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Flagellin-Stimulated Production of Interferon-β Promotes Anti-Flagellin IgG2c and IgA Responses
Kang, Wondae,Park, Areum,Huh, Ji-Won,You, Gihoon,Jung, Da-Jung,Song, Manki,Lee, Heung Kyu,Kim, You-Me Korean Society for Molecular and Cellular Biology 2020 Molecules and cells Vol.43 No.3
Flagellin, a major structural protein of the flagellum found in all motile bacteria, activates the TLR5- or NLRC4 inflammasome-dependent signaling pathway to induce innate immune responses. Flagellin can also serve as a specific antigen for the adaptive immune system and stimulate anti-flagellin antibody responses. Failure to recognize commensal-derived flagellin in TLR5-deficient mice leads to the reduction in anti-flagellin IgA antibodies at steady state and causes microbial dysbiosis and mucosal barrier breach by flagellated bacteria to promote chronic intestinal inflammation. Despite the important role of anti-flagellin antibodies in maintaining the intestinal homeostasis, regulatory mechanisms underlying the flagellin-specific antibody responses are not well understood. In this study, we show that flagellin induces interferon-β (IFN-β) production and subsequently activates type I IFN receptor signaling in a TLR5- and MyD88-dependent manner in vitro and in vivo. Internalization of TLR5 from the plasma membrane to the acidic environment of endolysosomes was required for the production of IFN-β, but not for other pro-inflammatory cytokines. In addition, we found that anti-flagellin IgG2c and IgA responses were severely impaired in interferon-alpha receptor 1 (IFNAR1)-deficient mice, suggesting that IFN-β produced by the flagellin stimulation regulates anti-flagellin antibody class switching. Our findings shed a new light on the regulation of flagellin-mediated immune activation and may help find new strategies to promote the intestinal health and develop mucosal vaccines.
Lee, Eun Young,Lee, Sena,Rho, Semi,Kim, Jae-Ouk,Choi, Seuk Keun,Lee, Young Jin,Park, Joo Young,Song, Manki,Yang, Jae Seung 대한백신학회 2018 Clinical and Experimental Vaccine Research Vol.7 No.2
<P><B>Purpose</B></P><P>An oral cholera vaccine (OCV), Euvichol, with thimerosal (TM) as preservative, was prequalified by the World Health Organization (WHO) in 2015. In recent years, public health services and regulatory bodies recommended to eliminate TM in vaccines due to theoretical safety concerns. In this study, we examined whether TM-free Euvichol induces comparable immunogenicity to its TM-containing formulation in animal model.</P><P><B>Materials and Methods</B></P><P>To evaluate and compare the immunogenicity of the two variations of OCV, mice were immunized with TM-free or TM-containing Euvichol twice at 2-week interval by intranasal or oral route. One week after the last immunization, mice were challenged with <I>Vibrio cholerae</I> O1 and daily monitored to examine the protective immunity against cholera infection. In addition, serum samples were obtained from mice to measure vibriocidal activity and vaccine-specific IgG, IgM, and IgA antibodies using vibriocidal assay and enzyme-linked immunosorbent assay, respectively.</P><P><B>Results</B></P><P>No significant difference in immunogenicity, including vibriocidal activity and vaccine-specific IgG, IgM, and IgA in serum, was observed between mice groups administered with TM-free and -containing Euvichol, regardless of immunization route. However, intranasally immunized mice elicited higher levels of serum antibodies than those immunized via oral route. Moreover, intranasal immunization completely protected mice against <I>V. cholerae</I> challenge but not oral immunization. There was no significant difference in protection between two Euvichol variations.</P><P><B>Conclusion</B></P><P>These results suggested that TM-free Euvichol could provide comparable immunogenicity to the WHO prequalified Euvichol containing TM as it was later confirmed in a clinical study. The pulmonary mouse cholera model can be considered useful to examine <I>in vivo</I> the potency of OCVs.</P>
<i>Vibrio cholerae</i> OmpU induces IL-8 expression in human intestinal epithelial cells
Yang, Jae Seung,Jeon, Jun Ho,Jang, Mi Seon,Kang, Seok-Seong,Ahn, Ki Bum,Song, Manki,Yun, Cheol-Heui,Han, Seung Hyun Elsevier 2018 Molecular immunology Vol.93 No.-
<P>Although Vibrio cholerae colonizes the small intestine and induces acute inflammatory responses, less is known about the molecular mechanisms of V. cholerae-induced inflammatory responses in the intestine. We recently reported that OmpU, one of the most abundant outer membrane proteins of V. cholerae, plays an important role in the innate immunity of the whole bacteria. In this study, we evaluated the role of OmpU in induction of IL-8, a representative chemokine that recruits various inflammatory immune cells, in the human intestinal epithelial cell (IEC) line, HT-29. Recombinant OmpU (rOmpU) of V. cholerae induced IL-8 expression at the mRNA and protein levels in a dose- and time-dependent manner. Interestingly, IL-8 was secreted through both apical and basolateral sides of the polarized HT-29 cells upon apical exposure to rOmpU but not upon basolateral exposure. rOmpU-induced IL-8 expression was inhibited by interference of lipid raft formation with nystatin, but not by blocking the formation of clathrin-coated pits with chlorpromazine. In addition, rOmpU-induced IL-8 expression was mediated via ERK1/2 and p38 kinase pathways, but not via JNK signaling pathway. Finally, V. cholerae lacking ompU elicited decreased IL-8 expression and adherence to HT-29 cells compared to the parental strain. Collectively, these results suggest that V. cholerae OmpU might play an important role in intestinal inflammation by inducing IL-8 expression in human IECs.</P>
Kim, Eun Jin,Lee, Dokyung,Moon, Se Hoon,Lee, Chan Hee,Kim, Sang Jun,Lee, Jae Hyun,Kim, Jae Ouk,Song, Manki,Das, Bhabatosh,Clemens, John D.,Pape, Jean William,Nair, G. Balakrish,Kim, Dong Wook Public Library of Science 2014 PLoS pathogens Vol.10 No.9
<▼1><P>Pandemic <I>V. cholerae</I> strains in the O1 serogroup have 2 biotypes: classical and El Tor. The classical biotype strains of the sixth pandemic, which encode the classical type cholera toxin (CT), have been replaced by El Tor biotype strains of the seventh pandemic. The prototype El Tor strains that produce biotype-specific cholera toxin are being replaced by atypical El Tor variants that harbor classical cholera toxin. Atypical El Tor strains are categorized into 2 groups, Wave 2 and Wave 3 strains, based on genomic variations and the CTX phage that they harbor. Whole-genome analysis of <I>V. cholerae</I> strains in the seventh cholera pandemic has demonstrated gradual changes in the genome of prototype and atypical El Tor strains, indicating that atypical strains arose from the prototype strains by replacing the CTX phages. We examined the molecular mechanisms that effected the emergence of El Tor strains with classical cholera toxin-carrying phage. We isolated an intermediary <I>V. cholerae</I> strain that carried two different CTX phages that encode El Tor and classical cholera toxin, respectively. We show here that the intermediary strain can be converted into various Wave 2 strains and can act as the source of the novel mosaic CTX phages. These results imply that the Wave 2 and Wave 3 strains may have been generated from such intermediary strains in nature. Prototype El Tor strains can become Wave 3 strains by excision of CTX-1 and re-equipping with the new CTX phages. Our data suggest that inter-chromosomal recombination between 2 types of CTX phages is possible when a host bacterial cell is infected by multiple CTX phages. Our study also provides molecular insights into population changes in <I>V. cholerae</I> in the absence of significant changes to the genome but by replacement of the CTX prophage that they harbor.</P></▼1><▼2><P><B>Author Summary</B></P><P>In this report, we suggest a genetic mechanism of how the <I>V. cholerae</I> atypical El Tor variants were generated from classical and prototype El Tor biotype strains. An intermediary strain, containing the CTX-1 and CTX-2 prophages, was identified among the clinical isolates that were collected in 1991, when the atypical strains emerged. This strain can be converted into various Wave 2 atypical El Tor strains by eliminating prototype components, CTX-1 and RS1. Further, new types of the CTX phage genome can be generated from the intermediary strain by inter-chromosomal recombination between CTX phages and recombination between the CTX phage and RS1. These new CTX phages can be transduced into other El Tor strains, transforming them into Wave 3 atypical strains. This is a demonstrated instance of how a single-segment-genome CTX phage re-organizes its genome through recombination between different types of phage, leading to generation of new phage variants and atypical El Tor strains.</P></▼2>
Orientia tsutsugamushi Infection Induces CD4+ T Cell Activation via Human Dendritic Cell Activity
( Hyuk Chu ),( Sung Moo Park ),( In Su Cheon ),( Mi Yeoun Park ),( Byoung Shik Shim ),( Byoung Cheol Gil ),( Woon Hee Jeung2 ),( Kyu Jam Hwang ),( Ki Duk Song ),( Kee Jong Hong ),( Manki Song ),( Hang 한국미생물 · 생명공학회 2013 Journal of microbiology and biotechnology Vol.23 No.8
Orientia tsutsugamushi, a gram-negative bacterium, causes severe acute febrile illness in humans. Despite this danger, the route of infection, infectivity, and protective mechanisms of the host``s immune response to O. tsutsugamushi are unclear. Dendritic cells (DCs) are one of the most important cell types in bridging the innate and adaptive immune responses. In this study, we observed that O. tsutsugamushi infects and replicates in monocyte-derived DCs (MODCs). During infection and replication, the expressions of the cytokines IL-12 and TNF-α, as well as the co-stimulatory molecules CD80, CD83, CD86, and CD40, were increased in MODCs. When O. tsutsugamushi-treated MODCs were co-cultured with autologous CD4+ T cells, they enhanced production of IFN-γ, a major Th1 cytokine. Collectively, our results show that O. tsutsugamushi can replicate in MODCs and can simultaneously induce MODC maturation and increase proinflammatory cytokine levels in MODCs that subsequently activate CD4+ T cells.