TLR4 activation concomitant to B. pertussis infection potentiates bacterial clearance

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

Congreso; Ninth International Bordetella Symposium.; 2010

<!-- /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-parent:""; margin:0cm; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:"Times New Roman"; mso-fareast-font-family:"Times New Roman";} @page Section1 {size:595.3pt 841.9pt; margin:70.85pt 3.0cm 70.85pt 3.0cm; mso-header-margin:35.4pt; mso-footer-margin:35.4pt; mso-paper-source:0;} div.Section1 {page:Section1;} --> Recently, a protective phenomenon termed Stimulated Innate Resistance (StIR) has been reported for inhaled microbial pathogen, consisting in an enhancement of resistence to inhaled pathogen challenge by previous activation of airways innate response. This protective effect was shown to be operative for different bacterial pathogens and even to other microbial classes such as virus and fungi. We tested the 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 well known capacity to stimulate lung innate response such as bacterial lipopolysaccharide (LPS), Falgellin (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 lung decreased drastically in comparison with those observed when B. pertussis suspension was used alone. This effect is TLR4-dependent, since was abolished in C3H/HeJ mouse strain and decreased when the LPS is 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, Eschericchia coli or Sinorhizobium meliloti, indicating a lack of species specificity. We observed similar results using LPS from a recombinant B. pertussis strain carrying the lipid A-modifying enzyme, PagL. This enzyme hydrolyzes the ester bond at 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 existence of TLR4-dependent mechanisms that contribute to host defense in the early stage of B. pertussis infection and complement previously described role of TLR4 dependent effects in shaping anti-B. pertussis adaptive immunity.