mSphere最新文献

{"title":"<i>Rickettsia rickettsii</i> RoaM negatively regulates expression of a limited number of rickettsial genes.","authors":"Adam M Nock, Tina R Clark, Sarah L Anzick, Elisabeth A Meyer, Rebecca Miller, Myndi G Holbrook, Stacy Ricklefs, Craig Martens, Justin Lack, Ted Hackstadt","doi":"10.1128/msphere.00077-25","DOIUrl":"https://doi.org/10.1128/msphere.00077-25","url":null,"abstract":"<p><p>The recently described rickettsial protein RoaM (regulator of actin-based motility) negatively regulates the production of actin tails, and its abrogation induces hyper-spreading behavior in many laboratory-adapted strains of <i>Rickettsia rickettsii</i>. RoaM is not surface exposed; thus, its mechanism of regulating actin-based motility is unclear. Using <i>R. rickettsii</i> strains derived from the virulent Sheila Smith strain that express varying levels of <i>roaM</i>, an RNA-seq experiment was performed. We found that <i>roaM</i>-overexpressing strains downregulate expression of at least six genes which may link the regulatory effects of RoaM to the phenotypic effect on motility. Genes regulated by RoaM were confirmed by RT-qPCR. Among the genes regulated is the secreted effector RarP2, which disrupts the trans-Golgi network. Two of the hypothetical proteins were shown to be secreted via fusion to a glycogen synthase kinase tag, which when phosphorylated reveals exposure to the host-cell cytosol. Taken together, these data support the hypothesis that RoaM affects transcription, downregulating rickettsial genes important for pathogenicity in the mammalian host but which are perhaps otherwise detrimental within the tick vector. To determine how RoaM activity may itself be regulated, we investigated a role of temperature in <i>roaM</i> transcription. RoaM expression itself is not temperature dependent, but many other rickettsial genes are, including some also regulated by RoaM. This suggests that rickettsiae utilize multiple mechanisms to control gene expression in response to environmental signals.</p><p><strong>Importance: </strong>RoaM was previously shown to repress the production of actin tails by unknown mechanisms. The <i>roaM</i> gene is negatively selected for in cell culture resulting in hyper-spreading mutants. This work reveals that rather than specifically regulating motility in <i>Rickettsia rickettsii</i>, a set of rickettsial genes is downregulated that includes the type IV secreted effector, <i>rarP2</i>, as well as two other secreted, putative effectors. Relatively few secreted effectors have been identified in <i>Rickettsia</i>. RoaM appears to be part of a larger biological program encompassing active spreading in mammalian cells and may be a critical component for <i>R. rickettsii</i> to transition from arthropod to mammalian host.</p>","PeriodicalId":19052,"journal":{"name":"mSphere","volume":" ","pages":"e0007725"},"PeriodicalIF":3.7,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803850","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":"Methods to evaluate the performance of a multicomponent meningococcal serogroup B vaccine.","authors":"Ray Borrow, Laura Tomasi Cont, Daniela Toneatto, Stefania Bambini, Shravani Bobde, Woo-Yun Sohn, Alessia Biolchi, Vega Masignani, Peter T Beernink, Maria Lattanzi","doi":"10.1128/msphere.00898-24","DOIUrl":"https://doi.org/10.1128/msphere.00898-24","url":null,"abstract":"<p><p>Meningococcal serogroup B (MenB) vaccine licensure was based on the assessment of vaccine-induced immune responses by human serum bactericidal antibody (hSBA) assay against a small number of antigen-specific strains complemented by strain coverage predictions. However, the evaluation of vaccine strain coverage is challenging because of genotypic and phenotypic diversity in surface-exposed MenB strain antigens. This narrative review considers the principal methods applied to assess the performance of a multicomponent MenB vaccine at different stages of its development. Traditional hSBA assay against a limited panel of strains is useful at all stages, while predicted strain coverage methods, such as the meningococcal antigen typing system, are used independent of clinical trials. A new method, the endogenous complement hSBA assay, has been developed to evaluate a vaccine's ability to induce a bactericidal immune response in clinical trials, in conditions that approximate real-world settings through the use of each vaccinee's serum as a source of complement and by testing against a panel of 110 epidemiologically representative MenB strains. Each assay, therefore, has a different scope during the vaccine's development and all complement each other, enabling comprehensive evaluation of the performance of multicomponent MenB vaccines, in advance of real-world evidence of vaccine effectiveness and vaccine impact.</p>","PeriodicalId":19052,"journal":{"name":"mSphere","volume":" ","pages":"e0089824"},"PeriodicalIF":3.7,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143803853","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":"A response to iron involving carbon metabolism in the opportunistic fungal pathogen <i>Candida albicans</i>.","authors":"Ritu Garg, Zhengkai Zhu, Francisco G Hernandez, Yiran Wang, Marika S David, Vincent M Bruno, Valeria C Culotta","doi":"10.1128/msphere.00040-25","DOIUrl":"https://doi.org/10.1128/msphere.00040-25","url":null,"abstract":"<p><p>Iron (Fe) is an essential micronutrient, and during infection, the host attempts to starve pathogens of this vital element through a process known as nutritional immunity. Successful pathogens have evolved means to evade this attack, an example being <i>Candida albicans,</i> the most prevalent human fungal pathogen. When Fe-starved, <i>C. albicans</i> induces multiple pathways for Fe uptake using the SEF1 trans-regulator, and we now describe a previously unrecognized effect of Fe on <i>C. albicans</i> metabolism that occurs independent of SEF1. Specifically, Fe limitation leads to inhibition of pyruvate dehydrogenase (PDH) connecting glycolysis to mitochondrial respiration. PDH inactivation involves loss of the LAT1 catalytic subunit harboring a lipoic acid co-factor. Protein lipoylation is a Fe-S dependent process, and lipoylated alpha-ketoglutarate dehydrogenase is also inhibited in Fe-starved <i>C. albicans</i>. SEF1 does not protect against PDH inactivation, and despite SEF1 induction of Fe import genes, cellular Fe levels drop dramatically during chronic Fe starvation. Such loss of LAT1 and lipoylation is also seen in Fe-starved bakers' yeast <i>Saccharomyces cerevisiae</i>. In both yeast species, glucose is diverted toward the pentose phosphate pathway (PPP) and PPP production of NADPH is increased in response to low Fe and PDH loss. Additionally, glucose consumption is lowered in Fe-starved <i>C. albicans</i>, and non-PDH alternatives to producing Ac-CoA are induced, including pyruvate bypass and fatty acid oxidation pathways. <i>C. albicans</i> can adapt well to the effects of micronutrient loss on cell metabolism.</p><p><strong>Importance: </strong>We describe a new response to Fe-starvation in a fungal pathogen involving carbon metabolism. Pyruvate dehydrogenase (PDH) that is central to glucose metabolism is inactivated at the post-translational level in Fe-starved cells. Nevertheless, the fungal pathogen can thrive by activating backup systems for metabolizing glucose. Methods that inhibit these compensatory pathways for carbon metabolism may prove beneficial in future anti-fungal strategies.</p>","PeriodicalId":19052,"journal":{"name":"mSphere","volume":" ","pages":"e0004025"},"PeriodicalIF":3.7,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143780615","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":"Metabolic adaptability and nutrient scavenging in <i>Toxoplasma gondii</i>: insights from ingestion pathway-deficient mutants.","authors":"Patrick A Rimple, Einar B Olafsson, Benedikt M Markus, Fengrong Wang, Leonardo Augusto, Sebastian Lourido, Vern B Carruthers","doi":"10.1128/msphere.01011-24","DOIUrl":"https://doi.org/10.1128/msphere.01011-24","url":null,"abstract":"&lt;p&gt;&lt;p&gt;The obligate intracellular parasite &lt;i&gt;Toxoplasma gondii&lt;/i&gt; replicates within a specialized compartment called the parasitophorous vacuole (PV). Recent work showed that despite living within a PV, &lt;i&gt;Toxoplasma&lt;/i&gt; endocytoses proteins from the cytosol of infected host cells via a so-called ingestion pathway. The ingestion pathway is initiated by dense granule protein GRA14, which binds host endosomal sorting complex required for transport (ESCRT) machinery to bud vesicles into the lumen of the PV. The protein-containing vesicles are internalized by the parasite and trafficked to the plant vacuole-like compartment (PLVAC), where cathepsin protease L (CPL) degrades the cargo, and the chloroquine resistance transporter (CRT) exports the resulting peptides and amino acids to the parasite cytosol. However, although the ingestion pathway was proposed to be a conduit for nutrients, there is limited evidence for this hypothesis. We reasoned that if &lt;i&gt;Toxoplasma&lt;/i&gt; uses the ingestion pathway to acquire nutrients, then parasites lacking GRA14, CPL, or CRT should rely more on biosynthetic pathways or alternative scavenging pathways. To explore this, we conducted a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screen in wild-type (WT) parasites and Δ&lt;i&gt;gra14&lt;/i&gt;, Δ&lt;i&gt;cpl&lt;/i&gt;, and Δ&lt;i&gt;crt&lt;/i&gt; mutants to identify genes that become more fitness conferring in ingestion-deficient parasites. Our screen revealed a significant overlap of genes that potentially become more fitness conferring in the ingestion mutants compared to WT. Pathway analysis indicated that Δ&lt;i&gt;cpl&lt;/i&gt; and Δ&lt;i&gt;crt&lt;/i&gt; mutants relied more on pyrimidine biosynthesis, fatty acid biosynthesis, tricarboxylic acid (TCA) cycle, and lysine degradation. Bulk metabolomic analysis showed reduced levels of glycolytic intermediates and amino acids in the ingestion mutants compared to WT, highlighting the pathway's potential role in host resource scavenging. Interestingly, Δ&lt;i&gt;cpl&lt;/i&gt; and Δ&lt;i&gt;crt&lt;/i&gt; showed an exacerbated growth defect when cultured in amino acid-depleted media, suggesting that disrupting proteolysis or the export of proteolytic products from the PLVAC affects parasite survival during nutrient scarcity.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Importance: &lt;/strong&gt;&lt;i&gt;Toxoplasma gondii&lt;/i&gt; is an obligate intracellular pathogen that infects virtually any nucleated cell in most warm-blooded animals. Infections are asymptomatic in most cases, but people with weakened immunity can experience severe disease. For the parasite to replicate within the host, it must efficiently acquire essential nutrients, especially as it is unable to make several key metabolites. Understanding the mechanisms by which &lt;i&gt;Toxoplasma&lt;/i&gt; scavenges nutrients from the host is crucial for identifying potential therapeutic targets. Our study suggests that the ingestion pathway contributes to sustaining parasite metabolites and parasite replication under amino acid-limiting conditions. This work advances our","PeriodicalId":19052,"journal":{"name":"mSphere","volume":" ","pages":"e0101124"},"PeriodicalIF":3.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764547","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":"Simple growth conditions improve targeted gene deletion in <i>Cryptococcus neoformans</i>.","authors":"Rebekah G Watson, Camaron R Hole","doi":"10.1128/msphere.01070-24","DOIUrl":"https://doi.org/10.1128/msphere.01070-24","url":null,"abstract":"<p><p><i>Cryptococcus neoformans</i> infections are a significant cause of morbidity and mortality among AIDS patients and the third most common invasive fungal infection in organ transplant recipients. The cryptococcal cell wall is very dynamic and can be modulated depending on growth conditions. It was reported that when <i>C. neoformans</i> is grown in unbuffered yeast nitrogen base (YNB) for 48 hours, the pH of the media drastically drops, and the cells start to shed their cell walls. With this observation, we sought to determine if YNB-grown cells could be used directly for genetic transformation. To test this, we targeted <i>ADE2</i> using TRACE (transient CRISPR-Cas9 coupled with electroporation) in YNB-grown or competent cells. Deletion of the <i>ADE2</i> gene results in red-pigmented colonies, allowing visual confirmation of disruption. We were able to successfully delete <i>ADE2</i> in YNB-grown cells with better efficiency compared to competent cells. Recent studies have shown that gene deletion can be accomplished using short (50  bp) homology arms in place of the normal long arms (~1 kb). However, it was inefficient, leading to more insertions and gene disruption than gene deletions. We tested short homology with YNB-grown cells vs. competent cells and found that gene deletion was significantly improved in YNB-grown cells, at around 60% compared to 6% in competent cells. This was also observed when we deleted <i>LAC1</i> with the short arms. Altogether, using simple growth conditions, we have greatly improved the speed and efficiency of cryptococcal genetic transformations.IMPORTANCEThe World Health Organization recently ranked <i>C. neoformans</i> as the highest-priority fungal pathogen based on unmet research and development needs and its public health importance. Understanding cryptococcal pathogenicity is key for developing treatments. We found that using simple growth conditions can greatly improve the speed and efficiency of cryptococcal genetic transformations. This finding will advance the field by expanding the ease of cryptococcal genetic manipulations.</p>","PeriodicalId":19052,"journal":{"name":"mSphere","volume":" ","pages":"e0107024"},"PeriodicalIF":3.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764470","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":"<i>Vibrio cholerae</i> O47 associated with a cholera-like diarrheal outbreak concurrent with seasonal cholera in Bangladesh.","authors":"Mohammad Tarequl Islam, Jarin Tasnim, Rabeya Basri, Mohammad Nazmus Sakib, Wali Ullah, Kazi Sumaita Nahar, Abdus Sadique, Marzia Sultana, Eiji Arakawa, Masatomo Morita, Haruo Watanabe, Yann F Boucher, Anwar Huq, Rita R Colwell, Munirul Alam","doi":"10.1128/msphere.00831-24","DOIUrl":"https://doi.org/10.1128/msphere.00831-24","url":null,"abstract":"<p><p>The Ganges delta of the Bay of Bengal is a recognized hotspot for the emergence and spread of novel variants of <i>Vibrio cholerae</i>. Despite being a diverse species, very little information is available concerning environmental and human-associated aspects of <i>V. cholerae</i> serogroups, other than the two major epidemic-related serogroups O1 and O139. This represents a crucial gap in understanding the spectrum of diversity, ecology, and epidemiology of the species influencing the dynamics of global cholera. In this study, we describe an emerging variant of <i>V. cholerae</i> displaying the antigenic property of serogroup O47, associated with a cholera-like outbreak in coastal Bangladesh where cholera has been endemic for centuries. This outbreak coincides with a rise in cases of cholera caused by <i>V. cholerae</i> O1, as well as frequency of isolation of serogroups O47 and O1 from the environment. The <i>V. cholerae</i> O47 isolates proved clonal in nature, and their genome biology revealed distinct features, with respect to multidrug resistance (MDR), serogroup-specific genes, genomic island combinations, and overall phylogenetic properties. Genome comparison confirmed the absence of canonical virulence factors of <i>V. cholerae</i> O1 and O139, namely, cholera toxin (CTX) and toxin-co-regulated pili (TCP), and the presence of putative virulence factors including type 3 secretion system (T3SS) and an MDR pseudo-compound transposon, carrying genes for macrolide resistance and extended spectrum beta-lactamase. Results of the study suggest that <i>V. cholerae</i> O47 could represent an emerging <i>Vibrio</i> pathogen with the potential to spread virulence and antimicrobial resistance traits impacting the management of cholera-like diseases.IMPORTANCEDespite the global insurgence of human diseases caused by Vibrios in recent years, most research focuses only on the O1 serogroup of <i>V. cholerae</i>, leaving a significant gap concerning the environmental and human-associated aspects of other serogroups found in nature. Although other serogroups are often found associated with sporadic diarrhea cases, in 1992-1993, a massive cholera-like diarrhea epidemic was initiated by a \"non-O1\" serogroup, namely, O139 that temporally displaced O1 from endemic cholera in the Bay of Bengal villages of Bangladesh and India, highlighting the potential threat they might pose. This study describes yet another emerging variant of <i>V. cholerae</i>, displaying the antigenic property of serogroup O47, associated with a cholera-like outbreak in a coastal locality in Bangladesh. Findings of the study offer critical insights into the genome biology of <i>V. cholerae</i> O47 and its potential implications for understanding their ecology and epidemiology of cholera-like diseases.</p>","PeriodicalId":19052,"journal":{"name":"mSphere","volume":" ","pages":"e0083124"},"PeriodicalIF":3.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764538","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":"<i>Lomentospora prolificans</i> synthesizes several types of melanin.","authors":"Livia C Liporagi-Lopes, Christine Chrissian, Emma Camacho, Arlind Kacirani, Ruth E Stark, Arturo Casadevall","doi":"10.1128/msphere.00963-24","DOIUrl":"https://doi.org/10.1128/msphere.00963-24","url":null,"abstract":"<p><p><i>Lomentospora prolificans</i> is a filamentous fungus with a global distribution, exhibiting a particularly higher prevalence in human-impacted environments. Melanins are biological compounds with important functions that contribute to the virulence of many pathogenic fungi. Like many fungi, <i>L. prolificans</i> produces melanin, but little is known about its structure and composition. In the current study, we characterized <i>L. prolificans</i>-associated melanin using chemical, biological, biophysical, and structural techniques while also assessing the impact of inhibitors of distinct melanization pathways. Our results reveal that this pathogenic fungus produces multiple types of melanin pigments and suggest the possibility of a new type of melanin, which is synthesized together with a mixture of DHN-, DOPA-, and pyomelanin types.IMPORTANCEThis fungal species is associated with a wide spectrum of human infections, especially in immunosuppressed individuals, for whom it causes severe and debilitating illnesses with high morbidity and mortality that are compounded by its pan-resistant profile with respect to antifungal drugs. Melanin is a ubiquitous pigment among fungi with a broad range of actions that include promoting fungal virulence. Although melanin is one of the most studied virulence factors in pathogenic fungi, relatively little is known about the chemistry of this pigment in <i>L. prolificans</i>. These insights enhance our understanding of <i>L. prolificans'</i> virulence mechanisms, paving the way for potential therapeutic interventions.</p>","PeriodicalId":19052,"journal":{"name":"mSphere","volume":" ","pages":"e0096324"},"PeriodicalIF":3.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764535","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":"Assessing toxicity and competitive fitness of <i>Vibrio</i> isolates from coastal waters in Israel.","authors":"Katarzyna Kanarek, Kinga Keppel, Hadar Cohen, Chaya Mushka Fridman, Motti Gerlic, Dor Salomon","doi":"10.1128/msphere.00025-25","DOIUrl":"https://doi.org/10.1128/msphere.00025-25","url":null,"abstract":"<p><p>Several species of aquatic bacteria belonging to the genus <i>Vibrio</i> are emerging pathogens of humans and marine animals. <i>Vibrio</i>-associated infections have been shown to correlate with the increase in the oceans' surface water temperatures. A slow yet steady increase in <i>Vibrio</i> isolates from clinical settings in Israel over the past decade led us to investigate their pathogenic potential in Israel's coastal waters. We sequenced the genomes of 23 <i>Vibrio</i> isolates from the Mediterranean and Red Seas. Analysis of these genomes revealed the presence of diverse toxin secretion systems and toxins, as well as mobile genetic elements known to facilitate the dissemination of fitness-enhancing determinants. Moreover, we showed that at least 10 of these isolates induce cell death in bone marrow-derived macrophages and that at least 12 isolates intoxicate a rival <i>Vibrio</i> strain in interbacterial competition. Lastly, we determined the susceptibility profiles of these isolates to common antibiotics used to treat <i>Vibrio</i> infections and found widespread resistance to azithromycin. Taken together, our results reveal pathogenic potential within the <i>Vibrio</i> population of Israel's coastal waters and underline the need for continued environmental monitoring of emerging pathogens.</p><p><strong>Importance: </strong>The ocean's surface water temperatures have increased in the past decades due to climate change. This increase correlates with the spread of <i>Vibrio</i>, a genus of aquatic bacteria, many of which are pathogens of humans and marine animals. Since <i>Vibrio</i>-associated illnesses are rising in Israel, we set out to investigate the <i>Vibrio</i> population in Israel's coastal environments and monitor their pathogenic potential. We found diverse repertoires of predicted toxins, the ability to kill mammalian immune cells, and traits that enhance bacterial fitness, such as antibacterial toxicity and resistance to antibiotics commonly used to treat <i>Vibrio</i> infections. These findings indicate that pathogenic traits are circulating within the environmental <i>Vibrio</i> population in Israel's coastal waters and suggest that continued monitoring is essential to identify emerging pathogenic strains.</p>","PeriodicalId":19052,"journal":{"name":"mSphere","volume":" ","pages":"e0002525"},"PeriodicalIF":3.7,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143764544","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":"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}