mBio最新文献

{"title":"Host GPCR-cAMP signaling balances Gαs and Gαi activity to control intracellular <i>Brucella</i> infection.","authors":"Yoon-Suk Kang, James E Kirby","doi":"10.1128/mbio.00040-26","DOIUrl":"10.1128/mbio.00040-26","url":null,"abstract":"<p><p>In this study, we investigated the impact of G protein-coupled receptor (GPCR) signaling on the intracellular replication of the model pathogen <i>Brucella neotomae</i>. Building on a prior chemical genetics screen, we identified agonists of the Gαi-coupled adenosine A1 and dopamine D4 receptors as potent inhibitors of intracellular <i>Brucella</i> replication. In contrast, agonists of Gαs-coupled adenosine A2A or dopamine D1 receptors, as well as antagonists of A1 or D4 receptors, either failed to inhibit or enhanced intracellular replication. Wild-type <i>B. neotomae</i> induced a rapid, type IV secretion system-dependent increase in host-cell cAMP during early infection. ENBA and cilostamide prevented this infection-associated cAMP increase and completely inhibited intracellular growth; this effect was partially reversed by cell-permeable cAMP analogs. Using a real-time NanoBRET biosensor, we detected rapid Gαs activation within minutes of infection that was sustained during wild type but not ΔvirB4 infection and was abrogated by ENBA or cilostamide. Disruption of early Gαs-cAMP signaling redirected <i>Brucella</i>-containing vacuoles (BCVs) to replication-incompatible phagolysosomal and autophagy-associated compartments. Collectively, these data support a model in which early GPCR signaling dynamics, balancing Gαs and Gαi pathways, are critical for the establishment of productive intracellular <i>Brucella</i> infection.IMPORTANCE<i>Brucella</i> species cause chronic infections by surviving and multiplying inside immune cells. To do this, <i>Brucella</i> must remodel the membrane-bound compartment that surrounds it after uptake, steering it away from destructive lysosomes and toward a permissive niche where replication can occur. We found that <i>Brucella</i> rapidly triggers a host signaling response controlled by G protein-coupled receptors, leading to a rise in a common cellular messenger molecule (cAMP) within minutes of infection. This early signal depends on the bacterial type IV secretion system and is required to build the replication-permissive compartment. When we disrupted this signaling with small molecules, bacteria were rerouted into degradative, autophagy-associated compartments and failed to establish productive infection. These results reveal an early host signaling checkpoint that <i>Brucella</i> engages to establish its intracellular niche and suggest that targeting host signaling dynamics, rather than bacterial viability directly, may provide new strategies to block intracellular infection.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0004026"},"PeriodicalIF":4.7,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147774770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Robust ammonia oxidation by \"<i>Candidatus</i> Nitrosacidococcus tergens\" across a broad pH range.","authors":"Ida F Peterse, Claudia Frey, Reinier A Egas, Guylaine H L Nuijten, Annelies J Veraart, Sebastian Lücker","doi":"10.1128/mbio.02975-25","DOIUrl":"https://doi.org/10.1128/mbio.02975-25","url":null,"abstract":"<p><p>Acidophilic ammonia-oxidizing bacteria (AOB) have only recently been discovered. These organisms hold great promise for acidic wastewater treatment; however, their physiology remains poorly understood compared to that of neutrophilic AOB. Here, we investigated the physiology of the acidophilic AOB <i>\"Candidatus</i> Nitrosacidococcus tergens<i>\"</i> sp. RJ19 across a broad pH range (2.5-7.0) using a specialized bioreactor system. We monitored nitrogen (N) transformations combined with microbial community composition and transcriptomic profiles, focusing on nitrogen metabolism and proton stress responses. Our results show that above pH 6.0, \"<i>Ca</i>. Na. tergens<i>\"</i> performs complete and stoichiometric conversion of ammonium to nitrite, coinciding with isotopic fractionation effects specific for ammonia oxidation and increased expression of key ammonia oxidation genes. The apparent absence of <i>nirK</i> and <i>cycA</i> did not impede ammonia oxidation, suggesting that these genes are non-essential in this context. Below pH 6.0, nitric oxide and nitrate accumulated, and nitrous oxide (N₂O) levels, although negligible compared to the other N-compounds, peaked near pH 4.0. Stable isotope analysis, including the site-specific ¹⁵N-enrichment at the inner (α) and outer (β) nitrogen positions of the N₂O molecule, indicated nitrifier-denitrification as the source of N₂O, supported by the highest <i>norB</i> expression at this pH. These findings provide new insights into the acid-tolerant physiology of \"<i>Ca</i>. Na. tergens<i>\"</i> and advance its potential application in engineered nitrogen removal systems under acidic conditions.</p><p><strong>Importance: </strong>The world is facing a climate crisis intensified by human-driven nutrient pollution. Ammonia and the bacteria that oxidize it are central both to the global nitrogen cycle and to wastewater treatment. The acidophilic ammonia oxidizer \"<i>Candidatus</i> Nitrosacidococcus tergens\" was previously shown to oxidize ammonia under highly acidic conditions; however, a complete understanding of its metabolism is lacking. Our study now shows that \"<i>Ca</i>. Na. tergens\" performs canonical ammonia oxidation across a broad pH range. At pH values below 6, however, a combination of chemical and biological processes leads to the production of nitrate, nitric oxide, and the greenhouse gas nitrous oxide. In addition, we show that these bacteria adapt to proton stress through mechanisms beyond transcriptional mechanisms. Our study highlights the robust metabolism of acidophilic ammonia oxidizers and expands our understanding of nitrification under acidic conditions.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0297525"},"PeriodicalIF":4.7,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147775727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Major type IV pilin of <i>Legionella pneumophila</i> enhances bacterial iron acquisition/assimilation, independently of its role in piliation.","authors":"Armando Barajas, Joshua Mayoral, Nicholas P Cianciotto","doi":"10.1128/mbio.00596-26","DOIUrl":"https://doi.org/10.1128/mbio.00596-26","url":null,"abstract":"<p><p>We identified a locus within the genome of <i>Legionella pneumophila</i> strain 130b that encodes two related type IV pilins, PilA1 and PilA2. Based on <i>in silico</i> analyses, both proteins were predicted to be major pilins in all <i>L. pneumophila</i> strains and nearly all <i>Legionella</i> species. Utilizing immunoblot analysis of sheared-cell supernatants, immunofluorescence microscopy, and whole-cell ELISA, we confirmed that PilA2 (but not PilA1) behaves as a major pilin, and mutant analysis documented that PilA2-containing type IV pili (T4P) are required for DNA uptake, and subject to retraction by PilT. Unexpectedly, a <i>pilA2</i> mutant, but not its complement, had impaired growth on solid and liquid media depleted of iron, indicating that PilA2 can promote growth in low-iron conditions. However, mutants lacking PilT, PilD, or PilS/PilR did not exhibit this phenotype, implying that PilA2's newfound role does not involve inclusion into T4P, cleavage/maturation from prepilin to pilin, or the signal transduction pathway that often modulates the expression of pilin, along with other genes. Mutants lacking the FeoB Fe²⁺ transporter, LbtC siderophore transporter, or Ccm cytochrome maturation showed even greater defects on low-iron agar media when <i>pilA2</i> mutations were introduced into them, suggesting that PilA2 functions within a novel iron-uptake pathway. Compatible with this, the <i>pilA2</i> mutant, but not its complement, exhibited increased resistance to streptonigrin and heightened expression of iron-regulated genes. Finally, although unimpaired for growth within amoebae, the <i>pilA2</i> mutant displayed increased biofilm formation. Overall, this study reveals a novel role for a type IV pilin in bacterial growth in iron acquisition/assimilation.</p><p><strong>Importance: </strong><i>Legionella pneumophila</i> is the main cause of Legionnaires' disease, an increasingly prevalent pneumonia. Prior studies indicated that <i>L. pneumophila</i> expresses type IV pili, a common form of pili that is mainly known for mediating DNA uptake, twitching motility, and attachment to biotic and abiotic surfaces. By utilizing a variety of <i>in silico</i> and experimental approaches, wehave helped redefine the major structural component (pilin) of the <i>L. pneumophila</i> pili. More significantly, we uncovered a heretofore unknown and seemingly novel role for the pilin in <i>L. pneumophila</i> growth in low-iron conditions and iron acquisition/assimilation. These findings have broad implications for understanding other bacteria and infectious diseases, as well as offering fresh insight into the roles of pilins in bacterial physiology and the mechanisms of iron assimilation.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0059626"},"PeriodicalIF":4.7,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147775335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emergence of vaccine-derived poliovirus strains from the novel oral polio vaccine in the Central African Republic.","authors":"Joël W Doté, Marie-Line Joffret, Arthur Mazitchi, Dimitra Klapsa, Georges Kouatcho, Ernest Kalthan, Nolwenn Jouvenet, Javier Martin, Ionela Gouandjika-Vasilache, Maël Bessaud","doi":"10.1128/mbio.00669-26","DOIUrl":"https://doi.org/10.1128/mbio.00669-26","url":null,"abstract":"&lt;p&gt;&lt;p&gt;The Central African Republic (CAR) is a high-risk country for poliomyelitis outbreaks because of difficulties in closing immunity gaps due to the lack of resources, logistics issues, and insecurity. The country experienced multiple poliomyelitis cases since 2019. A novel type 2 oral polio vaccine (nOPV2) engineered to lower the risk of reversion of the vaccine strain was deployed in the CAR in 2022-2023 to counter active serotype 2 poliovirus transmission. This study reports routine poliovirus surveillance conducted from November 2021 through October 2023 in the CAR. Polioviruses isolated from stools and wastewater were genetically characterized based on the VP1-encoding region that was sequenced by Sanger technique. Whole-genome sequencing was conducted on all nOPV2-derived isolates and on a subset of Sabin-2-derived isolates by using Illumina technology. Fifty-four vaccine-derived poliovirus type 2 isolates were identified, belonging to eight distinct emergences: four emergences were derived from the historical vaccine strain and four from the nOPV2. The nOPV2 derivatives that had kept the original 5' untranslated region (5'UTR) did not display any reversions in the modified domain V, which is the primary attenuation site. Nonetheless, some nOPV2 derivatives had lost this domain through recombination with members of species &lt;i&gt;Enterovirus coxsackiepol&lt;/i&gt; (EV-C). Our analyses demonstrate that recombination took place shortly after the vaccine rollout. The data demonstrate that nOPV2's genetic stabilization curtails genetic drift-driven reversion but does not eliminate recombination. This underscores the need for comprehensive EV-C surveillance alongside poliovirus monitoring, especially in Sub-Saharan Africa where they are relatively abundant.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Importance: &lt;/strong&gt;The novel oral polio vaccine of serotype 2 (nOPV2) was engineered to prevent the emergence of revertant polio vaccine strains, which caused numerous outbreaks in the 2000s and 2010. Since 2021, it has been used in many countries, especially in Sub-Saharan Africa, to contain poliomyelitis outbreaks. In 2023, double recombinant nOPV2-derived isolates that had lost all the attenuation determinants were detected in the Central African Republic (CAR). Several of these were the first nOPV2 revertant isolates ever reported to the Global Polio Eradication Initiative, thereby demonstrating that the engineered modifications in nOPV2 do not entirely prevent reversion via recombination with non-polio enteroviruses of species &lt;i&gt;Enterovirus coxsackiepol&lt;/i&gt; (EV-Cs). This study corroborates the increased genetic stability of nOPV2 compared to the historical vaccine strain but demonstrates that reversion through recombination with non-polio EV-Cs remains possible. This underscores the need for comprehensive EV-C surveillance alongside poliovirus monitoring, especially in Sub-Saharan Africa where EV-Cs are particularly abundant. In particular, assessing EV-C potential seasonal cir","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0066926"},"PeriodicalIF":4.7,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147774647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanical deformation inhibits growth and migration of <i>S. aureus</i> within submicrometer channels.","authors":"Kelsey G DeFrates, Junsung Lee, Gissell Jimenez, Jae Won Hwang, Mariana G Pinho, Christopher J Hernandez","doi":"10.1128/mbio.00194-26","DOIUrl":"https://doi.org/10.1128/mbio.00194-26","url":null,"abstract":"<p><p>Bacteria colonize surfaces in the environment and can also penetrate tissues and materials by entering micro- and nano-scale cracks and pores. <i>Staphylococcus aureus</i> has been observed within nanoscale channels in bone that are 2-3 times smaller than cell diameter. Inside the bone, bacteria are protected from host immunity and systemic antibiotics, potentially contributing to chronic and recurrent infections. The physical mechanisms that enable bacteria to enter channels smaller than the cell width are unclear. It has been proposed that bacteria traverse narrow passages through division, such that daughter cells form within small channels and proliferate in chains down the channel length. Here, we use microfluidics to test the idea that <i>S. aureus</i> can traverse submicrometer channels through growth. We examined the net migration of growing cell chains within tapered nanochannels (width ~1.5-0.3 μm). We found that proliferation can facilitate migration, but only to cell deformations of 600 nm (65% cell width). Below 600 nm, mechanical confinement significantly slows or completely inhibits division in single cells. Interestingly, growth arrest occurs independent of the Z-ring assembly and is unrelated to the initial orientation of the division plane. Thus, our findings suggest that it is unlikely for <i>S. aureus</i> to traverse nanoscale channels via division.</p><p><strong>Importance: </strong>Bacteria that colonize materials and tissues within the body can be difficult to remove, even with thorough cleaning and application of antibiotics. Recent studies show that bacteria not only colonize the surfaces of tissues in the body but can also squeeze into naturally occurring pores and channels and thereby gain protection from immune cells and antibiotics. Here, we ask how physical forces and cell growth might enable bacteria to enter small pores within materials. We use microfluidic devices to study the growth and migration of the human pathogenic bacteria, <i>S. aureus</i>.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0019426"},"PeriodicalIF":4.7,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147775578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phylogenetic diversity, functional pathways, and network interactions of ocular chlamydia-like organisms (CLOs) in trachoma-endemic Ethiopia.","authors":"Olusola Olagoke, Xinhe Zheng, Seongwon Chung, Hiwot Degineh Mengistie, Kaleb Asfaha, Timothy D Read, Deborah Dean","doi":"10.1128/mbio.00534-26","DOIUrl":"10.1128/mbio.00534-26","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Trachoma is the leading infectious cause of blindness worldwide and classically attributed to C&lt;i&gt;hlamydia trachomatis&lt;/i&gt; (Ct). However, other members of the phylum Chlamydiae, particularly environmental chlamydia-like organisms (CLOs), may modulate ocular ecology and influence disease outcomes. Here, we investigated CLO distribution, phylogeny, and microbiome associations among 1,059 individuals from trachoma-endemic communities in Ethiopia using targeted 16S rRNA sequencing and metagenomic shotgun sequencing. CLOs were detected in 249 (23.3%) participants of all ages and sexes and were significantly less likely to be associated with Ct or trachomatous scarring (TS) and trichiasis (TT). Phylogenetic analyses revealed extensive CLO diversity with six novel phylotypes, the most abundant of which was ancestral to &lt;i&gt;Sorochlamydiaceae&lt;/i&gt;-a family linking pathogenic &lt;i&gt;Chlamydiaceae&lt;/i&gt;, which includes the genus &lt;i&gt;Chlamydia&lt;/i&gt;, and symbionts of protists. CLO-positive microbiomes exhibited significantly greater species richness and evenness with distinct differences in community composition relative to CLO-negative microbiomes. These effects were most pronounced among males and older adults. Functional profiling revealed widespread depletion of biosynthetic and metabolic pathways in CLO-positive microbiomes, particularly in participants with TS/TT, suggesting reduced community biosynthetic capacity and niche modification. Species interaction network analyses demonstrated substantial reorganization of microbial associations in the presence of CLOs with increased connectivity and centrality compared to CLO-negative networks. These findings identify CLOs as prevalent, phylogenetically diverse, and ecologically influential members of the microbiome. Their inverse association with Ct and TS/TT underscores the importance of considering intracellular symbionts beyond Ct in understanding conjunctival microbial ecology, resilience, and trachoma pathogenesis and for designing novel control strategies.IMPORTANCETrachoma caused by &lt;i&gt;Chlamydia trachomatis&lt;/i&gt; (Ct) remains the leading infectious cause of blindness globally. While control efforts focus exclusively on Ct, other members of the phylum Chlamydiae, such as chlamydia-like organisms (CLOs), inhabit mucosal surfaces but remain understudied in the eye. Using targeted 16S rRNA and metagenomic shotgun sequencing of conjunctival samples from villagers in trachoma-endemic Ethiopia, CLOs were prevalent (23.3%; 249/1,059), phylogenetically diverse, including novel Chlamydiae phylotypes, and inversely associated with both Ct infection and severe scarring disease. CLO microbiomes had increased microbial diversity, altered community composition, depleted metabolic pathway abundance, and reorganized species interaction networks compared to CLO-negative microbiomes. These findings challenge the singular focus on Ct in trachoma control and research and suggest that CLOs represent ecologically significant memb","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0053426"},"PeriodicalIF":4.7,"publicationDate":"2026-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147775612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiple clades of regulators contribute to bacterial phosphate homeostasis and <i>Staphylococcus aureus</i> pathogenesis.","authors":"Caroline Vermilya, Eliot S Joya Sandoval, Jana N Radin, Gary J Olsen, Bin Z He, Thomas E Kehl-Fie","doi":"10.1128/mbio.00203-26","DOIUrl":"https://doi.org/10.1128/mbio.00203-26","url":null,"abstract":"<p><p>Phosphate is both essential for life and toxic, necessitating the tight regulation of its acquisition. Based on <i>Escherichia coli</i>, most bacteria are thought to use a single accessory protein that monitors import to regulate phosphate homeostasis. This work reveals that many bacteria possess multiple, distinct families of accessory regulators, with each family regulating homeostasis in conjunction with a unique importer family. The antibiotic-resistant pathogen <i>Staphylococcus aureus</i> can obtain phosphate from divergent environments and possesses accessory-transporter pairs from all three identified groups. Investigations with <i>S. aureus</i> revealed that all three accessory proteins can regulate phosphate homeostasis, but that there is a hierarchy, which is dictated by the environment. Multiple accessory regulators are independently necessary for <i>S. aureus</i> to cause infection. Thus, microbes possess not one, but multiple distinct groups of accessory regulatory proteins, and this diversity enables them to control phosphate homeostasis across environments, including those encountered during infection.IMPORTANCEPhosphate homeostasis is critical for bacterial survival, but this nutrient is simultaneously vital and harmful in excess. The prevailing model based on <i>Escherichia coli</i> proposed that bacteria monitor phosphate import through a sole accessory regulatory protein. This work both challenges and extends this paradigm by demonstrating that bacteria frequently possess multiple evolutionarily distinct accessory regulator families, with each tightly linked to a specific transporter. Using the versatile pathogen <i>Staphylococcus aureus</i>, this work demonstrates that these regulatory proteins function in an environment-dependent hierarchy to control phosphate balance. During host infection, multiple accessory regulators are independently necessary. This regulatory expansion represents a fundamental strategy by which bacteria adapt phosphate acquisition to their surroundings, particularly within a dynamic host environment.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0020326"},"PeriodicalIF":4.7,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147775600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pyrophosphate homeostasis in multiple subcellular compartments is essential in <i>Plasmodium falciparum</i>.","authors":"Ikechukwu Nwankwo, Hangjun Ke","doi":"10.1128/mbio.00475-26","DOIUrl":"https://doi.org/10.1128/mbio.00475-26","url":null,"abstract":"<p><p>Pyrophosphate is a byproduct of numerous cellular reactions that use ATP or other nucleoside triphosphates to synthesize DNA, RNA, protein, and various molecules. Its degradation into monophosphate is thus crucial for the survival and proliferation of all life forms. The human malaria parasite <i>Plasmodium falciparum</i> encodes two classes of pyrophosphatases to hydrolyze pyrophosphate. The first consists of <i>P. falciparum</i> proton pumping vacuolar pyrophosphatases (e.g., PfVP1), which localize to the parasite plasma membrane and work as proton pumps. The second includes <i>P. falciparum</i> soluble pyrophosphatases (PfsPPases), which have not been well characterized. Interestingly, the gene locus of PfsPPases encodes two isoforms, PfsPPase1 (PF3D7_0316300.1) and PfsPPase2 (PF3D7_0316300.2). PfsPPase2 contains a 51-amino acid organellar localization peptide that is absent in PfsPPase1. Here, we combine reverse genetics and biochemical approaches to identify the localization of PfsPPase1 and PfsPPase2 and elucidate their individual functions. We show that PfsPPases are essential for the asexual blood stages. While PfsPPase1 solely localizes to the cytoplasm, PfsPPase2 exhibits multiple localizations, including the mitochondrion, the apicoplast, and, to a lesser extent, the cytoplasm. Our data suggest that <i>P. falciparum</i> has taken a unique evolutionary trajectory in pyrophosphate metabolism by utilizing a leader sequence to direct sPPases to multiple organelles. This differs from model eukaryotes as they generally encode multiple sPPases at distinct genetic loci to facilitate pyrophosphate degradation in cytosolic and organellar compartments. The essentiality and divergence of PfsPPases also highlight them as promising targets for the development of novel antimalarial drugs.</p><p><strong>Importance: </strong>Malaria kills over 600,000 people annually. Understanding parasite biology is critical for identifying prospective drug targets. Malaria parasites maintain pyrophosphate (PPi) homeostasis in at least three subcellular compartments-the cytoplasm, mitochondrion, and apicoplast, where PPi is generated through various reactions. While cytoplasmic PPi is known to be degraded by soluble pyrophosphatase, it remains unclear how PPi is metabolized in the organelles of malaria parasites. Here, we discovered that <i>Plasmodium falciparum</i> encodes two soluble pyrophosphatase isoforms from a single genetic locus. The longer isoform contains an N-terminal leader sequence that targets the enzymes into the mitochondrion and the apicoplast. This dual targeting mechanism of soluble pyrophosphatases has not been previously reported in any organisms. We show that both isoforms are essential for parasite growth and development. These findings highlight the critical role of organellar PPi degradation and identify soluble pyrophosphatases as promising antimalarial drug targets.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0047526"},"PeriodicalIF":4.7,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147775730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Turning defense into damage: HIV-driven amyloidogenesis and neurotoxicity.","authors":"Feng Gu, Badeia Saed, Mojgan H Naghavi","doi":"10.1128/mbio.03083-25","DOIUrl":"https://doi.org/10.1128/mbio.03083-25","url":null,"abstract":"<p><p>With the continued spread of human immunodeficiency virus 1 (HIV-1) and its ability to enter and persist within the central nervous system (CNS), concerns have arisen regarding its impact on cognitive health. Indeed, during the early stages of the HIV pandemic, when effective treatments were unavailable, severe neurocognitive impairment was common. Although the widespread use of antiretroviral therapy (ART) has markedly reduced the severity, milder forms of HIV-associated neurocognitive disorders (HAND) remain prevalent. Similar to Alzheimer's disease (AD), elevated amyloid-β (Aβ) accumulation has been observed both intracellularly and extracellularly in the brains of HIV-infected individuals, based on autopsy studies. Aβ is generated through the amyloidogenic processing of amyloid precursor protein (APP), which is abundantly expressed in the brain. While the APP's role in AD pathogenesis has been well established, its broader physiological functions, particularly in the context of viral infections such as HIV-1, remain poorly understood. In the CNS, microglia are crucial for maintaining brain homeostasis and defending against viral infections. HIV-1, however, targets microglia, disrupting their antiviral capacity and contributing to neurotoxicity through multiple mechanisms, such as the release of viral proteins and host-derived neurotoxic factors including proinflammatory cytokines and Aβ. Moreover, HIV-infected microglia can influence neighboring cells such as astrocytes and neurons, further amplifying neurodegenerative processes. This review will focus on recent advances in understanding the antiviral role of APP and its processing during HIV-1 infection, highlighting how APP-mediated defense mechanisms intersect with neurotoxic pathways and the intercellular regulatory networks that link APP to HAND.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0308325"},"PeriodicalIF":4.7,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147729502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Met32 governs transcriptional control of sulfur metabolic flexibility and resistance to reactive sulfur species in the human fungal pathogen <i>Candida albicans</i>.","authors":"Anagha C T Menon, Faiza Tebbji, Mélanie Mecteau, Azadeh Alikashani, Antony T Vincent, Éric Rhéaume, Jean-Claude Tardif, Adnane Sellam","doi":"10.1128/mbio.00472-26","DOIUrl":"https://doi.org/10.1128/mbio.00472-26","url":null,"abstract":"<p><p>Although considerable advances have been made in understanding the metabolic machinery that enables bacteria to utilize sulfur sources, our understanding of the corresponding processes in fungi remains comparatively fragmentary. To explore the genetic circuit by which the highly prevalent human opportunistic yeast <i>Candida albicans</i> controls sulfur utilization, we characterized the transcriptional landscape associated with sulfur starvation in this fungus. We identified many desulfonation enzymes that were differentially modulated and showed that Jlp12, a sulfonate/α-ketoglutarate dioxygenase, was critical for the utilization of different sulfur sources found in many niches of the human host. We also uncovered that the zinc-finger transcription factor Met32 acts as a master regulator, modulating genes involved in sulfur utilization, including Jlp12. Importantly, we found that <i>C. albicans</i> Met32 exclusively regulates sulfur utilization genes, while in the <i>Saccharomyces cerevisiae</i> lineage, it controls methionine biosynthesis. This work also identified Seo13 as the first major facilitator superfamily transporter in fungi to transport the alternative sulfur source glutathione, under the direct control of Met32. Furthermore, we showed that Met32 modulates <i>C. albicans</i> tolerance to sulfite excess by tuning the basal transcriptional level of the superoxide dismutase Sod1. This underscores the dual role of Met32 in the breakdown of sulfur-containing metabolites and the neutralization of the resulting reactive sulfur species (RSS). Our study delineates a new mechanism by which fungal pathogens utilize sulfur sources and neutralize RSS and underscores its importance in fungal fitness <i>in vivo</i>.</p><p><strong>Importance: </strong><i>Candida albicans</i> is the most prevalent fungal colonizer of humans, and it is also the first cause of disseminated fungal infections leading to a high mortality rate. The ability of this yeast to metabolize a plethora of carbon and nitrogen sources inside the host is a critical asset for both the commensal and the pathogenic lifestyles of this yeast. Thus, these pathways represent attractive targets for antifungal therapy. While sulfur is an essential nutritional element for all living organisms, its contribution to fungal virulence remains understudied. Here, we describe new players of sulfur utilization metabolism in <i>C. albicans</i> and underline their importance in supporting fungal virulence. This work emphasizes the significance of targeting sulfur metabolic flexibility to manage fungal infections.</p>","PeriodicalId":18315,"journal":{"name":"mBio","volume":" ","pages":"e0047226"},"PeriodicalIF":4.7,"publicationDate":"2026-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147723346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}