Clincelin: a redesigned lincosamide combats ribosome resistance modification through enhanced binding and structural flexibility

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388971%3A_____%2F24%3A00599274" target="_blank" >RIV/61388971:_____/24:00599274 - isvavai.cz</a>

Výsledek na webu

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DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

Clincelin: a redesigned lincosamide combats ribosome resistance modification through enhanced binding and structural flexibility

Popis výsledku v původním jazyce

Filamentous hemagglutinin (FHA), a major virulence factor of classical Bordetellae, is a rod-shaped molecule that nplays an important role in the adherence of bacteria to ciliated epithelial cells of the upper respiratory tract and suppresses nthe host innate and adaptive immune response. FHA is translated as a 360-kDa FhaB precursor that is exported nacross the outer bacterial membrane by a two-partner secretion mechanism involving the outer membrane protein nFhaC and shed into external environment as an N-terminal ‘mature’ 220-kDa FHA protein after processing by surface exposed SphB1 protease. The remaining C-terminal 130-kDa FhaB prodomain is thought to regulate maturation process and nrapidly degraded in the periplasm. We show here that both the extreme C terminus (ECT) of the FhaB prodomain and the nmature FHA play the pivotal roles in the virulence of B. pertussis. The NMR-based structural analysis of ECT, na highly-conserved the C-terminal 100 residues of the FhaB precursor, revealed that the ECT polypeptide adopts a rigid nstructure with a ‘pilin-like’ protein fold. Deletion of the sequence encoding ECT (ΔECT) resulted in a significant ndecrease in bacterial colonization within the nasal cavity of infected mice, comparable to B. pertussis strain lacking the nFhaB precursor (ΔFhaB). Intriguingly, the ΔECT strain exhibited a complete loss of its ability to bind cilia on human nnasal epithelial cells grown at the air-liquid interface, emphasizing the indispensable role of ECT in the adherence nof Bordetella cells to ciliated epithelial cells. Furthermore, we demonstrate the mature FHA confers resistance of nB. pertussis to complement-mediated killing, highlighting its involvement in protection of bacterial cells against the host’s ninnate immune response. Collectively, these results provide novel insights into FHA biology, unraveling its multifaceted nrole in the virulence of pathogenic Bordetellae.

Název v anglickém jazyce

Clincelin: a redesigned lincosamide combats ribosome resistance modification through enhanced binding and structural flexibility

Popis výsledku anglicky

Filamentous hemagglutinin (FHA), a major virulence factor of classical Bordetellae, is a rod-shaped molecule that nplays an important role in the adherence of bacteria to ciliated epithelial cells of the upper respiratory tract and suppresses nthe host innate and adaptive immune response. FHA is translated as a 360-kDa FhaB precursor that is exported nacross the outer bacterial membrane by a two-partner secretion mechanism involving the outer membrane protein nFhaC and shed into external environment as an N-terminal ‘mature’ 220-kDa FHA protein after processing by surface exposed SphB1 protease. The remaining C-terminal 130-kDa FhaB prodomain is thought to regulate maturation process and nrapidly degraded in the periplasm. We show here that both the extreme C terminus (ECT) of the FhaB prodomain and the nmature FHA play the pivotal roles in the virulence of B. pertussis. The NMR-based structural analysis of ECT, na highly-conserved the C-terminal 100 residues of the FhaB precursor, revealed that the ECT polypeptide adopts a rigid nstructure with a ‘pilin-like’ protein fold. Deletion of the sequence encoding ECT (ΔECT) resulted in a significant ndecrease in bacterial colonization within the nasal cavity of infected mice, comparable to B. pertussis strain lacking the nFhaB precursor (ΔFhaB). Intriguingly, the ΔECT strain exhibited a complete loss of its ability to bind cilia on human nnasal epithelial cells grown at the air-liquid interface, emphasizing the indispensable role of ECT in the adherence nof Bordetella cells to ciliated epithelial cells. Furthermore, we demonstrate the mature FHA confers resistance of nB. pertussis to complement-mediated killing, highlighting its involvement in protection of bacterial cells against the host’s ninnate immune response. Collectively, these results provide novel insights into FHA biology, unraveling its multifaceted nrole in the virulence of pathogenic Bordetellae.

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

10606 - Microbiology

Projekt

<a href="/cs/project/LX22NPO5103" target="_blank" >LX22NPO5103: Národní institut virologie a bakteriologie</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2024

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů