Pub Date : 2024-04-01DOI: 10.1016/j.mucimm.2024.01.002
Saugata Majumder , Peng Li , Shreya Das , Tanvir Noor Nafiz , Sudeep Kumar , Guangchun Bai , Hazel Dellario , Haixin Sui , Ziqiang Guan , Roy Curtiss 3rd , Yoichi Furuya , Wei Sun
Streptococcus pneumoniae (Spn) is a common pathogen causing a secondary bacterial infection following influenza, which leads to severe morbidity and mortality during seasonal and pandemic influenza. Therefore, there is an urgent need to develop bacterial vaccines that prevent severe post-influenza bacterial pneumonia. Here, an improved Yersinia pseudotuberculosis strain (designated as YptbS46) possessing an Asd+ plasmid pSMV92 could synthesize high amounts of the Spn pneumococcal surface protein A (PspA) antigen and monophosphoryl lipid A as an adjuvant. The recombinant strain produced outer membrane vesicles (OMVs) enclosing a high amount of PspA protein (designated as OMV-PspA). A prime-boost intramuscular immunization with OMV-PspA induced both memory adaptive and innate immune responses in vaccinated mice, reduced the viral and bacterial burden, and provided complete protection against influenza-mediated secondary Spn infection. Also, the OMV-PspA immunization afforded significant cross-protection against the secondary Spn A66.1 infection and long-term protection against the secondary Spn D39 challenge. Our study implies that an OMV vaccine delivering Spn antigens can be a new promising pneumococcal vaccine candidate.
{"title":"A bacterial vesicle-based pneumococcal vaccine against influenza-mediated secondary Streptococcus pneumoniae pulmonary infection","authors":"Saugata Majumder , Peng Li , Shreya Das , Tanvir Noor Nafiz , Sudeep Kumar , Guangchun Bai , Hazel Dellario , Haixin Sui , Ziqiang Guan , Roy Curtiss 3rd , Yoichi Furuya , Wei Sun","doi":"10.1016/j.mucimm.2024.01.002","DOIUrl":"10.1016/j.mucimm.2024.01.002","url":null,"abstract":"<div><p><em>Streptococcus pneumoniae</em> (Spn) is a common pathogen causing a secondary bacterial infection following influenza, which leads to severe morbidity and mortality during seasonal and pandemic influenza. Therefore, there is an urgent need to develop bacterial vaccines that prevent severe post-influenza bacterial pneumonia. Here, an improved <em>Yersinia pseudotuberculosis</em> strain (designated as YptbS46) possessing an Asd<sup>+</sup> plasmid pSMV92 could synthesize high amounts of the Spn pneumococcal surface protein A (PspA) antigen and monophosphoryl lipid A as an adjuvant. The recombinant strain produced outer membrane vesicles (OMVs) enclosing a high amount of PspA protein (designated as OMV-PspA). A prime-boost intramuscular immunization with OMV-PspA induced both memory adaptive and innate immune responses in vaccinated mice, reduced the viral and bacterial burden, and provided complete protection against influenza-mediated secondary Spn infection. Also, the OMV-PspA immunization afforded significant cross-protection against the secondary Spn A66.1 infection and long-term protection against the secondary Spn D39 challenge. Our study implies that an OMV vaccine delivering Spn antigens can be a new promising pneumococcal vaccine candidate.</p></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1933021924000023/pdfft?md5=580daefb21e141765e4fc122d099a1de&pid=1-s2.0-S1933021924000023-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139432672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-01DOI: 10.1016/j.mucimm.2024.02.004
Jiaoyan Huang , Xin Zhang , Hongkai Xu , Liuhui Fu , Yuke Liu , Jie Zhao , Jida Huang , Zuodong Song , Mingzhao Zhu , Yang-Xin Fu , Ye-Guang Chen , Xiaohuan Guo
Chemotherapy and radiotherapy frequently lead to intestinal damage. The mechanisms governing the repair or regeneration of intestinal damage are still not fully elucidated. Intraepithelial lymphocytes (IELs) are the primary immune cells residing in the intestinal epithelial layer. However, whether IELs are involved in intestinal epithelial injury repair remains unclear. Here, we found that IELs rapidly infiltrated the intestinal crypt region and are crucial for the recovery of the intestinal epithelium post-chemotherapy. Interestingly, IELs predominantly promoted intestinal regeneration by modulating the proliferation of transit-amplifying (TA) cells. Mechanistically, the expression of CD160 on IELs allows for interaction with herpes virus entry mediator (HVEM) on the intestinal epithelium, thereby activating downstream nuclear factor kappa (NF-κB) signaling and further promoting intestinal regeneration. Deficiency in either CD160 or HVEM resulted in reduced proliferation of intestinal progenitor cells, impaired intestinal damage repair, and increased mortality following chemotherapy. Remarkably, the adoptive transfer of CD160-sufficient IELs rescued the Rag1 deficient mice from chemotherapy-induced intestinal inflammation. Overall, our study underscores the critical role of IELs in intestinal regeneration and highlights the potential applications of targeting the CD160-HVEM axis for managing intestinal adverse events post-chemotherapy and radiotherapy.
{"title":"Intraepithelial lymphocytes promote intestinal regeneration through CD160/HVEM signaling","authors":"Jiaoyan Huang , Xin Zhang , Hongkai Xu , Liuhui Fu , Yuke Liu , Jie Zhao , Jida Huang , Zuodong Song , Mingzhao Zhu , Yang-Xin Fu , Ye-Guang Chen , Xiaohuan Guo","doi":"10.1016/j.mucimm.2024.02.004","DOIUrl":"10.1016/j.mucimm.2024.02.004","url":null,"abstract":"<div><p>Chemotherapy and radiotherapy frequently lead to intestinal damage. The mechanisms governing the repair or regeneration of intestinal damage are still not fully elucidated. Intraepithelial lymphocytes (IELs) are the primary immune cells residing in the intestinal epithelial layer. However, whether IELs are involved in intestinal epithelial injury repair remains unclear. Here, we found that IELs rapidly infiltrated the intestinal crypt region and are crucial for the recovery of the intestinal epithelium post-chemotherapy. Interestingly, IELs predominantly promoted intestinal regeneration by modulating the proliferation of transit-amplifying (TA) cells. Mechanistically, the expression of CD160 on IELs allows for interaction with herpes virus entry mediator (HVEM) on the intestinal epithelium, thereby activating downstream nuclear factor kappa (NF-κB) signaling and further promoting intestinal regeneration. Deficiency in either CD160 or HVEM resulted in reduced proliferation of intestinal progenitor cells, impaired intestinal damage repair, and increased mortality following chemotherapy. Remarkably, the adoptive transfer of CD160-sufficient IELs rescued the <em>Rag1</em> deficient mice from chemotherapy-induced intestinal inflammation. Overall, our study underscores the critical role of IELs in intestinal regeneration and highlights the potential applications of targeting the CD160-HVEM axis for managing intestinal adverse events post-chemotherapy and radiotherapy.</p></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1933021924000084/pdfft?md5=4343b0d5eaf9e630559a35bd594283e2&pid=1-s2.0-S1933021924000084-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139716224","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-01DOI: 10.1016/j.mucimm.2024.02.002
Qiaochu Lin , Meggie Kuypers , Yuriy Baglaenko , Eric Cao , Kebria Hezaveh , Tijana Despot , Carolina de Amat Herbozo , Mayra Cruz Tleugabulova , Juan Mauricio Umaña , Tracy L. McGaha , Dana J. Philpott , Thierry Mallevaey
Invariant Natural Killer T (iNKT) cells are unconventional T cells that respond to microbe-derived glycolipid antigens. iNKT cells exert fast innate effector functions that regulate immune responses in a variety of contexts, including during infection, cancer, or inflammation. The roles these unconventional T cells play in intestinal inflammation remain poorly defined and vary based on the disease model and species. Our previous work suggested that the gut microbiota influenced iNKT cell functions during dextran sulfate sodium-induced colitis in mice. This study, shows that iNKT cell homeostasis and response following activation are altered in germ-free mice. Using prenatal fecal transplant in specific pathogen-free mice, we show that the transcriptional signatures of iNKT cells at steady state and following αGC-mediated activation in vivo are modulated by the microbiota. Our data suggest that iNKT cells sense the microbiota at homeostasis independently of their T cell receptors. Finally, iNKT cell transcriptional signatures are different in male and female mice. Collectively, our findings suggest that sex and the intestinal microbiota are important factors that regulate iNKT cell homeostasis and responses. A deeper understanding of microbiota-iNKT cell interactions and the impact of sex could improve the development of iNKT cell-based immunotherapies.
不变型杀伤性 T 细胞(iNKT)是对微生物衍生的糖脂抗原做出反应的非常规 T 细胞。iNKT 细胞具有快速的先天效应功能,可在感染、癌症或炎症等多种情况下调节免疫反应。这些非常规 T 细胞在肠道炎症中所起的作用仍未明确,而且因疾病模型和物种而异。我们之前的研究表明,在葡聚糖硫酸钠诱导的小鼠结肠炎中,肠道微生物群会影响 iNKT 细胞的功能。在这项研究中,我们发现无菌小鼠的 iNKT 细胞稳态和激活后的反应发生了改变。通过在特异性无病原体小鼠体内进行产前粪便移植,我们发现 iNKT 细胞在稳态和αGC 介导的体内激活后的转录特征受到微生物群的调节。我们的数据表明,iNKT 细胞在平衡状态下对微生物群的感知与它们的 TCR 无关。最后,雌雄小鼠的 iNKT 细胞转录特征也不同。总之,我们的研究结果表明,性别和肠道微生物群是调节 iNKT 细胞平衡和反应的重要因素。更深入地了解微生物群与 iNKT 细胞之间的相互作用以及性别的影响可以改善基于 iNKT 细胞的免疫疗法的开发。
{"title":"The intestinal microbiota modulates the transcriptional landscape of iNKT cells at steady-state and following antigen exposure","authors":"Qiaochu Lin , Meggie Kuypers , Yuriy Baglaenko , Eric Cao , Kebria Hezaveh , Tijana Despot , Carolina de Amat Herbozo , Mayra Cruz Tleugabulova , Juan Mauricio Umaña , Tracy L. McGaha , Dana J. Philpott , Thierry Mallevaey","doi":"10.1016/j.mucimm.2024.02.002","DOIUrl":"10.1016/j.mucimm.2024.02.002","url":null,"abstract":"<div><p>Invariant Natural Killer T (iNKT) cells are unconventional T cells that respond to microbe-derived glycolipid antigens. iNKT cells exert fast innate effector functions that regulate immune responses in a variety of contexts, including during infection, cancer, or inflammation. The roles these unconventional T cells play in intestinal inflammation remain poorly defined and vary based on the disease model and species. Our previous work suggested that the gut microbiota influenced iNKT cell functions during dextran sulfate sodium-induced colitis in mice. This study, shows that iNKT cell homeostasis and response following activation are altered in germ-free mice. Using prenatal fecal transplant in specific pathogen-free mice, we show that the transcriptional signatures of iNKT cells at steady state and following αGC-mediated activation <em>in vivo</em> are modulated by the microbiota. Our data suggest that iNKT cells sense the microbiota at homeostasis independently of their T cell receptors. Finally, iNKT cell transcriptional signatures are different in male and female mice. Collectively, our findings suggest that sex and the intestinal microbiota are important factors that regulate iNKT cell homeostasis and responses. A deeper understanding of microbiota-iNKT cell interactions and the impact of sex could improve the development of iNKT cell-based immunotherapies.</p></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1933021924000059/pdfft?md5=26a46334a268bc1fafaecd2b8d907f7d&pid=1-s2.0-S1933021924000059-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139707278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-01DOI: 10.1016/j.mucimm.2024.02.005
Ziyin Wang , Leah F. Cuthbertson , Chubicka Thomas , Hadijatou J Sallah , Lucy G. Mosscrop , Haoyuan Li , Tiina Talts , Kartik Kumar , Miriam F. Moffatt , John S. Tregoning
Respiratory viral infections remain a major cause of hospitalization and death worldwide. Patients with respiratory infections often lose weight. While acute weight loss is speculated to be a tolerance mechanism to limit pathogen growth, severe weight loss following infection can cause quality of life deterioration. Despite the clinical relevance of respiratory infection-induced weight loss, its mechanism is not yet completely understood. We utilized a model of CD 8+ T cell-driven weight loss during respiratory syncytial virus (RSV) infection to dissect the immune regulation of post-infection weight loss. Supporting previous data, bulk RNA sequencing indicated significant enrichment of the interleukin (IL)-1 signaling pathway after RSV infection. Despite increased viral load, infection-associated weight loss was significantly reduced after IL-1α (but not IL-1β) blockade. IL-1α depletion resulted in a reversal of the gut microbiota changes observed following RSV infection. Direct nasal instillation of IL-1α also caused weight loss. Of note, we detected IL-1α in the brain after either infection or nasal delivery. This was associated with changes in genes controlling appetite after RSV infection and corresponding changes in signaling molecules such as leptin and growth/differentiation factor 15. Together, these findings indicate a lung-brain-gut signaling axis for IL-1α in regulating weight loss after RSV infection.
{"title":"IL-1α is required for T cell-driven weight loss after respiratory viral infection","authors":"Ziyin Wang , Leah F. Cuthbertson , Chubicka Thomas , Hadijatou J Sallah , Lucy G. Mosscrop , Haoyuan Li , Tiina Talts , Kartik Kumar , Miriam F. Moffatt , John S. Tregoning","doi":"10.1016/j.mucimm.2024.02.005","DOIUrl":"10.1016/j.mucimm.2024.02.005","url":null,"abstract":"<div><p>Respiratory viral infections remain a major cause of hospitalization and death worldwide. Patients with respiratory infections often lose weight. While acute weight loss is speculated to be a tolerance mechanism to limit pathogen growth, severe weight loss following infection can cause quality of life deterioration. Despite the clinical relevance of respiratory infection-induced weight loss, its mechanism is not yet completely understood. We utilized a model of CD 8<sup>+</sup> T cell-driven weight loss during respiratory syncytial virus (RSV) infection to dissect the immune regulation of post-infection weight loss. Supporting previous data, bulk RNA sequencing indicated significant enrichment of the interleukin (IL)-1 signaling pathway after RSV infection. Despite increased viral load, infection-associated weight loss was significantly reduced after IL-1α (but not IL-1β) blockade. IL-1α depletion resulted in a reversal of the gut microbiota changes observed following RSV infection. Direct nasal instillation of IL-1α also caused weight loss. Of note, we detected IL-1α in the brain after either infection or nasal delivery. This was associated with changes in genes controlling appetite after RSV infection and corresponding changes in signaling molecules such as leptin and growth/differentiation factor 15. Together, these findings indicate a lung-brain-gut signaling axis for IL-1α in regulating weight loss after RSV infection.</p></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1933021924000096/pdfft?md5=1e592548d066f32a36434581cfb5c3f6&pid=1-s2.0-S1933021924000096-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139932040","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-01DOI: 10.1016/j.mucimm.2024.02.003
Lucas M. Ethgen , Christopher Pastore , Cailu Lin , Danielle R Reed , Li-Yin Hung , Bonnie Douglas , Dominic Sinker , De'Broski R. Herbert , Nicole M. Belle
Host defense at the mucosal interface requires collaborative interactions between diverse cell lineages. Epithelial cells damaged by microbial invaders release reparative proteins such as the Trefoil factor family (TFF) peptides that functionally restore barrier integrity. However, whether TFF peptides and their receptors also serve instructive roles for immune cell function during infection is incompletely understood. Here, we demonstrate that the intestinal trefoil factor, TFF3, restrains (T cell helper) TH1 cell proliferation and promotes host-protective type 2 immunity against the gastrointestinal parasitic nematode Trichuris muris. Accordingly, T cell-specific deletion of the TFF3 receptor, leucine-rich repeat and immunoglobulin containing nogo receptor 2 (LINGO2), impairs TH2 cell commitment, allows proliferative expansion of interferon (IFN)g+ cluster of differentiation (CD)4+ TH1 cells and blocks normal worm expulsion through an IFNg-dependent mechanism. This study indicates that TFF3, in addition to its known tissue reparative functions, drives anti-helminth immunity by controlling the balance between TH1/TH2 subsets.
{"title":"A Trefoil factor 3-Lingo2 axis restrains proliferative expansion of type-1 T helper cells during GI nematode infection","authors":"Lucas M. Ethgen , Christopher Pastore , Cailu Lin , Danielle R Reed , Li-Yin Hung , Bonnie Douglas , Dominic Sinker , De'Broski R. Herbert , Nicole M. Belle","doi":"10.1016/j.mucimm.2024.02.003","DOIUrl":"10.1016/j.mucimm.2024.02.003","url":null,"abstract":"<div><p>Host defense at the mucosal interface requires collaborative interactions between diverse cell lineages. Epithelial cells damaged by microbial invaders release reparative proteins such as the Trefoil factor family (TFF) peptides that functionally restore barrier integrity. However, whether TFF peptides and their receptors also serve instructive roles for immune cell function during infection is incompletely understood. Here, we demonstrate that the intestinal trefoil factor, TFF3, restrains (T cell helper) T<sub>H</sub>1 cell proliferation and promotes host-protective type 2 immunity against the gastrointestinal parasitic nematode <em>Trichuris muris</em>. Accordingly, T cell-specific deletion of the TFF3 receptor, leucine-rich repeat and immunoglobulin containing nogo receptor 2 (LINGO2), impairs T<sub>H</sub>2 cell commitment, allows proliferative expansion of interferon (IFN)g<sup>+</sup> cluster of differentiation (CD)4<sup>+</sup> T<sub>H</sub>1 cells and blocks normal worm expulsion through an IFNg-dependent mechanism. This study indicates that TFF3, in addition to its known tissue reparative functions, drives anti-helminth immunity by controlling the balance between T<sub>H</sub>1/T<sub>H</sub>2 subsets.</p></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1933021924000072/pdfft?md5=b55060312fc328b7840367c8f5b26dcd&pid=1-s2.0-S1933021924000072-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139712647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-01DOI: 10.1016/j.mucimm.2024.02.001
Ruoxun Yu , Sijing Liu , Yan Li , Liyuan Lu , Shuoya Huang , Xinwei Chen , Yunxia Xue , Ting Fu , Jun Liu , Zhijie Li
Allergic conjunctivitis (AC), an allergen-induced ocular inflammatory disease, primarily involves mast cells (MCs) and eosinophils. The role of neuroimmune mechanisms in AC, however, remains to be elucidated. We investigated the effects of transient receptor potential vanilloid 1 (TRPV1)-positive sensory nerve ablation (using resiniferatoxin) and TRPV1 blockade (using Acetamide, N-[4-[[6-[4-(trifluoromethyl)phenyl]-4-pyrimidinyl]oxy]-2-benzothiazolyl] (AMG-517)) on ovalbumin-induced conjunctival allergic inflammation in mice. The results showed an exacerbation of allergic inflammation as evidenced by increased inflammatory gene expression, MC degranulation, tumor necrosis factor-α production by MCs, eosinophil infiltration and activation, and C-C motif chemokine 11 (CCL11) (eotaxin-1) expression in fibroblasts. Subsequent findings demonstrated that TRPV1+ sensory nerves secrete somatostatin (SST), which binds to SST receptor 5 (SSTR5) on MCs and conjunctival fibroblasts. SST effectively inhibited tumor necrosis factor-α production in MCs and CCL11 expression in fibroblasts, thereby reducing eosinophil infiltration and alleviating AC symptoms, including eyelid swelling, lacrimation, conjunctival chemosis, and redness. These findings suggest that targeting TRPV1+ sensory nerve-mediated SST-SSTR5 signaling could be a promising therapeutic strategy for AC, offering insights into neuroimmune mechanisms and potential targeted treatments.
{"title":"TRPV1+ sensory nerves suppress conjunctival inflammation via SST-SSTR5 signaling in murine allergic conjunctivitis","authors":"Ruoxun Yu , Sijing Liu , Yan Li , Liyuan Lu , Shuoya Huang , Xinwei Chen , Yunxia Xue , Ting Fu , Jun Liu , Zhijie Li","doi":"10.1016/j.mucimm.2024.02.001","DOIUrl":"10.1016/j.mucimm.2024.02.001","url":null,"abstract":"<div><p>Allergic conjunctivitis (AC), an allergen-induced ocular inflammatory disease, primarily involves mast cells (MCs) and eosinophils. The role of neuroimmune mechanisms in AC, however, remains to be elucidated. We investigated the effects of transient receptor potential vanilloid 1 (TRPV1)-positive sensory nerve ablation (using resiniferatoxin) and TRPV1 blockade (using Acetamide, N-[4-[[6-[4-(trifluoromethyl)phenyl]-4-pyrimidinyl]oxy]-2-benzothiazolyl] (AMG-517)) on ovalbumin-induced conjunctival allergic inflammation in mice. The results showed an exacerbation of allergic inflammation as evidenced by increased inflammatory gene expression, MC degranulation, tumor necrosis factor-α production by MCs, eosinophil infiltration and activation, and C-C motif chemokine 11 (CCL11) (eotaxin-1) expression in fibroblasts. Subsequent findings demonstrated that TRPV1<sup>+</sup> sensory nerves secrete somatostatin (SST), which binds to SST receptor 5 (SSTR5) on MCs and conjunctival fibroblasts. SST effectively inhibited tumor necrosis factor-α production in MCs and CCL11 expression in fibroblasts, thereby reducing eosinophil infiltration and alleviating AC symptoms, including eyelid swelling, lacrimation, conjunctival chemosis, and redness. These findings suggest that targeting TRPV1<sup>+</sup> sensory nerve-mediated SST-SSTR5 signaling could be a promising therapeutic strategy for AC, offering insights into neuroimmune mechanisms and potential targeted treatments.</p></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1933021924000060/pdfft?md5=1900996c48b6af9ced6038dc60fe0faa&pid=1-s2.0-S1933021924000060-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139707279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-01DOI: 10.1016/j.mucimm.2024.02.006
Yuting Wu , Panrui Zhang , Tianlu Shi , Dan Cao , Wen Pan
Immunoglobulin superfamily (IgSF) members are known for their role as glycoproteins expressed on the surface of immune cells, enabling protein-protein interactions to sense external signals during immune responses. However, the functions of immunoglobulins localized within subcellular compartments have been less explored. In this study, we identified an endoplasmic reticulum (ER)-localized immunoglobulin, IgSF member 6 (IgSF6), that regulates ER stress and the inflammatory response in intestinal macrophages. Igsf6 expression is sustained by microbiota and significantly upregulated upon bacterial infection. Mice lacking Igsf6 displayed resistance to Salmonella typhimurium challenge but increased susceptibility to dextran sulfate sodium-induced colitis. Mechanistically, deficiency of Igsf6 enhanced inositol-requiring enzyme 1α/-X-box binding protein 1 pathway, inflammatory response, and reactive oxygen species production leading to increased bactericidal activity of intestinal macrophages. Inhibition of reactive oxygen species or inositol-requiring enzyme 1α-X-box binding protein 1 pathway reduced the advantage of Igsf6 deficiency in bactericidal capacity. Together, our findings provide insight into the role of IgSF6 in intestinal macrophages that modulate the ER stress response and maintain intestinal homeostasis.
{"title":"Deficiency of immunoglobulin IgSF6 enhances antibacterial effects by promoting endoplasmic reticulum stress and the inflammatory response in intestinal macrophages","authors":"Yuting Wu , Panrui Zhang , Tianlu Shi , Dan Cao , Wen Pan","doi":"10.1016/j.mucimm.2024.02.006","DOIUrl":"10.1016/j.mucimm.2024.02.006","url":null,"abstract":"<div><p>Immunoglobulin superfamily (IgSF) members are known for their role as glycoproteins expressed on the surface of immune cells, enabling protein-protein interactions to sense external signals during immune responses. However, the functions of immunoglobulins localized within subcellular compartments have been less explored. In this study, we identified an endoplasmic reticulum (ER)-localized immunoglobulin, IgSF member 6 (IgSF6), that regulates ER stress and the inflammatory response in intestinal macrophages. <em>Igsf6</em> expression is sustained by microbiota and significantly upregulated upon bacterial infection. Mice lacking <em>Igsf6</em> displayed resistance to <em>Salmonella typhimurium</em> challenge but increased susceptibility to dextran sulfate sodium-induced colitis. Mechanistically, deficiency of <em>Igsf6</em> enhanced inositol-requiring enzyme 1α/-X-box binding protein 1 pathway, inflammatory response, and reactive oxygen species production leading to increased bactericidal activity of intestinal macrophages. Inhibition of reactive oxygen species or inositol-requiring enzyme 1α-X-box binding protein 1 pathway reduced the advantage of <em>Igsf6</em> deficiency in bactericidal capacity. Together, our findings provide insight into the role of IgSF6 in intestinal macrophages that modulate the ER stress response and maintain intestinal homeostasis.</p></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1933021924000151/pdfft?md5=e4dc93d456f5fc73f0fc46f9e0a6c30d&pid=1-s2.0-S1933021924000151-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139932039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-01DOI: 10.1016/j.mucimm.2024.01.003
Dylan Launder , John T. Dillon , Leah M. Wuescher , Trevor Glanz , Nora Abdul-Aziz , Elise Mein-Chiain Yi , Julian R. Naglik , Randall G. Worth , Heather R. Conti
The fungus Candida albicans can cause mucosal infections including oropharyngeal candidiasis (OPC) in immunocompromised patients. In humans, an increased risk of fungal infections correlates with thrombocytopenia. However, our understanding of platelets and megakaryocytes (Mks) in mucosal fungal infections is almost entirely unknown. When megakaryocyte- and platelet-depleted mice were infected with OPC, the tongue showed higher fungal burden, due to decreased neutrophil accumulation. Protection depended on a distinct population of oral-resident Mks. Interleukin-17, important in antifungal immunity, was required since mice lacking the IL-17 receptor had decreased circulating platelets and their oral Mks did not expand during OPC. The secretion of the peptide toxin candidalysin activated human Mks to release platelets with antifungal capacity. Infection with a candidalysin-deficient strain resulted in decreased expansion of tongue Mks during OPC. This is the first time that a distinct megakaryocyte population was identified in the oral mucosa which is critical for immunity against fungal infection.
{"title":"Immunity to pathogenic mucosal C. albicans infections mediated by oral megakaryocytes activated by IL-17 and candidalysin","authors":"Dylan Launder , John T. Dillon , Leah M. Wuescher , Trevor Glanz , Nora Abdul-Aziz , Elise Mein-Chiain Yi , Julian R. Naglik , Randall G. Worth , Heather R. Conti","doi":"10.1016/j.mucimm.2024.01.003","DOIUrl":"10.1016/j.mucimm.2024.01.003","url":null,"abstract":"<div><p>The fungus <em>Candida albicans</em> can cause mucosal infections including oropharyngeal candidiasis (OPC) in immunocompromised patients. In humans, an increased risk of fungal infections correlates with thrombocytopenia. However, our understanding of platelets and megakaryocytes (Mks) in mucosal fungal infections is almost entirely unknown. When megakaryocyte- and platelet-depleted mice were infected with OPC, the tongue showed higher fungal burden, due to decreased neutrophil accumulation. Protection depended on a distinct population of oral-resident Mks. Interleukin-17, important in antifungal immunity, was required since mice lacking the IL-17 receptor had decreased circulating platelets and their oral Mks did not expand during OPC. The secretion of the peptide toxin candidalysin activated human Mks to release platelets with antifungal capacity. Infection with a candidalysin-deficient strain resulted in decreased expansion of tongue Mks during OPC. This is the first time that a distinct megakaryocyte population was identified in the oral mucosa which is critical for immunity against fungal infection.</p></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1933021924000035/pdfft?md5=d3d57914f1b6cac4d7cbdccb57d7d8b8&pid=1-s2.0-S1933021924000035-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139513250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-01DOI: 10.1016/j.mucimm.2024.01.004
Sabryna Nantel , Salma Sheikh-Mohamed , Gary Y.C. Chao , Alexandra Kurtesi , Queenie Hu , Heidi Wood , Karen Colwill , Zhijie Li , Ying Liu , Laurie Seifried , Benoîte Bourdin , Allison McGeer , William R. Hardy , Olga L. Rojas , Tho-Alfakar Al-Aubodah , Zhiyang Liu , Mario A. Ostrowski , Mark A. Brockman , Ciriaco A. Piccirillo , Caroline Quach , Jennifer L. Gommerman
Our understanding of the quality of cellular and humoral immunity conferred by COVID-19 vaccination alone versus vaccination plus SARS-CoV-2 breakthrough (BT) infection remains incomplete. While the current (2023) SARS-CoV-2 immune landscape of Canadians is complex, in late 2021 most Canadians had either just received a third dose of COVID-19 vaccine, or had received their two-dose primary series and then experienced an Omicron BT. Herein we took advantage of this coincident timing to contrast cellular and humoral immunity conferred by three doses of vaccine versus two doses plus BT. Our results show thatBT infection induces cell-mediated immune responses to variants comparable to an intramuscular vaccine booster dose. In contrast, BT subjects had higher salivary immunoglobulin (Ig)G and IgA levels against the Omicron spike and enhanced reactivity to the ancestral spike for the IgA isotype, which also reacted with SARS-CoV-1. Serumneutralizing antibody levels against the ancestral strain and the variants were also higher after BT infection. Our results support the need for the development of intranasal vaccines that could emulate the enhanced mucosal and humoral immunity induced by Omicron BT without exposing individuals to the risks associated with SARS-CoV-2 infection.
{"title":"Comparison of Omicron breakthrough infection versus monovalent SARS-CoV-2 intramuscular booster reveals differences in mucosal and systemic humoral immunity","authors":"Sabryna Nantel , Salma Sheikh-Mohamed , Gary Y.C. Chao , Alexandra Kurtesi , Queenie Hu , Heidi Wood , Karen Colwill , Zhijie Li , Ying Liu , Laurie Seifried , Benoîte Bourdin , Allison McGeer , William R. Hardy , Olga L. Rojas , Tho-Alfakar Al-Aubodah , Zhiyang Liu , Mario A. Ostrowski , Mark A. Brockman , Ciriaco A. Piccirillo , Caroline Quach , Jennifer L. Gommerman","doi":"10.1016/j.mucimm.2024.01.004","DOIUrl":"10.1016/j.mucimm.2024.01.004","url":null,"abstract":"<div><p>Our understanding of the quality of cellular and humoral immunity conferred by COVID-19 vaccination alone versus vaccination plus SARS-CoV-2 breakthrough (BT) infection remains incomplete. While the current (2023) SARS-CoV-2 immune landscape of Canadians is complex, in late 2021 most Canadians had either just received a third dose of COVID-19 vaccine, or had received their two-dose primary series and then experienced an Omicron BT. Herein we took advantage of this coincident timing to contrast cellular and humoral immunity conferred by three doses of vaccine versus two doses plus BT. Our results show thatBT infection induces cell-mediated immune responses to variants comparable to an intramuscular vaccine booster dose. In contrast, BT subjects had higher salivary immunoglobulin (Ig)G and IgA levels against the Omicron spike and enhanced reactivity to the ancestral spike for the IgA isotype, which also reacted with SARS-CoV-1. Serumneutralizing antibody levels against the ancestral strain and the variants were also higher after BT infection. Our results support the need for the development of intranasal vaccines that could emulate the enhanced mucosal and humoral immunity induced by Omicron BT without exposing individuals to the risks associated with SARS-CoV-2 infection.</p></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1933021924000047/pdfft?md5=2d844e1ed81ce93c27def9b02d042c8e&pid=1-s2.0-S1933021924000047-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139567307","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-01DOI: 10.1016/j.mucimm.2024.01.001
Angélica M. Olmo-Fontánez , Julia M. Scordo , Alyssa Schami , Andreu Garcia-Vilanova , Paula A. Pino , Amberlee Hicks , Richa Mishra , Diego Jose Maselli , Jay I. Peters , Blanca I. Restrepo , Kievershen Nargan , Threnesan Naidoo , Daniel L. Clemens , Adrie J.C. Steyn , Vivek V. Thacker , Joanne Turner , Larry S. Schlesinger , Jordi B. Torrelles
The elderly population is highly susceptible to developing respiratory diseases, including tuberculosis, a devastating disease caused by the airborne pathogen Mycobacterium tuberculosis (M.tb) that kills one person every 18 seconds. Once M.tb reaches the alveolar space, it contacts alveolar lining fluid (ALF), which dictates host-cell interactions. We previously determined that age-associated dysfunction of soluble innate components in human ALF leads to accelerated M.tb growth within human alveolar macrophages. Here we determined the impact of human ALF on M.tb infection of alveolar epithelial type cells (ATs), another critical lung cellular determinant of infection. We observed that elderly ALF (E-ALF)-exposed M.tb had significantly increased intracellular growth with rapid replication in ATs compared to adult ALF (A-ALF)-exposed bacteria, as well as a dampened inflammatory response. A potential mechanism underlying this accelerated growth in ATs was our observation of increased bacterial translocation into the cytosol, a compartment that favors bacterial replication. These findings in the context of our previous studies highlight how the oxidative and dysfunctional status of the elderly lung mucosa determines susceptibility to M.tb infection, including dampening immune responses and favoring bacterial replication within alveolar resident cell populations, including ATs, the most abundant resident cell type within the alveoli.
{"title":"Human alveolar lining fluid from the elderly promotes Mycobacterium tuberculosis intracellular growth and translocation into the cytosol of alveolar epithelial cells","authors":"Angélica M. Olmo-Fontánez , Julia M. Scordo , Alyssa Schami , Andreu Garcia-Vilanova , Paula A. Pino , Amberlee Hicks , Richa Mishra , Diego Jose Maselli , Jay I. Peters , Blanca I. Restrepo , Kievershen Nargan , Threnesan Naidoo , Daniel L. Clemens , Adrie J.C. Steyn , Vivek V. Thacker , Joanne Turner , Larry S. Schlesinger , Jordi B. Torrelles","doi":"10.1016/j.mucimm.2024.01.001","DOIUrl":"10.1016/j.mucimm.2024.01.001","url":null,"abstract":"<div><p>The elderly population is highly susceptible to developing respiratory diseases, including tuberculosis, a devastating disease caused by the airborne pathogen <em>Mycobacterium tuberculosis</em> (<em>M.tb</em>) that kills one person every 18 seconds. Once <em>M.tb</em> reaches the alveolar space, it contacts alveolar lining fluid (ALF), which dictates host-cell interactions. We previously determined that age-associated dysfunction of soluble innate components in human ALF leads to accelerated <em>M.tb</em> growth within human alveolar macrophages. Here we determined the impact of human ALF on <em>M.tb</em> infection of alveolar epithelial type cells (ATs), another critical lung cellular determinant of infection. We observed that elderly ALF (E-ALF)-exposed <em>M.tb</em> had significantly increased intracellular growth with rapid replication in ATs compared to adult ALF (A-ALF)-exposed bacteria, as well as a dampened inflammatory response. A potential mechanism underlying this accelerated growth in ATs was our observation of increased bacterial translocation into the cytosol, a compartment that favors bacterial replication. These findings in the context of our previous studies highlight how the oxidative and dysfunctional status of the elderly lung mucosa determines susceptibility to <em>M.tb</em> infection, including dampening immune responses and favoring bacterial replication within alveolar resident cell populations, including ATs, the most abundant resident cell type within the alveoli.</p></div>","PeriodicalId":18877,"journal":{"name":"Mucosal Immunology","volume":null,"pages":null},"PeriodicalIF":8.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1933021924000011/pdfft?md5=4e3b7413de6752a7043b6414fc657de4&pid=1-s2.0-S1933021924000011-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139377998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}