显著影响，但它们在 "踢杀 "策略中的作用可能是上调 CD4+ T 细胞中 HIV 的表达，而不是直接增强 NK 细胞的效应功能。这表明，PKC 调节剂主要是增强这种艾滋病毒治疗方法的 "踢 "而不是 "杀 "的作用。
{"title":"Defining the Effects of PKC Modulator HIV Latency-Reversing Agents on Natural Killer Cells","authors":"M. Dimapasoc, Jose Moran, Steve Cole, Alok Ranjan, Rami Hourani, Jocelyn Kim, Paul A Wender, Matthew Marsden, Jerome Zack","doi":"10.20411/pai.v9i1.673","DOIUrl":"https://doi.org/10.20411/pai.v9i1.673","url":null,"abstract":"Background: Latency reversing agents (LRAs) such as protein kinase C (PKC) modulators can reduce rebound-competent HIV reservoirs in small animal models. Furthermore, administration of natural killer (NK) cells following LRA treatment improves this reservoir reduction. It is currently unknown why the combination of a PKC modulator and NK cells is so potent and whether exposure to PKC modulators may augment NK cell function in some way.\u0000Methods: Primary human NK cells were treated with PKC modulators (bryostatin-1, prostratin, or the designed, synthetic bryostatin-1 analog SUW133), and evaluated by examining expression of activation markers by flow cytometry, analyzing transcriptomic profiles by RNA sequencing, measuring cytotoxicity by co-culturing with K562 cells, assessing cytokine production by Luminex assay, and examining the ability of cytokines and secreted factors to independently reverse HIV latency by co-culturing with Jurkat-Latency (J-Lat) cells.\u0000Results: PKC modulators increased expression of proteins involved in NK cell activation. Transcriptomic profiles from PKC-treated NK cells displayed signatures of cellular activation and enrichment of genes associated with the NFκB pathway. NK cell cytotoxicity was unaffected by prostratin but significantly decreased by bryostatin-1 and SUW133. Cytokines from PKC-stimulated NK cells did not induce latency reversal in J-Lat cell lines. \u0000Conclusions: Although PKC modulators have some significant effects on NK cells, their contribution in “kick and kill” strategies is likely due to upregulating HIV expression in CD4+ T cells, not directly enhancing the effector functions of NK cells. This suggests that PKC modulators are primarily augmenting the “kick” rather than the “kill” arm of this HIV cure approach.","PeriodicalId":36419,"journal":{"name":"Pathogens and Immunity","volume":"34 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140665954","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}
C. Jinadatha, Lucas Jones, Jennifer Hailes, Emma Marshall, Munok Hwang, Jennifer Cadnum, Hosoon Choi, Piyali Chatterjee, Ernest Chan, Peter Zimmerman, Nadim G. El Chakhtoura, Elie Saade, C. Donskey
Background: Understanding routes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission in long-term care facilities is essential for the development of effective control measures. Methods: Between March 1, 2020, and August 31, 2023, we identified coronavirus disease 2019 (COVID-19) cases among residents and employees in a Veterans Affairs community living center that conducted routine screening for asymptomatic COVID-19. Contact tracing was conducted to identify suspected transmission events, and whole genome sequencing was performed to determine the relatedness of SARS-CoV-2 samples. Results: During the 42-month study period, 269 cases of COVID-19 were diagnosed, including 199 employees and 70 residents. A total of 48 (24.1%) employees and 30 (42.9%) residents were asymptomatic. Sequencing analysis provided support for multiple events in which employees transmitted SARS-CoV-2 to co-workers and residents. There was 1 episode of likely transmission of SARS-CoV-2 from one resident to another resident, but no documented transmissions from residents to employees. Conclusions: Transmission of SARS-CoV-2 in the community living center predominantly involved transmission from employees to co-workers and residents. There is a need for improved measures to prevent transmission of SARS-CoV-2 by healthcare personnel.
{"title":"Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 Among Residents and Employees in a Veterans Affairs Community Living Center: A 42-Month Prospective Cohort Study","authors":"C. Jinadatha, Lucas Jones, Jennifer Hailes, Emma Marshall, Munok Hwang, Jennifer Cadnum, Hosoon Choi, Piyali Chatterjee, Ernest Chan, Peter Zimmerman, Nadim G. El Chakhtoura, Elie Saade, C. Donskey","doi":"10.20411/pai.v9i1.691","DOIUrl":"https://doi.org/10.20411/pai.v9i1.691","url":null,"abstract":"Background: Understanding routes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission in long-term care facilities is essential for the development of effective control measures. \u0000Methods: Between March 1, 2020, and August 31, 2023, we identified coronavirus disease 2019 (COVID-19) cases among residents and employees in a Veterans Affairs community living center that conducted routine screening for asymptomatic COVID-19. Contact tracing was conducted to identify suspected transmission events, and whole genome sequencing was performed to determine the relatedness of SARS-CoV-2 samples. \u0000Results: During the 42-month study period, 269 cases of COVID-19 were diagnosed, including 199 employees and 70 residents. A total of 48 (24.1%) employees and 30 (42.9%) residents were asymptomatic. Sequencing analysis provided support for multiple events in which employees transmitted SARS-CoV-2 to co-workers and residents. There was 1 episode of likely transmission of SARS-CoV-2 from one resident to another resident, but no documented transmissions from residents to employees. \u0000Conclusions: Transmission of SARS-CoV-2 in the community living center predominantly involved transmission from employees to co-workers and residents. There is a need for improved measures to prevent transmission of SARS-CoV-2 by healthcare personnel.","PeriodicalId":36419,"journal":{"name":"Pathogens and Immunity","volume":"27 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140660601","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}
There are a growing number of studies linking the composition of the human microbiome to disease states and treatment responses, especially in the context of cancer. This has raised significant interest in developing microbes and microbial products as cancer immunotherapeutics that mimic or recapitulate the beneficial effects of host-microbe interactions. Bacterial extracellular vesicles (bEVs) are nano-sized, membrane-bound particles secreted by essentially all bacteria species and contain a diverse bioactive cargo of the producing cell. They have a fundamental role in facilitating interactions among cells of the same species, different microbial species, and even with multicellular host organisms in the context of colonization (microbiome) and infection. The interaction of bEVs with the immune system has been studied extensively in the context of infection and suggests that bEV effects depend largely on the producing species. They thus provide functional diversity, while also being nonreplicative, having inherent cell-targeting qualities, and potentially overcoming natural barriers. These characteristics make them highly appealing for development as cancer immunotherapeutics. Both natively secreted and engineered bEVs are now being investigated for their application as immunotherapeutics, vaccines, drug delivery vehicles, and combinations of the above, with promising early results. This suggests that both the intrinsic immunomodulatory properties of bEVs and their ability to be modified could be harnessed for the development of next-generation microbe-inspired therapies. Nonetheless, there remain major outstanding questions regarding how the observed preclinical effectiveness will translate from murine models to primates, and humans in particular. Moreover, research into the pharmacology, toxicology, and mass manufacturing of this potential novel therapeutic platform is still at early stages. In this review, we highlight the breadth of bEV interactions with host cells, focusing on immunologic effects as the main mechanism of action of bEVs currently in preclinical development. We review the literature on ongoing efforts to develop natively secreted and engineered bEVs from a variety of bacterial species for cancer therapy and finally discuss efforts to overcome outstanding challenges that remain for clinical translation.
{"title":"Harnessing Bacterial Extracellular Vesicle Immune Effects for Cancer Therapy","authors":"Irem Karaman, Asmita Pathak, Defne Bayik, Dionysios Watson","doi":"10.20411/pai.v9i1.657","DOIUrl":"https://doi.org/10.20411/pai.v9i1.657","url":null,"abstract":"There are a growing number of studies linking the composition of the human microbiome to disease states and treatment responses, especially in the context of cancer. This has raised significant interest in developing microbes and microbial products as cancer immunotherapeutics that mimic or recapitulate the beneficial effects of host-microbe interactions. Bacterial extracellular vesicles (bEVs) are nano-sized, membrane-bound particles secreted by essentially all bacteria species and contain a diverse bioactive cargo of the producing cell. They have a fundamental role in facilitating interactions among cells of the same species, different microbial species, and even with multicellular host organisms in the context of colonization (microbiome) and infection. The interaction of bEVs with the immune system has been studied extensively in the context of infection and suggests that bEV effects depend largely on the producing species. They thus provide functional diversity, while also being nonreplicative, having inherent cell-targeting qualities, and potentially overcoming natural barriers. These characteristics make them highly appealing for development as cancer immunotherapeutics. Both natively secreted and engineered bEVs are now being investigated for their application as immunotherapeutics, vaccines, drug delivery vehicles, and combinations of the above, with promising early results. This suggests that both the intrinsic immunomodulatory properties of bEVs and their ability to be modified could be harnessed for the development of next-generation microbe-inspired therapies. Nonetheless, there remain major outstanding questions regarding how the observed preclinical effectiveness will translate from murine models to primates, and humans in particular. Moreover, research into the pharmacology, toxicology, and mass manufacturing of this potential novel therapeutic platform is still at early stages. In this review, we highlight the breadth of bEV interactions with host cells, focusing on immunologic effects as the main mechanism of action of bEVs currently in preclinical development. We review the literature on ongoing efforts to develop natively secreted and engineered bEVs from a variety of bacterial species for cancer therapy and finally discuss efforts to overcome outstanding challenges that remain for clinical translation.","PeriodicalId":36419,"journal":{"name":"Pathogens and Immunity","volume":"54 22","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140667146","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}
Background: The effective elimination of encapsulated bacteria like Haemophilus influenzae type a (Hia) relies on immune mechanisms such as complement-mediated opsonophagocytosis by neutrophils in coordination with opsonization by anti-capsular antibodies. This study evaluated if Hia could activate the immune response through neutrophils and if these responses differed between encapsulated versus unencapsulated or invasive versus non-invasive strains. Methods: HL-60-derived neutrophil-like cells (dHL-60), differentiated with 1.25% dimethyl sulfoxide over 9 days, were used in an opsonophagocytosis assay and in vitro infection model to measure Hia’s susceptibility to killing and dHL-60 surface molecule expression, respectively. The impact of strain-specific features on the immune response was investigated using clinical isolates of a dominant North American sequence type (ST)-23, including Hia 11-139 (encapsulated, invasive), 14-61 (encapsulated, non-invasive), 13-0074 (unencapsulated, invasive), as well as a representative ST-4 isolate (Hia 13-240, encapsulated, invasive), and a nontypeable strain (NTHi 375, unencapsulated, non-invasive). Results: Unencapsulated and non-invasive Hi strains were more susceptible to killing by the innate immune response while the ST-23 invasive strain, Hia 11-139 required serum antibodies for destruction. Flow cytometry analysis showed increased expression of co-stimulatory molecule ICAM-1 and Fc receptors (CD89, CD64) but decreased expression of the Fc receptor CD16, revealing potential mechanisms of neutrophil-mediated defense against Hia that extend to both non-invasive and invasive strains. Conclusions: Hia clinical isolates with diverse pathogenicity illustrated contrasting susceptibility to killing by immune mechanisms while maintaining the same capacity to activate neutrophil-like cells, further underscoring the need for additional studies on Hia’s pathogenesis.
{"title":"Invasive and Non-invasive Clinical Haemophilus influenzae Type A Isolates Activate Differentiated HL-60 Cells In Vitro","authors":"Courtney Ferris, Marina Ulanova","doi":"10.20411/pai.v9i1.659","DOIUrl":"https://doi.org/10.20411/pai.v9i1.659","url":null,"abstract":"Background: The effective elimination of encapsulated bacteria like Haemophilus influenzae type a (Hia) relies on immune mechanisms such as complement-mediated opsonophagocytosis by neutrophils in coordination with opsonization by anti-capsular antibodies. This study evaluated if Hia could activate the immune response through neutrophils and if these responses differed between encapsulated versus unencapsulated or invasive versus non-invasive strains.\u0000Methods: HL-60-derived neutrophil-like cells (dHL-60), differentiated with 1.25% dimethyl sulfoxide over 9 days, were used in an opsonophagocytosis assay and in vitro infection model to measure Hia’s susceptibility to killing and dHL-60 surface molecule expression, respectively. The impact of strain-specific features on the immune response was investigated using clinical isolates of a dominant North American sequence type (ST)-23, including Hia 11-139 (encapsulated, invasive), 14-61 (encapsulated, non-invasive), 13-0074 (unencapsulated, invasive), as well as a representative ST-4 isolate (Hia 13-240, encapsulated, invasive), and a nontypeable strain (NTHi 375, unencapsulated, non-invasive).\u0000Results: Unencapsulated and non-invasive Hi strains were more susceptible to killing by the innate immune response while the ST-23 invasive strain, Hia 11-139 required serum antibodies for destruction. Flow cytometry analysis showed increased expression of co-stimulatory molecule ICAM-1 and Fc receptors (CD89, CD64) but decreased expression of the Fc receptor CD16, revealing potential mechanisms of neutrophil-mediated defense against Hia that extend to both non-invasive and invasive strains.\u0000Conclusions: Hia clinical isolates with diverse pathogenicity illustrated contrasting susceptibility to killing by immune mechanisms while maintaining the same capacity to activate neutrophil-like cells, further underscoring the need for additional studies on Hia’s pathogenesis.","PeriodicalId":36419,"journal":{"name":"Pathogens and Immunity","volume":" 45","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140692768","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}
Drew Weissman, MD, PhD, received the 2023 Nobel Prize in Physiology or Medicine together with Katalin Karikó, PhD. Dr. Weissman received his bachelor's and master's degrees from Brandeis University, Waltham, MA, in 1981. He received his MD and PhD in 1987 from Boston University, Boston, MA, and this was followed by a residency at Beth Israel Deaconess Medical Center, Boston, MA. He then completed a fellowship at the National Institute of Allergy and Infectious Diseases under the supervision of Anthony Fauci, MD. He joined the Faculty at the University of Pennsylvania, Philadelphia, in 1997, where, in collaboration with Dr. Katalin Karikó, he explored the use of messenger RNA (mRNA) to drive heterologous gene expression in human cells. They overcame the notorious susceptibility of RNAs to degradation by packaging the mRNA in lipid nanoparticles and learned to both optimize protein expression and attenuate the inflammatory response to the exogenous RNAs by [covalently] modifying bases in the RNA sequence. This work has revolutionized immunization technology and allowed for the production of the most effective vaccines to prevent COVID-19.
{"title":"Interview with Drew Weissman, 2023 Nobel Laureate in Physiology or Medicine","authors":"Michael Lederman, Neil Greenspan","doi":"10.20411/pai.v9i1.698","DOIUrl":"https://doi.org/10.20411/pai.v9i1.698","url":null,"abstract":"Drew Weissman, MD, PhD, received the 2023 Nobel Prize in Physiology or Medicine together with Katalin Karikó, PhD. Dr. Weissman received his bachelor's and master's degrees from Brandeis University, Waltham, MA, in 1981. He received his MD and PhD in 1987 from Boston University, Boston, MA, and this was followed by a residency at Beth Israel Deaconess Medical Center, Boston, MA. He then completed a fellowship at the National Institute of Allergy and Infectious Diseases under the supervision of Anthony Fauci, MD. He joined the Faculty at the University of Pennsylvania, Philadelphia, in 1997, where, in collaboration with Dr. Katalin Karikó, he explored the use of messenger RNA (mRNA) to drive heterologous gene expression in human cells. They overcame the notorious susceptibility of RNAs to degradation by packaging the mRNA in lipid nanoparticles and learned to both optimize protein expression and attenuate the inflammatory response to the exogenous RNAs by [covalently] modifying bases in the RNA sequence. This work has revolutionized immunization technology and allowed for the production of the most effective vaccines to prevent COVID-19.","PeriodicalId":36419,"journal":{"name":"Pathogens and Immunity","volume":"11 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140695946","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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