mSphere最新文献

{"title":"Advances in cytokine gene polymorphisms in tuberculosis.","authors":"Haiyang Fu, Wenqiang Sun, Ye Xu, Haiyun Zhang","doi":"10.1128/msphere.00944-24","DOIUrl":"https://doi.org/10.1128/msphere.00944-24","url":null,"abstract":"<p><p>Tuberculosis (TB), especially pulmonary tuberculosis (PTB), is a prevalent infectious disease affecting the respiratory system and is characterized by high morbidity, disability, and mortality rates that significantly impact the quality of life of patients and their families. Host genetic susceptibility plays a crucial role in the infection process of <i>Mycobacterium tuberculosis</i> (<i>M. tuberculosis</i>) with single nucleotide polymorphisms (SNPs) identified as key factors in the genetic loci associated with tuberculosis occurrence and progression. Research indicates that polymorphisms in cytokine genes-including interferons, interleukins, tumor necrosis factors, and chemokines-are closely linked to the onset, progression, and treatment outcomes of pulmonary tuberculosis. Investigating cytokine gene polymorphisms in PTB patients is essential for understanding disease mechanisms and prognosis. This review summarizes the role of cytokine polymorphisms in tuberculosis morbidity, elucidates the biological genetic mechanisms involved at the molecular level, and provides insights into clinical treatment strategies for TB.</p>","PeriodicalId":19052,"journal":{"name":"mSphere","volume":" ","pages":"e0094424"},"PeriodicalIF":3.7,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intranasal application of a bifunctional pertactin-RTX fusion antigen elicits protection of mouse airway mucosa against <i>Bordetella pertussis</i> colonization.","authors":"Carlos Espinosa-Vinals, Jana Holubova, Ondrej Stanek, Radim Osicka, Jiri Masin, Fresia Esther Arellano Herencia, Peter Sebo","doi":"10.1128/msphere.00959-24","DOIUrl":"https://doi.org/10.1128/msphere.00959-24","url":null,"abstract":"&lt;p&gt;&lt;p&gt;The adenylate cyclase toxin (ACT, AC-Hly, or CyaA) plays a key role in airway infections by &lt;i&gt;Bordetella pertussis&lt;/i&gt; and ablates the oxidative burst and opsonophagocytic capacity of sentinel phagocytes. CyaA fragments eliciting toxin-neutralizing antibodies are considered prime antigen candidates for improved acellular pertussis (aP) vaccines but their contribution to aP-mediated protection against &lt;i&gt;B. pertussis&lt;/i&gt; infection awaits demonstration. We explored whether hybrid antigens inducing simultaneously CyaA-neutralizing and anti-Prn opsonizing antibody responses can enhance aP-elicited protection of mouse airways from infection. Fusion to the N-terminus of an RTX908 antigen derived from CyaA enabled an accelerated folding of the pertactin passenger domain (rPrn) in function of calcium loading of the RTX908 moiety and conferred on the rPrn-RTX908 fusion antigen a superior capacity to induce functional anti-Prn IgG antibodies. The rPrn-RTX908 fusion antigen also elicited CyaA neutralizing anti-RTX antibodies that relieved the toxin-imposed inhibition of oxidative burst and opsonophagocytic uptake of &lt;i&gt;B. pertussis&lt;/i&gt; bacteria by HL-60 cells exposed to physiological concentrations of the CyaA toxin. Intranasal immunization of mice with the rPrn-RTX908 antigen admixed into a PT and FHA-based aP vaccine elicited specific sIgA responses in mucosal secretions (saliva) and conferred a significantly enhanced protection of mouse lung and nose mucosa against &lt;i&gt;B. pertussis&lt;/i&gt; infection, yielding a significantly accelerated clearance of bacteria from the infected lungs within a single day from infection. These results demonstrate the added value of anti-CyaA antibodies elicited by intranasal application of the rPrn-RTX908 fusion antigen in the protection of the airway against &lt;i&gt;B. pertussis&lt;/i&gt; infection.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Importance: &lt;/strong&gt;Despite high vaccine coverage, unexpectedly massive whooping cough outbreaks are currently resurging in the most developed countries using the acellular pertussis (aP) vaccine. Accelerated development of improved aP vaccines, conferring a more complete and longer-lasting protection of the airway from &lt;i&gt;Bordetella pertussis&lt;/i&gt; infection, is sorely needed. The highly immunosuppressive RTX adenylate cyclase toxin (CyaA) was proposed as a prime antigen candidate for inclusion into improved aP vaccines. We show here that a soluble RTX-derived antigen fused to the major opsonizing antibody target pertactin (rPrn-RTX908 hybrid) elicits opsonizing and toxin-neutralizing antibody responses that relieve the CyaA-imposed block of bactericidal opsonophagocytic uptake capacities of sentinel phagocytes. Intranasal immunization with the rPrn-RTX908 hybrid antigen then enables a significantly accelerated clearance of &lt;i&gt;B. pertussis&lt;/i&gt; bacteria from mouse lungs and superior protection of mouse nasal mucosa from bacterial infection. These results unravel the added value of RTX antigen inclusion into the next generati","PeriodicalId":19052,"journal":{"name":"mSphere","volume":" ","pages":"e0095924"},"PeriodicalIF":3.7,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Variable phylosymbiosis and cophylogeny patterns in wild fish gut microbiota of a large subtropical river.","authors":"Yaqiu Liu, Xinhui Li, Konstantinos Ar Kormas, Yuefei Li, Huifeng Li, Jie Li","doi":"10.1128/msphere.00982-24","DOIUrl":"https://doi.org/10.1128/msphere.00982-24","url":null,"abstract":"<p><p>The persistence and specificity of fish host-microbial interaction during evolution is an important part of exploring the host-microbial symbiosis mechanism. However, it remains unclear how the environmental and host factors shape fish host-microbe symbiotic relationships in subtropical rivers with complex natural environments. Freshwater fish are important consumers in rivers and lakes and are considered keystone species in maintaining the stability of food webs there. In this study, patterns and mechanisms shaping gut microbiota community in 42 fish species from the Pearl River, in the subtropical zone of China, were investigated. The results showed that fish host specificity is a key driver of gut microbiota evolution and diversification. Different taxonomic levels of the host showed different degrees of contribution to gut microbiota variation. Geographical location and habitat type were the next most important factors in shaping gut microbiota across the 42 fishes, followed by diet and gut trait. Our results emphasized the contribution of stochastic processes (drift and homogenizing dispersal) in the gut microbial community assembly of freshwater fishes in the middle and lower reaches of the Pearl River. Phylosymbiosis is evident at both global and local levels, which are jointly shaped by complex factors including ecological or host physiological filtration and evolutionary processes. The core microbiota showed co-evolutionary relationships of varying degrees with different taxonomic groups. We speculate that host genetic isolation or habitat variation facilitates the heterogeneous selection (deterministic process), which occurs and results in different host-core bacterium specificity.</p><p><strong>Importance: </strong>Freshwater fish are regarded as the dominant consumers in rivers and lakes. Due to their diverse feeding modes, fish significantly enhance the trophic link and nutrient recycling/retention in aquatic habitats. For this, they are often considered keystone species in maintaining the stability of food webs in rivers and lakes. A significant part of fish nutrition is essentially mediated by their gut microbiota, which can enhance fish tolerance to fluctuations in external resources and improve the efficiency of nutrients extracted from various food sources. As gut bacterial symbionts have a profound impact on the nutrition and development of their hosts, as well as their overall fitness, it is critical to answer the question of how hosts maintain these benefits by procuring or inheriting these vital symbionts, which is still largely unanswered, especially for freshwater fish. Our study provides new insights into the co-evolutionary relationship between wild fish and their symbiotic microbiome, the hidden diversity of gut microbiome, and the ecological adaptation potential of wild freshwater fish.</p>","PeriodicalId":19052,"journal":{"name":"mSphere","volume":" ","pages":"e0098224"},"PeriodicalIF":3.7,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143731036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamics of the gut microbiome in subjects challenged with <i>Shigella sonnei</i> 53G in a controlled human infection model.","authors":"Zachary Liechty, Arianna Baldwin, Sandra Isidean, Akamol Suvarnapunya, Robert Frenck, Chad Porter, Michael Goodson","doi":"10.1128/msphere.00906-24","DOIUrl":"https://doi.org/10.1128/msphere.00906-24","url":null,"abstract":"&lt;p&gt;&lt;p&gt;&lt;i&gt;Shigella&lt;/i&gt; is a significant cause of diarrhea, predominantly affecting children in low- and middle-income countries, as well as international travelers. Not all individuals exposed to &lt;i&gt;Shigella&lt;/i&gt; or other enteropathogens have symptomatic responses, and investigating the differences between symptomatic and asymptomatic individuals can further our understanding of enteropathogen proliferation and symptomatic responses. Here, we profiled the fecal microbiomes of 45 individuals infected with &lt;i&gt;Shigella sonnei&lt;/i&gt; strain 53G through 16S rRNA sequencing in a controlled human infection model before and during infection, after antibiotic treatment, and after clinical recovery. This model allowed for a detailed exploration of microbiome temporal dynamics during infection, as well as a comparative analysis between those with shigellosis (defined as severe symptoms caused by &lt;i&gt;Shigella&lt;/i&gt; infection, including severe diarrhea, fever, and/or abdominal pain) and those without shigellosis. Alpha diversity decreased to a greater degree in individuals with shigellosis. Perturbations in microbial composition during infection and antibiotic treatment were significantly larger in individuals diagnosed with shigellosis than in those who were not. Participants with shigellosis had persistent changes to their microbiomes after recovery, while those without shigellosis recovered to a composition resembling their pre-infection microbiomes. These persistent changes included taxa associated with gut inflammation, such as a decrease in &lt;i&gt;Faecalibacterium&lt;/i&gt; and an increase in &lt;i&gt;Ruminococcus gnavus&lt;/i&gt;. Furthermore, the initial microbiomes of participants who did not develop shigellosis had a greater abundance of taxa associated with short-chain fatty acid production than participants who did develop shigellosis, including &lt;i&gt;Bifidobacterium&lt;/i&gt;, &lt;i&gt;Roseburia&lt;/i&gt;, and &lt;i&gt;Faecalibacterium&lt;/i&gt;. These data could help prevent &lt;i&gt;Shigella&lt;/i&gt; infection or symptoms.IMPORTANCEDiarrheal disease is a major contributor to the global disease burden and can lead to an increased individual risk of chronic sequelae post-infection, such as irritable bowel syndrome, reactive arthritis, and altered gut permeability. Understanding the differential responses of individuals to enteropathogen exposure can elucidate factors that could lead to treatments or preventative measures to reduce the disease burden. Here, we use a controlled human infection model study to directly identify the effects of &lt;i&gt;Shigella sonnei&lt;/i&gt; 53G infection on the microbiome. We identified taxa that were more or less abundant in participants who would develop shigellosis during the study, as well as persistent changes after recovery in the microbiomes of participants who developed severe symptoms. Understanding these changes could elucidate ways to prevent &lt;i&gt;Shigella&lt;/i&gt; infection or recover altered microbiomes after recovery.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT02816","PeriodicalId":19052,"journal":{"name":"mSphere","volume":" ","pages":"e0090624"},"PeriodicalIF":3.7,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143731029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The essential kinase TgGSK regulates centrosome segregation and endodyogeny in <i>Toxoplasma gondii</i>.","authors":"Amanda Krueger, Sofia Horjales, Chunlin Yang, William J Blakely, Maria E Francia, Gustavo Arrizabalaga","doi":"10.1128/msphere.00111-25","DOIUrl":"10.1128/msphere.00111-25","url":null,"abstract":"<p><p>Intracellular replication is crucial for the success of apicomplexan parasites, including <i>Toxoplasma gondii</i>. Therefore, essential players in parasite replication represent potential targets for drug development. We have characterized TgGSK, a glycogen synthase kinase homolog that plays an important role in <i>Toxoplasma</i> endodyogeny. We have shown that TgGSK has a dynamic localization that is concurrent with the cell cycle. In non-dividing parasites, this kinase is highly concentrated in the nucleus. However, during division, TgGSK displays a cytosolic localization, with concentration foci at the centrosomes, a key organelle involved in parasite division, and the basal end. Conditional knockdown of TgGSK determined that it is essential for the completion of the lytic cycle and proper parasite division. Parasites lacking endogenous protein levels of TgGSK exhibited defects in division synchronicity and the segregation of the nucleus and apicoplast into forming daughter cells. These phenotypes are associated with defects in centrosome duplication and fission. Global phosphoproteomic analysis determined TgGSK-dependent phosphorylation of RNA-processing, basal end, and centrosome proteins. Consistent with the putative regulation of RNA-processing proteins, global transcriptomic analysis suggests that TgGSK is needed for proper splicing. Finally, we show that TgGSK interacts with GCN5b, a well-characterized acetyltransferase with roles in transcriptional control. Conversely, GCN5b chemical inhibition results in specific degradation of TgGSK. Thus, these studies reveal the involvement of TgGSK in various crucial processes, including endodyogeny and splicing, and identify acetylation as a possible mechanism by which this essential kinase is regulated.</p><p><strong>Importance: </strong>While infection with the parasite <i>Toxplasma gondii</i> is largely asymptomatic in healthy adults, severe disease and death can result in immunocompromised individuals and in those infected congenitally. With minimal treatments for toxoplasmosis available, it is crucial to study parasite-specific processes to identify new drug targets. This study investigated the protein TgGSK, uncovering its essentiality for parasite proper division and survival. We performed an in-depth study of the functional role of this kinase. Importantly, TgGSK was shown to bear higher homology to plant proteins than its mammalian counterparts, which may allow for specific targeting of this protein.</p>","PeriodicalId":19052,"journal":{"name":"mSphere","volume":" ","pages":"e0011125"},"PeriodicalIF":3.7,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143731032","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Seasonality and dynamics of schistosomiasis in the environment: usefulness of environmental DNA (eDNA) surveillance system at a community level for risk mapping schistosomiasis in Ekiran Village, Leyte, Philippines.","authors":"Mark June Revolteado, Marcello Otake Sato, Joseph Valencia, Mario Jiz, Eleonor Cervantes, Ralph Aniceto, Marianette Inobaya, Darren Gray, Catherine A Gordon, Pengfei Cai, Yasuhito Sako, Megumi Sato","doi":"10.1128/msphere.01061-24","DOIUrl":"https://doi.org/10.1128/msphere.01061-24","url":null,"abstract":"<p><p>Schistosomiasis, primarily caused by <i>Schistosoma japonicum</i> (Sj) in Asia, remains a major health concern in the Philippines, affecting 12.4 million people and causing symptoms like fever, abdominal pain, and hepatosplenomegaly. Chronic disease leads to stunting in children, and reinfection persists despite efforts to reduce morbidity. Current strategies focused on mass drug administration (MDA) and sporadic snail surveys, leaving gaps in monitoring and mitigating schistosomiasis transmission in the environment. To address these issues, this study refined an environmental DNA (eDNA)-based qualitative real-time polymerase chain reaction assay by making it field-applicable and multiplex, to detect both the parasite <i>S. japonicum</i> and its intermediate snail host, <i>Oncomelania hupensis quadrasi</i> (Ohq), using water samples. We surveyed the 30 sentinel sites quarterly-from July 2023 to March 2024-in Ekiran Village, Alangalang, Leyte, Philippines. Collectively, the eDNA of <i>O.h. quadrasi</i> was detected in 18 sites and that of <i>S. japonicum</i> eDNA was detected in 16 sites, while direct snail observation confirmed the presence in only five sites, with infected snails found in only one site. Consequently, the assay described temporal variation of Ohq and Sj, revealing the dynamics of Ohq colonies and Sj in Ekiran's water sources. The eDNA confirmed the focality of Ohq and showed the erratic presence of Sj. Interestingly, both target species' eDNA was observed more during the rainy season (December and March), which suggests a higher infection probability during this period. Integrating eDNA detection system with the existing control programs will enhance the identification of transmission hotspots, which may aid in reducing exposure risk for both humans and animals in the endemic areas.</p><p><strong>Importance: </strong>This study aimed to fill the gaps in monitoring and mitigating schistosomiasis transmission in the environment. This field-applicable environmental DNA (eDNA)-based qualitative real-time polymerase chain reaction (qPCR) detection system focused on effectively detecting <i>Schistosoma japonicum</i> and its snail intermediate host, <i>Oncomelania hupensis quadrasi</i>, at the community level, moving from the traditional detection methods that are labor-intensive, less sensitive, and exposing surveyors to potential risk of infection. By introducing a field-applicable eDNA-based qPCR assay, this research provides a sensitive, non-invasive, and rapid molecular method for detecting <i>S. japonicum</i> and <i>O.h. quadrasi</i> in the environment. Additionally, the study not only provided insights in enhanced surveillance strategies but also contributed to a holistic eco-health approach by generating hazard maps for potential transmission and contamination sites, which could improve future control efforts and resource allocation for schistosomiasis elimination.</p>","PeriodicalId":19052,"journal":{"name":"mSphere","volume":" ","pages":"e0106124"},"PeriodicalIF":3.7,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143710685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reply to Nachamkin, \"Diversity of <i>Campylobacter</i> species in a rhesus macaque breeding colony\".","authors":"Rebecca L Bacon, Carolyn L Hodo, Sara D Lawhon","doi":"10.1128/msphere.00041-25","DOIUrl":"https://doi.org/10.1128/msphere.00041-25","url":null,"abstract":"","PeriodicalId":19052,"journal":{"name":"mSphere","volume":" ","pages":"e0004125"},"PeriodicalIF":3.7,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143701126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BALF editome profiling reveals A-to-I RNA editing associated with severity and complications of <i>Mycoplasma pneumoniae</i> pneumonia in children.","authors":"Yun-Yun Jin, Yun Guo, Su-Wan Xiong, Na Zhang, Jian-Huan Chen, Feng Liu","doi":"10.1128/msphere.01012-24","DOIUrl":"10.1128/msphere.01012-24","url":null,"abstract":"<p><p><i>Mycoplasma pneumoniae</i> is an important human respiratory pathogen that causes mild-to-moderate community-acquired <i>M. pneumoniae</i> pneumonia (MPP), particularly in children. RNA editing plays a vital role in pathogen infection and host immune response, but it remains largely unknown how it could be involved in the epigenetic regulation of host response to <i>M. pneumoniae</i> infection. In the present study, we performed an epitranscriptomic analysis of adenosine to inosine (A-to-I) editing in 39 bronchoalveolar lavage fluid (BALF) samples from the severe side (SS) and the opposite side (OS) of patients with MPP. Our editome profiling identified 87 differential RNA editing (DRE) events in 50 genes, especially missense editing events that recoded C-C motif chemokine receptor-like 2 (<i>CCRL2</i>, p.K147R) and cyclin I (<i>CCNI</i>, p.R75G). The expression of adenosine deaminase acting on RNA (<i>ADAR</i>) significantly increased on SS compared to OS and positively correlated with the average RNA editing level and individual DRE events. Meanwhile, functional enrichment analysis showed that DRE was observed in genes primarily associated with the negative regulation of innate immune response, type I interferon production, and cytokine production. Further comparison of SS between complicated MPP (CMPP) and non-complicated MPP (NCMPP) revealed RNA editing events associated with MPP complications, with a higher <i>ADAR</i> expression in CMPP than NCMPP. By identifying DRE events as biomarkers associated with MPP severity and complications, our editome profiling provides new insight into the potential role played by A-to-I RNA editing in modulating the host's immune system during <i>M. pneumoniae</i> infection.IMPORTANCEOur research investigates how <i>Mycoplasma pneumoniae</i>, a common respiratory pathogen, influences how our cells modify their genetic instructions. By studying RNA editing changes in bronchoalveolar lavage fluid from patients with <i>M. pneumoniae</i> pneumonia, we aim to investigate how <i>M. pneumoniae</i> infection alters epigenetics and contributes to the disease severity and complications. Understanding such epigenetic alterations not only sheds light on the mechanisms underlying <i>M. pneumoniae</i> infection but also holds potential implications for developing better diagnostic tools and therapies. Ultimately, this work may facilitate the design of more targeted treatments to alleviate the impact of respiratory infections caused by the pathogen. Our findings may also offer broader insights into how microbial infections reshape immune processes, highlighting the importance of RNA editing in host-pathogen interactions.</p>","PeriodicalId":19052,"journal":{"name":"mSphere","volume":" ","pages":"e0101224"},"PeriodicalIF":3.7,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11934315/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the differential localization of protein kinase A isoforms in <i>Candida albicans</i>.","authors":"Saif Hossain, Zhongle Liu, Nicole Robbins, Leah E Cowen","doi":"10.1128/msphere.01037-24","DOIUrl":"10.1128/msphere.01037-24","url":null,"abstract":"<p><p>The cAMP-dependent protein kinase A (PKA) plays important roles in a wide range of biological processes in eukaryotic organisms. In the fungal pathogen <i>Candida albicans</i>, PKA is a critical regulator of morphological transitions, which are a key virulence trait. PKA is composed of two catalytic isoforms, Tpk1 and Tpk2, which are often thought to act together in a complex with the regulatory subunit Bcy1. Although Tpk1 and Tpk2 have some redundant functions, they also have distinct cellular functions for which the mechanistic underpinnings remain largely elusive. Here, we constructed functional GFP-tagged fusion proteins for Tpk1, Tpk2, and Bcy1 to explore the localization of PKA isoforms. We observed that the PKA holoenzyme is mainly found in the cytoplasm, as Bcy1 is always excluded from the nucleus. Under glucose-replete conditions, both Tpk1 and Tpk2 translocate into the nucleus from the cytosol. In the presence of glycerol, Tpk1 resides in the cytosol, whereas Tpk2 and Bcy1 become enriched on the vacuolar membrane. As the C-terminal domains of Tpk are highly homologous, we investigated the localization and function of hybrid Tpk proteins with exchanged N-terminal domains. We found the catalytic C-terminus of Tpk1 is required for morphogenesis in solid medium, whereas the C-terminus of Tpk2 is critical for filamentation in liquid. Interestingly, the N-terminus of Tpk2 drives its localization to the vacuolar membrane. Our work highlights environmentally contingent localization patterns for the PKA subunits and suggests that the nuclear localization of Tpk is not sufficient to induce the filamentation program in a leading fungal pathogen of humans.IMPORTANCEFungal pathogens have a devastating impact on human health worldwide. They infect billions of people and kill more than 2.5 million per year. <i>Candida albicans</i> is a leading human fungal pathogen responsible for causing life-threatening systemic disease in immunocompromised individuals. A key virulence trait in <i>C. albicans</i> is the ability to switch between yeast and filamentous forms. The conserved protein kinase A (PKA) regulates diverse functions in the cell, including growth and filamentation. Although PKA has been studied in <i>C. albicans</i> for decades, the subcellular localization of PKA has not been thoroughly investigated. Here, we constructed functional GFP-tagged PKA subunits to explore their localization. We identified differential localization patterns for the PKA subunits that are carbon-source dependent and report that these proteins localize into foci in response to diverse environmental stresses. These findings further our understanding of a critical regulator of growth and virulence in <i>C. albicans</i>.</p>","PeriodicalId":19052,"journal":{"name":"mSphere","volume":" ","pages":"e0103724"},"PeriodicalIF":3.7,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11934313/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of l-serine and l-threonine in the energy metabolism and nutritional stress response of <i>Trypanosoma cruzi</i>.","authors":"Mayke Bezerra Alencar, Richard Marcel Bruno Moreira Girard, Marcell Crispim, Carlos Gustavo Baptista, Marc Biran, Frederic Bringaud, Ariel Mariano Silber","doi":"10.1128/msphere.00983-24","DOIUrl":"10.1128/msphere.00983-24","url":null,"abstract":"&lt;p&gt;&lt;p&gt;l-Serine and l-threonine have versatile roles in metabolism. In addition to their use in protein synthesis, these amino acids participate in the biosynthesis pathways of other amino acids and even phospholipids. Furthermore, l-serine and l-threonine can be substrates for a serine/threonine dehydratase (Ser/ThrDH), resulting in pyruvate and 2-oxobutyrate, respectively, thus being amino acids with anaplerotic potential. &lt;i&gt;Trypanosoma cruzi&lt;/i&gt;, the etiological agent of Chagas disease, uses amino acids in several biological processes: metacyclogenesis, infection, resistance to nutritional and oxidative stress, osmotic control, etc. This study investigated the import and metabolism of l-serine, l-threonine, and glycine in &lt;i&gt;T. cruzi&lt;/i&gt;. Our results demonstrate that these amino acids are transported from the extracellular environment into &lt;i&gt;T. cruzi&lt;/i&gt; cells through a saturable transport system that fits the Michaelis-Menten model. Our results show that l-serine and l-threonine can sustain epimastigote cell viability under nutritional stress conditions and stimulate oxygen consumption, maintaining intracellular ATP levels. Additionally, our findings indicate that serine plays a role in establishing the mitochondrial membrane potential in &lt;i&gt;T. cruzi&lt;/i&gt;. Serine is also involved in energy metabolism via the serine-pyruvate pathway, which stimulates the production and subsequent excretion of acetate and alanine. Our results demonstrate the importance of l-serine and l-threonine in the energy metabolism of &lt;i&gt;T. cruzi&lt;/i&gt; and provide new insights into the metabolic adaptations of this parasite during its life cycle.IMPORTANCE&lt;i&gt;Trypanosoma cruzi&lt;/i&gt;, the parasite responsible for Chagas disease, impacts 5-6 million individuals in the Americas and is rapidly spreading globally due to significant human migration. This parasitic organism undergoes a complex life cycle involving triatomine insects and mammalian hosts, thriving in diverse environments, such as various regions within the insect's digestive tract and mammalian cell cytoplasm. Crucially, its transmission hinges on its adaptive capabilities to varying environments. One of the most challenging environments is the insect's digestive tract, marked by nutrient scarcity between blood meals, redox imbalance, and osmotic stresses induced by the triatomine's metabolism. To endure these conditions, &lt;i&gt;T. cruzi&lt;/i&gt; has developed a remarkably versatile metabolic network enabling it to metabolize sugars, lipids, and amino acids efficiently. However, the full extent of metabolites this parasite can thrive on remains incompletely understood. This study reveals that, beyond conventional carbon and energy sources (glucose, palmitic acids, proline, histidine, glutamine, and alanine), three additional metabolites (serine, threonine, and glycine) play vital roles in the parasite's survival during starvation. Remarkably, serine and threonine directly contribute to ATP production through a serine/threonine ","PeriodicalId":19052,"journal":{"name":"mSphere","volume":" ","pages":"e0098324"},"PeriodicalIF":3.7,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11934319/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143557464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}