mBio最新文献

{"title":"Human parainfluenza virus 3 field strains undergo extracellular fusion protein cleavage to activate entry.","authors":"Kyle Stearns, George Lampe, Rachel Hanan, Tara Marcink, Stefan Niewiesk, Samuel H Sternberg, Alexander L Greninger, Matteo Porotto, Anne Moscona","doi":"10.1128/mbio.02327-24","DOIUrl":"10.1128/mbio.02327-24","url":null,"abstract":"<p><p>Human parainfluenza virus 3 (HPIV3) infection is driven by the coordinated action of viral surface glycoproteins hemagglutinin-neuraminidase (HN) and fusion protein (F). Receptor-engaged HN activates F to insert into the target cell membrane and drive virion-cell membrane fusion. For F to mediate entry, its precursor (F0) must first be cleaved by host proteases. F0 cleavage has been thought to be executed during viral glycoprotein transit through the trans-Golgi network by the ubiquitously expressed furin because F0 proteins of laboratory-adapted viruses contain a furin recognition dibasic cleavage motif RXKR around residue 108. Here, we show that the F proteins of field strains have a different cleavage motif from laboratory-adapted strains and are cleaved by unidentified proteases expressed in only a narrow subset of cell types. We demonstrate that extracellular serine protease inhibitors block HPIV3 F0 cleavage for field strains, suggesting F0 cleavage occurs at the cell surface facilitated by transmembrane proteases. Candidate proteases that may process HPIV3 F <i>in vivo</i> were identified by a genome-wide CRISPRa screen in HEK293/dCas9-VP64 + MPH cells. The lung-expressed extracellular serine proteases TMPRSS2 and TMPRSS13 are both sufficient to cleave HPIV3 F and enable infectious virus release by otherwise non-permissive cells. Our findings support an alternative mechanism of F activation <i>in vivo</i>, reliant on extracellular membrane-bound serine proteases expressed in a narrow subset of cells. The proportion of HPIV3 F proteins cleaved and infectious virus release is determined by host cell expression of requisite proteases, allowing just-in-time activation of F and positioning F cleavage as another key regulator of HPIV3 spread.</p><p><strong>Importance: </strong>Enveloped viruses cause a wide range of diseases in humans. At the first step of infection, these viruses must fuse their envelope with a cell membrane to initiate infection. This fusion is mediated by viral proteins that require a critical activating cleavage event. It was previously thought that for parainfluenza virus 3, an important cause of respiratory disease and a representative of a group of important pathogens, this cleavage event was mediated by furin in the cell secretory pathways prior to formation of the virions. We show that this is only true for laboratory strain viruses, and that clinical viruses that infect humans utilize extracellular proteases that are only made by a small subset of cells. These results highlight the importance of studying authentic clinical viruses that infect human tissues for understanding natural infection.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0232724"},"PeriodicalIF":5.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11559058/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A review of virus host factor discovery using CRISPR screening.","authors":"Wayne Ren See, Meisam Yousefi, Yaw Shin Ooi","doi":"10.1128/mbio.03205-23","DOIUrl":"10.1128/mbio.03205-23","url":null,"abstract":"<p><p>The emergence of genome-scale forward genetic screening techniques, such as Haploid Genetic screen and clustered regularly interspaced short palindromic repeats (CRISPR) knockout screen has opened new horizons in our understanding of virus infection biology. CRISPR screening has become a popular tool for the discovery of novel host factors for several viruses due to its specificity and efficiency in genome editing. Here, we review how CRISPR screening has revolutionized our understanding of virus-host interactions from scientific and technological viewpoints. A summary of the published screens conducted thus far to uncover virus host factors is presented, highlighting their experimental design and significant findings. We will outline relevant methods for customizing the CRISPR screening process to answer more specific hypotheses and compile a glossary of conducted CRISPR screens to show their design aspects. Furthermore, using flaviviruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as examples, we hope to offer a broad-based perspective on the capabilities of CRISPR screening to serve as a reference point to guide future unbiased discovery of virus host factors.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0320523"},"PeriodicalIF":5.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11559068/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142469435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rab6a enables BICD2/dynein-mediated trafficking of human papillomavirus from the <i>trans-</i>Golgi network during virus entry.","authors":"Jeongjoon Choi, Kaitlyn Speckhart, Billy Tsai, Daniel DiMaio","doi":"10.1128/mbio.02811-24","DOIUrl":"10.1128/mbio.02811-24","url":null,"abstract":"<p><p>Rab GTPases control intracellular vesicular transport, including retrograde trafficking of human papillomavirus (HPV) during cell entry, guiding the virus from the endosome to the <i>trans-</i>Golgi network (TGN), the Golgi apparatus, and eventually the nucleus. Rab proteins have been identified that act prior to the arrival of HPV at the TGN, but Rab proteins operating in later stages of entry remain elusive. Here, we report that knockdown of Rab6a impairs HPV entry by preventing HPV exit from the TGN and impeding intra-Golgi transport of the incoming virus. Rab6a supports HPV trafficking by facilitating the association of HPV with dynein, a motor protein complex, and BICD2, a dynein adaptor, in the TGN. L2 can bind directly to GTP-Rab6a <i>in vitro</i>, and excess of either GTP-Rab6a or GDP-Rab6 inhibits HPV entry, suggesting that cycling between GDP-Rab6 and GTP-Rab6 is critical. Notably, Rab6a is crucial for HPV-BICD2 and HPV-dynein association in the TGN of infected cells but not in the endosome. Our findings reveal important features of the molecular basis of HPV infection, including the discovery that HPV uses different mechanisms to engage dynein at different times during entry, and identify potential targets for therapeutic approaches to inhibit HPV infection.</p><p><strong>Importance: </strong>Human papillomaviruses (HPVs) are small, non-enveloped DNA viruses that cause approximately 5% of human cancer. Like most other DNA viruses, HPV traffics to the nucleus during virus entry to successfully infect cells. We show here that HPV utilizes a cellular enzyme, Rab6a, during virus entry to engage the dynein molecular motor for transport along microtubules. Rab6a is required for complex formation between the HPV L2 capsid protein, dynein, and the dynein adaptor BICD2 in the <i>trans</i>-Golgi network (TGN). This complex is required for transport of the incoming virus out of the TGN as it journeys to the nucleus. Our findings identify potential targets for therapeutic approaches.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0281124"},"PeriodicalIF":5.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11559006/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142469443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fpa (YlaN) is an iron(II) binding protein that functions to relieve Fur-mediated repression of gene expression in <i>Staphylococcus aureus</i>.","authors":"Jeffrey M Boyd, Kylie Ryan Kaler, Karla Esquilín-Lebrón, Ashley Pall, Courtney J Campbell, Mary E Foley, Gustavo Rios-Delgado, Emilee M Mustor, Timothy G Stephens, Hannah Bovermann, Todd M Greco, Ileana M Cristea, Valerie J Carabetta, William N Beavers, Debashish Bhattacharya, Eric P Skaar, Lindsey N Shaw, Timothy L Stemmler","doi":"10.1128/mbio.02310-24","DOIUrl":"10.1128/mbio.02310-24","url":null,"abstract":"<p><p>Iron (Fe) is a trace nutrient required by nearly all organisms. As a result of the demand for Fe and the toxicity of non-chelated cytosolic ionic Fe, regulatory systems have evolved to tightly balance Fe acquisition and usage while limiting overload. In most bacteria, including the mammalian pathogen <i>Staphylococcus aureus</i>, the ferric uptake regulator (Fur) is the primary transcriptional regulator controlling the transcription of genes that code for Fe uptake and utilization proteins. Fpa (formerly YlaN) was demonstrated to be essential in <i>Bacillus subtilis</i> unless excess Fe is added to the growth medium, suggesting a role in Fe homeostasis. Here, we demonstrate that Fpa is essential in <i>S. aureus</i> upon Fe deprivation. Null <i>fur</i> alleles bypassed the essentiality of Fpa. The absence of Fpa abolished the derepression of Fur-regulated genes during Fe limitation. Bioinformatic analyses suggest that <i>fpa</i> was recruited to Gram-positive bacteria and, once acquired, was maintained in the genome as it co-evolved with Fur. Consistent with a role for Fpa in alleviating Fur-dependent repression, Fpa and Fur interacted <i>in vivo</i>, and Fpa decreased the DNA-binding ability of Fur <i>in vitro</i>. Fpa bound Fe(II) <i>in vitro</i> using oxygen or nitrogen ligands with an association constant that is consistent with a physiological role in Fe homeostasis. These findings have led to a model wherein Fpa is an Fe(II) binding protein that influences Fur-dependent regulation through direct interaction.IMPORTANCEIron (Fe) is an essential nutrient for nearly all organisms. If Fe homeostasis is not maintained, Fe may accumulate in the cytosol, which can be toxic. Questions remain about how cells efficiently balance Fe uptake and usage to prevent overload. Iron uptake and proper metalation of proteins are essential processes in the mammalian bacterial pathogen <i>Staphylococcus aureus</i>. Understanding the gene products involved in the genetic regulation of Fe uptake and usage and the physiological adaptations that <i>S. aureus</i> uses to survive in Fe-depleted conditions provides insight into pathogenesis. Herein, we demonstrate that the DNA-binding activity of the ferric uptake regulator transcriptional repressor is alleviated under Fe limitation, but uniquely, in <i>S. aureus</i>, alleviation requires the presence of Fpa.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0231024"},"PeriodicalIF":5.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11559061/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142503524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adaptive traits of <i>Nitrosocosmicus</i> clade ammonia-oxidizing archaea.","authors":"Saem Han, Seongwook Kim, Christopher J Sedlacek, Adeel Farooq, Chihong Song, Sujin Lee, Shurong Liu, Nicolas Brüggemann, Lena Rohe, Miye Kwon, Sung-Keun Rhee, Man-Young Jung","doi":"10.1128/mbio.02169-24","DOIUrl":"10.1128/mbio.02169-24","url":null,"abstract":"<p><p>Nitrification is a core process in the global nitrogen (N) cycle mediated by ammonia-oxidizing microorganisms, including ammonia-oxidizing archaea (AOA) as a key player. Although much is known about AOA abundance and diversity across environments, the genetic drivers of the ecophysiological adaptations of the AOA are often less clearly defined. This is especially true for AOA within the genus <i>Nitrosocosmicus</i>, which have several unique physiological traits (e.g., high substrate tolerance, low substrate affinity, and large cell size). To better understand what separates the physiology of <i>Nitrosocosmicus</i> AOA, we performed comparative genomics with genomes from 39 cultured AOA, including five <i>Nitrosocosmicus</i> AOA. The absence of a canonical high-affinity type ammonium transporter and typical S-layer structural genes was found to be conserved across all <i>Nitrosocosmicus</i> AOA. In agreement, cryo-electron tomography confirmed the absence of a visible outermost S-layer structure, which has been observed in other AOA. In contrast to other AOA, the cryo-electron tomography highlighted the possibility that <i>Nitrosocosmicus</i> AOA may possess a glycoprotein or glycolipid-based glycocalyx cell covering outer layer. Together, the genomic, physiological, and metabolic properties revealed in this study provide insight into niche adaptation mechanisms and the overall ecophysiology of members of the <i>Nitrosocosmicus</i> clade in various terrestrial ecosystems.</p><p><strong>Importance: </strong>Nitrification is a vital process within the global biogeochemical nitrogen cycle but plays a significant role in the eutrophication of aquatic ecosystems and the production of the greenhouse gas nitrous oxide (N₂O) from industrial agriculture ecosystems. While various types of ammonia-oxidizing microorganisms play a critical role in the N cycle, ammonia-oxidizing archaea (AOA) are often the most abundant nitrifiers in natural environments. Members of the genus <i>Nitrosocosmicus</i> are one of the prevalent AOA groups detected in undisturbed terrestrial ecosystems and have previously been reported to possess a range of physiological characteristics that set their physiology apart from other AOA species. This study provides significant progress in understanding these unique physiological traits and their genetic drivers. Our results highlight how physiological studies based on comparative genomics-driven hypotheses can contribute to understanding the unique niche of <i>Nitrosocosmicus</i> AOA.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0216924"},"PeriodicalIF":5.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11559005/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365783","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A dual program for CRP-mediated regulation in bacterial alarmone (p)ppGpp.","authors":"Li Zhao, Shi-Yu Zhou, Yu Fu, Jin-Long Shen, Bin-Cheng Yin, Di You, Bang-Ce Ye","doi":"10.1128/mbio.02430-24","DOIUrl":"10.1128/mbio.02430-24","url":null,"abstract":"<p><p>Gene expression and proper downstream cellular functions upon facing environmental shifts depend on the combined and cooperative regulation of genetic networks. Here, we identified cAMP receptor protein (CRP) as a master regulator of (p)ppGpp (guanosine tetra- and penta-phosphate) homeostasis. Via CRP-mediated direct transcriptional regulation of the (p)ppGpp synthetase/hydrolase RelA and SpoT, cAMP-CRP stimulates pervasive accumulation of (p)ppGpp under glucose-limiting conditions. Notably, CRP exerts a nonclassical property as a translational regulator through YfiQ-dependent acetylation of ribosome protein S1 at K247, which further enhances the translation of RelA, SpoT, and CRP itself. From a synthetic biology perspective, this self-activating feedback loop for (p)ppGpp synthesis highlights the function of <b><u>C</u></b>RP-<b><u>m</u></b>ediated <b><u>d</u></b>ual <b><u>e</u></b>nhancement (CMDE) in controlling bacterial gene expression, which enables stable activation of genetic circuits. CMDE applied in synthetic circuits leads to a stable increase in <i>p</i>-coumaric acid, cinnamic acid, and pinosylvin production. Our findings showed that CRP-mediated dual circuits for (p)ppGpp regulation enable robust activation that could address bioproduction and other biotechnological needs.IMPORTANCETranscriptional-translational coordination is fundamental for rapid and efficient gene expression in most bacteria. Here, we uncovered the roles of cAMP-CRP in this process. We found that CRP distinctly increases RelA and SpoT transcription and translation, and that acetylation of S1 at K247 accelerates the self-activation of the leading CRP under glucose-limiting conditions. We further found that elevated (p)ppGpp significantly impedes the formation of the cAMP-CRP complex, an active form responsible for transcriptional activation. A model was created in which cAMP-CRP and (p)ppGpp cooperate to dynamically modulate the efficiency of transcriptional-translational coordination responses to stress. More broadly, productive activation in synthetic circuits was achieved through the application of <b><u>C</u></b>RP-<b><u>m</u></b>ediated <b><u>d</u></b>ual <b><u>e</u></b>nhancement (CMDE), promising to inspire new approaches for the development of cell-based biotechnologies.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0243024"},"PeriodicalIF":5.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11559003/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SARS-CoV-2 ORF3a induces COVID-19-associated kidney injury through HMGB1-mediated cytokine production.","authors":"Chenyu Zhang, Volodymyr Gerzanich, Ruth Cruz-Cosme, Jiantao Zhang, Orest Tsymbalyuk, Cigdem Tosun, Bhargava Teja Sallapalli, Dongxiao Liu, Kaspar Keledjian, John C Papadimitriou, Cinthia B Drachenberg, Mohamed Nasr, Yanjin Zhang, Qiyi Tang, J Marc Simard, Richard Y Zhao","doi":"10.1128/mbio.02308-24","DOIUrl":"10.1128/mbio.02308-24","url":null,"abstract":"&lt;p&gt;&lt;p&gt;The primary challenge posed by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is COVID-19-related mortality, often exacerbated by additional medical complications, such as COVID-19-associated kidney injuries (CAKIs). Up to half of COVID-19 patients experience kidney complications, with those facing acute respiratory failure and kidney injury having the worst overall prognosis. Despite the significant impact of CAKI on COVID-19-related mortality and its enduring effects in long COVID, the underlying causes and molecular mechanisms of CAKI remain elusive. In this study, we identified a functional relationship between the expression of the SARS-CoV-2 ORF3a protein and inflammation-driven apoptotic death of renal tubular epithelial cells in patients with CAKI. We demonstrate &lt;i&gt;in vitro&lt;/i&gt; that ORF3a independently induces renal cell-specific apoptotic cell death, as evidenced by the elevation of kidney injury molecule-1 (KIM-1) and the activation of NF-kB-mediated proinflammatory cytokine (TNFα and IL-6) production. By examining kidney tissues of SARS-CoV-2-infected K18-ACE2 transgenic mice, we observed a similar correlation between ORF3a-induced cytopathic changes and kidney injury. This correlation was further validated through reconstitution of the ORF3a effects via direct adenoviral injection into mouse kidneys. Through medicinal analysis, we identified a natural compound, glycyrrhizin (GL4419), which not only blocks viral replication in renal cells, but also mitigates ORF3a-induced renal cell death by inhibiting activation of a high mobility group box 1 (HMGB1) protein, leading to a reduction of KIM-1. Moreover, ORF3a interacts with HMGB1. Overproduction or downregulation of &lt;i&gt;hmgb1&lt;/i&gt; expression results in correlative changes in renal cellular KIM-1 response and respective cytokine production, implicating a crucial role of HMGB1 in ORF3a-inflicted kidney injuries. Our data suggest a direct functional link between ORF3a and kidney injury, highlighting ORF3a as a unique therapeutic target contributing to CAKI.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Importance: &lt;/strong&gt;The major challenge of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the pandemic is COVID-19-related mortality, which has tragically claimed millions of lives. COVID-19-associated morbidity and mortality are often exacerbated by pre-existing medical conditions, such as chronic kidney diseases (CKDs), or the development of acute kidney injury (AKI) due to COVID-19, collectively known as COVID-19-associated kidney injuries (CAKIs). Patients who experience acute respiratory failure with CAKI have the poorest clinical outcomes, including increased mortality. Despite these alarming clinical findings, there is a critical gap in our understanding of the underlying causes of CAKI. Our study establishes a direct correlation between the expression of the SARS-CoV-2 viral ORF3a protein and kidney injury induced by ORF3a linking to CAKI. This functional","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0230824"},"PeriodicalIF":5.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11559048/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142349642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanisms regulating host cell death during <i>Leishmania</i> infection.","authors":"Juliane C R Fernandes, Dario S Zamboni","doi":"10.1128/mbio.01980-23","DOIUrl":"10.1128/mbio.01980-23","url":null,"abstract":"<p><p>Parasites from the <i>Leishmania</i> genus are the causative agents of leishmaniasis and primarily reside within macrophages during mammalian infection. Their ability to establish intracellular infection provides a secure niche for proliferation while evading detection. However, successful multiplication within mammalian cells requires the orchestration of multiple mechanisms that control host cell viability. In contrast, innate immune cells, such as macrophages, can undergo different forms of cell death in response to pathogenic intracellular microbes. Thus, modulation of these different forms of host cell death is crucial for Leishmaniasis development. The regulation of host cell apoptosis, a form of programmed cell death, is crucial for sustaining parasites within viable host cells. Accordingly, several studies have demonstrated evasion of apoptosis induced by dermotropic and viscerotropic <i>Leishmania</i> species. Conversely, the prevention of pyroptosis, an inflammatory form of cell death, ensures the establishment of infection by silencing the release of mediators that could trigger massive proinflammatory responses. This manuscript explores how <i>Leishmania</i> regulates various host cell death pathways and overviews seminal studies on regulating host cell apoptosis by different <i>Leishmania</i> species.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0198023"},"PeriodicalIF":5.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11559009/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142400698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emergent ecology in a microscale model of the surface ocean.","authors":"Falk Eigemann, Jutta Hoffmann, Charlotte Schampera, Shuting Liu, Luis M Bolaños, Mats Heemeyer, Craig A Carlson, Stephen Giovannoni, Ferdi L Hellweger","doi":"10.1128/mbio.02372-24","DOIUrl":"10.1128/mbio.02372-24","url":null,"abstract":"<p><p>Microbial processes operate at the microscale, which is not resolved by existing ecosystem models. Here, we present a novel model that simulates a 1 mL three-dimensional cube using a hybrid Lagrangian-Eulerian approach, at ecologically relevant timescales. The model simulates individual microbes, including three phytoplankton size classes with healthy, senescent, and dead lifecycle stages; copiotrophic and oligotrophic heterotrophic bacteria; and dissolved organic matter at 50 µm resolution. Diffusion, shear, sedimentation, chemotaxis, and attachment processes are explicitly resolved. The emerging quantitative representation of the ecosystem shows that (1) copiotrophs grow mostly attached to eukaryotic phytoplankters and get almost all of their carbon from them vs. oligotrophs that grow on exudates and lysates of cyanobacteria; (2) contrasting diel patterns in substrate appearance in the phycosphere vs. ambient water and growth of particle-associated copiotrophs vs. free-living oligotrophs; (3) attached bacteria reduce carbon flux from the phycosphere, lowering chemotactic efficiency toward eukaryotes below that toward cyanobacteria; (4) shear reduces chemotactic efficiency and fitness of the copiotroph; and (5) the main benefit of chemotaxis is to locate attachment partners. These patterns are consistent with available observations. Our study provides insights into the microscale ecology of marine bacteria, and the open-source code is a tool for further research in this area.IMPORTANCEA large amount of global CO₂ fixation is performed by marine phytoplankton, and a substantial fraction of that is released as dissolved organic carbon and further processed by heterotrophic bacteria. The interaction between phytoplankton and bacteria, i.e., the carbon flux between them, is therefore an important process in the global carbon and climate system. Some bacteria have developed specialized behavioral traits, like swimming and attachment, to increase their carbon acquisition. These interactions occur at the micrometer scale, for example, the immediate vicinity of phytoplankters (the phycosphere), but existing biogeochemical models typically only simulate down to the 1 meter vertical or ~100 kilometer horizontal scale. We present a new microscale model and use it to predict fluxes and other features in the surface ocean. The model makes important predictions about the fluxes between various types of phytoplankton and bacteria and the role of behavioral traits, and it provides a basis and tool for further research in this area.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0237224"},"PeriodicalIF":5.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11559031/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipophilic bisphosphonates reduced cyst burden and ameliorated hyperactivity of mice chronically infected with <i>Toxoplasma gondii</i>.","authors":"Melissa A Sleda, Zaid F Pitafi, WenZhan Song, Eric Oldfield, Silvia N J Moreno","doi":"10.1128/mbio.01756-24","DOIUrl":"10.1128/mbio.01756-24","url":null,"abstract":"<p><p>The current treatments for toxoplasmosis are only active against fast-growing tachyzoites, present in acute infections, with little effect on slow-growing bradyzoites within tissue cysts, present in latent chronic infections. The mitochondrion of <i>Toxoplasma gondii</i> is essential for its survival, and one of the major anti-parasitic drugs, atovaquone, inhibits the mitochondrial electron transport chain at the coenzyme Q:cytochrome c oxidoreductase site. Coenzyme Q (also known as ubiquinone [UQ]) consists of a quinone head and a lipophilic, isoprenoid tail that anchors UQ to membranes. The synthesis of the isoprenoid unit is essential for cell growth and is inhibited by lipophilic bisphosphonates, which inhibit the parasite growth. In this work, we investigated the effect of lipophilic bisphosphonates on the chronic stages of <i>T. gondii</i>. We discovered that three lipophilic bisphosphonates (BPH-1218, BPH-1236, and BPH-1238), effective for the acute infection, were also effective in controlling the development of chronic stages. We showed effectiveness by testing them against <i>in vitro</i> cysts and <i>in vivo</i> derived tissue cysts and, most importantly, these compounds reduced the cyst burden in the brains of chronically infected mice. We monitored the activity of infected mice non-invasively and continuously with a novel device termed the CageDot. A decrease in activity accompanied the acute phase, but mice recovered to normal activity and showed signs of hyperactivity when the chronic infection was established. Moreover, treatment with atovaquone or BPH-1218 ameliorated the hyperactivity observed during the chronic infection.IMPORTANCETreatment for toxoplasmosis is challenged by a lack of effective drugs to eradicate the chronic stages. Most of the drugs currently used are poorly distributed to the central nervous system, and they trigger allergic reactions in a large number of patients. There is a compelling need for safe and effective treatments for toxoplasmosis. Bisphosphonates (BPs) are analogs of inorganic pyrophosphate and are used for the treatment of bone disorders. BPs target the isoprenoid pathway and are effective against several experimental parasitic infections. Some lipophilic BPs can specifically inhibit the mitochondrial activity of <i>Toxoplasma gondii</i> by interfering with the mechanism by which ubiquinone is inserted into the inner mitochondrial membrane. In this work, we present the effect of three lipophilic BPs against <i>T. gondii</i> chronic stages. We also present a new strategy for the monitoring of animal activity during disease and treatment that is non-invasive and continuous.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0175624"},"PeriodicalIF":5.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11558998/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142469441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}