biostudies-literatureZhang YFundamental Research Funds for the Central Universities, Nankai UniversityNational Science Foundation of ChinaTianjin Municipal Science and Technology Committee (Tianjin Municipal Science and Technology Commission)Tianjin Municipal Science and Technology Committeee0278425https://www.ebi.ac.uk/biostudies/studies/S-EPMC12691604biostudies-literatureUnknown16(12)<i>Pseudomonas aeruginosa</i> is an environmental bacterium and opportunistic human pathogen capable of causing a wide range of infections in humans. The type III secretion system (T3SS) plays a key role in the pathogenesis of acute <i>P. aeruginosa</i> infections. Expression of the T3SS is controlled by a master activator ExsA, whose transcription is driven by its operon promoter P<i>_exsC</i> as well as its own promoter P<i>_exsA</i>. Here, we found that plasmid replication initiation protein TrfA acts as a repressor for the T3SS gene expression in <i>P. aeruginosa</i>. Production of the TrfA reduced the expression of the T3SS genes and the bacterial pathogenicity in a mouse acute pneumonia model. Further analysis revealed that the expression of <i>trfA</i> resulted imBioPlasmid replication initiator protein TrfA represses the host type III secretion system in &lt;i&gt;Pseudomonas aeruginosa&lt;/i&gt;.PMC1269160422JCYBJC00790632310486323104722JCYBJC005603217017732170199Zhang YJin SBian YLiu QShen CMa ZHa U-HWu WJin YYin LWang LCheng ZfalsePlasmid replication initiator protein TrfA represses the host type III secretion system in &lt;i&gt;Pseudomonas aeruginosa&lt;/i&gt;.<i>Pseudomonas aeruginosa</i> is an environmental bacterium and opportunistic human pathogen capable of causing a wide range of infections in humans. The type III secretion system (T3SS) plays a key role in the pathogenesis of acute <i>P. aeruginosa</i> infections. Expression of the T3SS is controlled by a master activator ExsA, whose transcription is driven by its operon promoter P<i>_exsC</i> as well as its own promoter P<i>_exsA</i>. Here, we found that plasmid replication initiation protein TrfA acts as a repressor for the T3SS gene expression in <i>P. aeruginosa</i>. Production of the TrfA reduced the expression of the T3SS genes and the bacterial pathogenicity in a mouse acute pneumonia model. Further analysis revealed that the expression of <i>trfA</i> resulted i2025-01-01T00:00:00Z2025 Dec2026-06-06T00:12:29.118Z2026-05-23T03:13:58.57ZS-EPMC126916044119065610.1128/mbio.02784-25