{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T19:52:31Z","timestamp":1788378751670,"version":"build-2803163510"},"reference-count":53,"publisher":"FapUNIFESP (SciELO)","license":[{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FAPERJ, CNPq, CAPES, FIOCRUZ"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Mem. Inst. Oswaldo Cruz"],"abstract":"<jats:p>Klebsiella pneumoniae (Kp) is currently a top priority for the development of alternative therapeutic strategies, according to the World Health Organisation, due to serious concerns regarding infections caused by multiple drug resistant (MDR) bacteria. The convergence of hypervirulence and MDR represents a major threat to public health worldwide. Kp displays an extensive genomic diversity, reflecting a variable repertoire of resistance and virulence factors. Despite this heterogeneity, the type VI secretion system (T6SS) is encoded in most Kp-genomes and plays important roles in competition and pathogenesis. The T6SS is a large macromolecular complex assembled in the cytoplasm that spans the inner and outer membranes. Upon activation, it undergoes conformational changes allowing the delivery of effectors into the extracellular milieu or target cells. Herein, we summarise the current knowledge on the Kp-T6SS, presenting a chronological overview of published studies, discussing the mechanisms, signals, and regulators involved in T6SS expression. Next, we detail both predicted and characterised effector proteins, including Tle1, Pld1 and VgrG4. Finally, we discuss the presence of Kp-T6SS in mobile genetic elements or in clinical samples, highlighting the importance of genomic vigilance and Kp-T6SS detection in high-risk cases. This review integrates available evidence, identifies knowledge gaps, and outlines future directions.<\/jats:p>","DOI":"10.1590\/0074-02760260010","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T11:09:55Z","timestamp":1784545795000},"source":"Crossref","is-referenced-by-count":1,"title":["Piecing together the puzzle: current knowledge and open questions about the Klebsiella pneumoniae type VI secretion system (T6SS)"],"prefix":"10.1590","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5733-8294","authenticated-orcid":false,"given":"Leticia Miranda Santos","family":"Lery","sequence":"first","affiliation":[{"name":"Funda\u00e7\u00e3o Oswaldo Cruz-Fiocruz,  Brasil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paulo Ricardo","family":"Batista","sequence":"additional","affiliation":[{"name":"Funda\u00e7\u00e3o Oswaldo Cruz-Fiocruz,  Brasil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"530","published-online":{"date-parts":[[2026]]},"reference":[{"issue":"5","key":"ref1","doi-asserted-by":"crossref","first-page":"1528","DOI":"10.1073\/pnas.0510322103","article-title":"Identification of a conserved bacterial protein secretion system in Vibrio cholerae using the Dictyostelium host model system","volume":"103","author":"Pukatzki S","year":"2006","journal-title":"Proc Natl Acad Sci USA"},{"issue":"5779","key":"ref2","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1126\/science.1128393","article-title":"A virulence locus of Pseudomonas aeruginosa encodes a protein secretion apparatus","volume":"312","author":"Mougous JD","year":"2006","journal-title":"Science"},{"issue":"1","key":"ref3","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.tim.2015.10.005","article-title":"Aim, load, fire: the type VI secretion system, a bacterial nanoweapon","volume":"24","author":"Cianfanelli FR","year":"2016","journal-title":"Trends Microbiol"},{"issue":"5","key":"ref4","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1099\/mic.0.000789","article-title":"The type VI secretion system: a versatile bacterial weapon","volume":"165","author":"Coulthurst S","year":"2019","journal-title":"Microbiology (Reading)"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"756136","DOI":"10.3389\/fmicb.2021.756136","article-title":"Roles of type VI secretion system in transport of metal ions","volume":"12","author":"Yang X","year":"2021","journal-title":"Front Microbiol"},{"issue":"1","key":"ref6","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.cell.2016.08.023","article-title":"Type VI secretion system substrates are transferred and reused among sister cells","volume":"167","author":"Vettiger A","year":"2016","journal-title":"Cell"},{"issue":"1","key":"ref7","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.chom.2010.06.012","article-title":"Type VI secretion: not just for pathogenesis anymore","volume":"8","author":"Jani AJ","year":"2010","journal-title":"Cell Host Microbe"},{"issue":"4","key":"ref8","doi-asserted-by":"crossref","first-page":"e0111521","DOI":"10.1128\/mBio.01115-21","article-title":"Engineered type six secretion systems deliver active exogenous effectors and cre recombinase","volume":"12","author":"Hersch SJ","year":"2021","journal-title":"mBio"},{"issue":"1","key":"ref9","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/s13036-025-00497-w","article-title":"Engineering the T6SS of Pseudomonas for targeted delivery of antibacterial and antifungal effectors","volume":"19","author":"P\u00e9rez-Lorente AI","year":"2025","journal-title":"J Biol Eng"},{"issue":"1679","key":"ref10","doi-asserted-by":"crossref","first-page":"20150021","DOI":"10.1098\/rstb.2015.0021","article-title":"Type VI secretion system: secretion by a contractile nanomachine","volume":"370","author":"Basler M","year":"2015","journal-title":"Philos Trans R Soc Lond B Biol Sci"},{"issue":"4","key":"ref11","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1111\/j.1365-2958.2010.07171.x","article-title":"Tubules and donuts: a type VI secretion story","volume":"76","author":"B\u00f6nemann G","year":"2010","journal-title":"Mol Microbiol"},{"issue":"1592","key":"ref12","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1098\/rstb.2011.0209","article-title":"Structural biology of type VI secretion systems","volume":"367","author":"Cascales E","year":"2012","journal-title":"Philos Trans R Soc Lond B Biol Sci"},{"issue":"3","key":"ref13","doi-asserted-by":"crossref","first-page":"e0045524","DOI":"10.1128\/jb.00455-24","article-title":"Not just passengers: effectors contribute to the assembly of the type VI secretion system as structural building blocks","volume":"207","author":"Dyrma S","year":"2025","journal-title":"J Bacteriol"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.sbi.2018.01.007","article-title":"Towards a complete structural deciphering of type VI secretion system","volume":"49","author":"Nguyen VS","year":"2018","journal-title":"Curr Opin Struct Biol"},{"issue":"1","key":"ref15","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1094\/MPMI.2003.16.1.53","article-title":"Infection-blocking genes of a symbiotic Rhizobium leguminosarum strain that are involved in temperature-dependent protein secretion","volume":"16","author":"Bladergroen MR","year":"2003","journal-title":"Mol Plant Microbe Interact"},{"issue":"2","key":"ref16","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1111\/j.1365-2958.2004.04123.x","article-title":"Use of proteomics to identify novel virulence determinants that are required for Edwardsiella tarda pathogenesis","volume":"53","author":"Rao PS","year":"2004","journal-title":"Mol Microbiol"},{"issue":"4","key":"ref17","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1111\/j.1365-2958.2005.04918.x","article-title":"Identification of Klebsiella pneumoniae virulence determinants using an intranasal infection model","volume":"58","author":"Lawlor MS","year":"2005","journal-title":"Mol Microbiol"},{"issue":"1","key":"ref18","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.meegid.2010.09.006","article-title":"Distribution of the putative type VI secretion system core genes in Klebsiella spp.","volume":"11","author":"Sarris PF","year":"2011","journal-title":"Infect Genet Evol"},{"key":"ref19","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/1741-7007-12-41","article-title":"Comparative analysis of Klebsiella pneumoniae genomes identifies a phospholipase D family protein as a novel virulence factor","volume":"12","author":"Lery LM","year":"2014","journal-title":"BMC Biol"},{"issue":"12","key":"ref20","doi-asserted-by":"crossref","first-page":"e0168788","DOI":"10.1371\/journal.pone.0168788","article-title":"A rapid spin column-based method to enrich pathogen transcripts from eukaryotic host cells prior to sequencing","volume":"11","author":"Bent ZW","year":"2016","journal-title":"PLoS One"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"442","DOI":"10.3389\/fcimb.2017.00442","article-title":"Identification and characterization of an antibacterial type VI secretion system in the carbapenem-resistant strain","volume":"7","author":"Liu L","year":"2017","journal-title":"Front Cell Infect Microbiol"},{"issue":"1","key":"ref22","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1186\/s12864-019-5885-9","article-title":"Insights into Klebsiella pneumoniae type VI secretion system transcriptional regulation","volume":"20","author":"Barbosa VAA","year":"2019","journal-title":"BMC Genomics"},{"issue":"4","key":"ref23","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1093\/infdis\/jiy534","article-title":"Klebsiella pneumoniae type VI secretion system contributes to bacterial competition, cell invasion, type-1 fimbriae expression, and in vivo colonization","volume":"219","author":"Hsieh PF","year":"2019","journal-title":"J Infect Dis"},{"issue":"3","key":"ref24","doi-asserted-by":"crossref","first-page":"e1007969","DOI":"10.1371\/journal.ppat.1007969","article-title":"Klebsiella pneumoniae type VI secretion system-mediated microbial competition is PhoPQ controlled and reactive oxygen species dependent","volume":"16","author":"Storey D","year":"2020","journal-title":"PLoS Pathog"},{"issue":"1","key":"ref25","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1038\/s41467-023-36629-3","article-title":"A trans-kingdom T6SS effector induces the fragmentation of the mitochondrial network and activates innate immune receptor NLRX1 to promote infection","volume":"14","author":"S\u00e1-Pessoa J","year":"2023","journal-title":"Nat Commun"},{"issue":"9","key":"ref26","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1002\/prot.26344","article-title":"The C-terminal extension of VgrG4 from Klebsiella pneumoniae remodels host cell microfilaments","volume":"90","author":"Soares TN","year":"2022","journal-title":"Proteins"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"853744","DOI":"10.3389\/fmicb.2022.853744","article-title":"Identification and comparative genomic analysis of type VI secretion systems and effectors in Klebsiella pneumoniae","volume":"13","author":"Li W","year":"2022","journal-title":"Front Microbiol"},{"issue":"1","key":"ref28","doi-asserted-by":"crossref","first-page":"16968","DOI":"10.1038\/s41598-022-21396-w","article-title":"Role of Klebsiella pneumoniae type VI secretion system (T6SS) in long-term gastrointestinal colonization","volume":"12","author":"Merciecca T","year":"2022","journal-title":"Sci Rep"},{"issue":"5","key":"ref29","doi-asserted-by":"crossref","first-page":"e0037822","DOI":"10.1128\/spectrum.00378-22","article-title":"Identification of the BolA protein reveals a novel virulence factor in K. pneumoniae that contributes to survival in host","volume":"10","author":"Zhang F","year":"2022","journal-title":"Microbiol Spectr"},{"issue":"5","key":"ref30","doi-asserted-by":"crossref","first-page":"e0117023","DOI":"10.1128\/spectrum.01170-23","article-title":"The role of integration host factor in biofilm and virulence of high-alcohol-producing Klebsiella pneumoniae","volume":"11","author":"Fan Z","year":"2023","journal-title":"Microbiol Spectr"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"1259472","DOI":"10.3389\/fcimb.2023.1259472","article-title":"Transcriptomic and phenotype analysis revealed the role of rpoS in stress resistance and virulence of a novel ST3355 ESBL-producing hypervirulent Klebsiella pneumoniae isolate","volume":"13","author":"Zhou Y","year":"2023","journal-title":"Front Cell Infect Microbiol"},{"issue":"3","key":"ref32","doi-asserted-by":"crossref","first-page":"e0082223","DOI":"10.1128\/msphere.00822-23","article-title":"A combination of genomics and transcriptomics provides insights into the distribution and differential mRNA expression of type VI secretion system in clinical Klebsiella pneumoniae","volume":"9","author":"Li W","year":"2024","journal-title":"mSphere"},{"issue":"4","key":"ref33","doi-asserted-by":"crossref","first-page":"e1011900","DOI":"10.1371\/journal.ppat.1011900","article-title":"In vivo single-cell high-dimensional mass cytometry analysis to track the interactions between Klebsiella pneumoniae and myeloid cells","volume":"20","author":"Calderon-Gonzalez R","year":"2024","journal-title":"PLoS Pathog"},{"issue":"1","key":"ref34","doi-asserted-by":"crossref","first-page":"940","DOI":"10.1038\/s41467-025-56309-8","article-title":"Klebsiella pneumoniae employs a type VI secretion system to overcome microbiota-mediated colonization resistance","volume":"16","author":"Bray AS","year":"2025","journal-title":"Nat Commun"},{"issue":"2","key":"ref35","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1007\/s15010-024-02456-x","article-title":"The type VI secretion system as a potential predictor of subsequent bloodstream infection of carbapenem-resistant Klebsiella pneumoniae strains on intestinal colonization","volume":"53","author":"Zhao C","year":"2025","journal-title":"Infection"},{"issue":"9","key":"ref36","doi-asserted-by":"crossref","first-page":"e1011878","DOI":"10.1371\/journal.pgen.1011878","article-title":"Genomic profiling and experimental validation of type VI secretion system-associated proteins in Klebsiella","volume":"21","author":"Zhu N","year":"2025","journal-title":"PLoS Genet"},{"issue":"6","key":"ref37","doi-asserted-by":"crossref","first-page":"2874","DOI":"10.1021\/acs.jproteome.4c01146","article-title":"Dual role for Pld1 in Klebsiella pneumoniae virulence: transcriptomics and proteomics provide insights into direct and indirect effects","volume":"24","author":"de Carvalho MML","year":"2025","journal-title":"J Proteome Res"},{"issue":"6","key":"ref38","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1038\/s41579-019-0315-1","article-title":"Population genomics of Klebsiella pneumoniae","volume":"18","author":"Wyres KL","year":"2020","journal-title":"Nat Rev Microbiol"},{"key":"ref39","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.mib.2018.04.004","article-title":"Klebsiella pneumoniae as a key trafficker of drug resistance genes from environmental to clinically important bacteria","volume":"45","author":"Wyres KL","year":"2018","journal-title":"Curr Opin Microbiol"},{"issue":"11","key":"ref40","doi-asserted-by":"crossref","first-page":"2281","DOI":"10.3390\/microorganisms10112281","article-title":"Genomics of Klebsiella pneumoniae species complex reveals the circulation of high-risk multidrug-resistant pandemic clones in human, animal, and environmental sources","volume":"10","author":"Morgado S","year":"2022","journal-title":"Microorganisms"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.jgar.2021.02.020","article-title":"A global perspective on the convergence of hypervirulence and carbapenem resistance in Klebsiella pneumoniae","volume":"25","author":"Lan P","year":"2021","journal-title":"J Glob Antimicrob Resist"},{"issue":"6","key":"ref42","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1093\/jac\/dkz093","article-title":"Genetic characterization of an MDR\/virulence genomic element carrying two T6SS gene clusters in a clinical Klebsiella pneumoniae isolate of swine origin","volume":"74","author":"Chen F","year":"2019","journal-title":"J Antimicrob Chemother"},{"issue":"5","key":"ref43","doi-asserted-by":"crossref","first-page":"596","DOI":"10.3390\/antibiotics11050596","article-title":"Genomic analysis of multidrug-resistant hypervirulent (Hypermucoviscous) Klebsiella pneumoniae strain lacking the hypermucoviscous regulators (rmpA\/rmpA2)","volume":"11","author":"Altayb HN","year":"2022","journal-title":"Antibiotics (Basel)"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1016\/j.jgar.2022.09.005","article-title":"Genomic landscape of blaGES-5- and blaGES-24-harboring Gram-negative bacteria from hospital wastewater: emergence of class 3 integron-associated blaGES-24 genes","volume":"31","author":"Takizawa S","year":"2022","journal-title":"J Glob Antimicrob Resist"},{"key":"ref45","doi-asserted-by":"crossref","first-page":"152425","DOI":"10.1016\/j.bbrc.2025.152425","article-title":"Emergence of a dual-threat ST1322 clinical isolate: hypervirulent and carbapenem-resistant Klebsiella pneumoniae revealed by genomic and virulence analysis","volume":"779","author":"Liu T","year":"2025","journal-title":"Biochem Biophys Res Commun"},{"issue":"11","key":"ref46","doi-asserted-by":"crossref","first-page":"e23459","DOI":"10.1002\/jcla.23459","article-title":"Epidemiology and molecular characteristics of the type VI secretion system in Klebsiella pneumoniae isolated from bloodstream infections","volume":"34","author":"Zhou M","year":"2020","journal-title":"J Clin Lab Anal"},{"key":"ref47","doi-asserted-by":"crossref","first-page":"105085","DOI":"10.1016\/j.micpath.2021.105085","article-title":"Distribution of type VI secretion system (T6SS) in clinical Klebsiella pneumoniae strains from a Chinese hospital and its potential relationship with virulence and drug resistance","volume":"162","author":"Liao W","year":"2022","journal-title":"Microb Pathog"},{"key":"ref48","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.2147\/IDR.S353858","article-title":"Virulence genotype and correlation of clinical severeness with presence of the type VI secretion system in Klebsiella pneumoniae isolates causing bloodstream infections","volume":"15","author":"Zhang Y","year":"2022","journal-title":"Infect Drug Resist"},{"issue":"8","key":"ref49","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1093\/infdis\/jiad166","article-title":"The type VI secretion system contributes to the invasiveness of liver abscess caused by Klebsiella pneumoniae","volume":"228","author":"Wang H","year":"2023","journal-title":"J Infect Dis"},{"issue":"5","key":"ref50","first-page":"601","article-title":"Type VI secretion system (T6SS) in Klebsiella pneumoniae, relation to antibiotic resistance and biofilm formation","volume":"15","author":"Mohamed NA","year":"2023","journal-title":"Iran J Microbiol"},{"key":"ref51","doi-asserted-by":"crossref","first-page":"9634257","DOI":"10.1155\/ijm\/9634257","article-title":"Identification of antimicrobial resistance patterns, type VI secretion system, and virulence factors in clinical isolates of Klebsiella pneumoniae: a cross-sectional study","volume":"2025","author":"Haddadi MH","year":"2025","journal-title":"Int J Microbiol"},{"issue":"4","key":"ref52","doi-asserted-by":"crossref","first-page":"e0134821","DOI":"10.1128\/mBio.01348-21","article-title":"Inhibiting type VI secretion system activity with a biomimetic peptide designed to target the baseplate wedge complex","volume":"12","author":"Cherrak Y","year":"2021","journal-title":"mBio"},{"key":"ref53","doi-asserted-by":"crossref","first-page":"6911","DOI":"10.2147\/IDR.S426657","article-title":"The biological and regulatory role of type VI secretion system of Klebsiella pneumoniae","volume":"16","author":"Liu W","year":"2023","journal-title":"Infect Drug Resist"}],"container-title":["Mem\u00f3rias do Instituto Oswaldo Cruz"],"original-title":[],"link":[{"URL":"http:\/\/www.scielo.br\/scielo.php?script=sci_pdf&pid=S0074-02762026000101001&tlng=en","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T11:10:01Z","timestamp":1784545801000},"score":1,"resource":{"primary":{"URL":"http:\/\/www.scielo.br\/scielo.php?script=sci_arttext&pid=S0074-02762026000101001&tlng=en"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026]]},"references-count":53,"alternative-id":["S0074-02762026000101001"],"URL":"https:\/\/doi.org\/10.1590\/0074-02760260010","relation":{},"ISSN":["1678-8060","0074-0276"],"issn-type":[{"value":"1678-8060","type":"electronic"},{"value":"0074-0276","type":"print"}],"subject":[],"published":{"date-parts":[[2026]]},"article-number":"e260010"}}