TLR4 activation concomitant to B. pertussis infection potentiates bacterial clearance

ZURITA, MARIA EUGENIA; ERREA, AGUSTINA; FRITZ, MARIANA; SISTI, FEDERICO; MORENO, GRISELDA; RUMBO, MARTIN; HOZBOR, DANIELA

Baltimore

Simposio; 9th International Bordetella Symposium; 2010

Recently, a protective phenomenon termed Stimulated Innate Resistance (StIR) has been reported for inhaled microbial pathogens, consisting in an enhancement of resistance to inhales pathogen challenge by a previous activation of the airways innante response. This protetive effect was shown to be operative for different bacterial pathogens and even to for other microbial classes such as virus and fungi. We tested de occurrence of StIR-like phenomenon in a Bordetella pertussis infection model by performing mice infections upon airway stimulation with different pathogen associated molecular patterns (PAMPs). We used TLR agonists with a well known capacity to stimulate lung innate response such as bacterial lipopolisaccharide (LPS), Flagellin (FLiC) and poly I:C. We observed that when mice were treated with a suspension of B. pertussis supplemented with LPS, the number of bacteria recovered from the lungs decreased drastically in comparison with those observed when B. pertussis suspension was used alone. This effect is TLR4-dependent, since it was abolished in C3H/HeJ mice and decreased when the LPS was administered 48 h or even 24 h before infection with B. pertussis. Similar results were obtained using either the LPS from B. pertussis, B. bronchiseptica, Escherichia coli or Sinorhizodium meliloti, indicating a lack of species specificity. We observed similar relults using LPS from recombinant B. pertussis strin carrying the lipid A- modifying enzyme, PagL. This enzyme hydrolizes the ester bond al the 3 position of lipid A modulating the recognition of lipid A by the TLR4/MD-2 complex and consequently decreasing the endotoxic activity. All these findings indicate the existance of TLR4-dependent mechanisms that contribute to host defense in the early stages of B. pertussis infection and complement a previously described role of TLR4-dependent effects in shaping anti-B. pertussis adaptive immunity.