Melioidosis is caused by the Gram-negative bacterium Burkholderia pseudomallei, whose portals of entry into the body include subcutaneous, ingestion and inhalation routes. Animal models play an important role in furthering our understanding of this disease, which is associated with high morbidity and mortality in susceptible subjects. Previous studies using intranasal inoculation showed a differential susceptibility to inhalational melioidosis in BALB/c and C57Bl/6 mice and attributed the difference to genetic factors and host response. However, a recent study found no difference in susceptibility when the two species of mice were exposed to nebulized bacteria. We sought to address this discrepancy by using a nasal route only, instead of whole-body aerosol exposure system. Employing three different clinical strains of B. pseudomallei and following the progression of disease development in both BALB/c and C57Bl/6 mice, we found that BALB/c mice were at least 10-to 100-fold more susceptible to infection than C57Bl/6 mice. Comparison of bacterial burdens in aerosol-challenged mice, at both the pulmonary and distant sites of infection, suggests that C57Bl/6 mice were more efficient in clearing the bacteria than BALB/c mice. In addition, a comprehensive study of a wide panel of chemokines and cytokines at the protein level demonstrated that hyperproduction of proinflammatory cytokines in aerosol-challenged BALB/c mice did not translate into better protection and survival of these mice, whereas a moderate increase in these proteins in aerosol-challenged C57Bl/6 mice was more beneficial in clearing the infection. This suggests that high levels of proinflammatory cytokines are detrimental and contribute to the immunopathogenesis of the infection.

Protective antigen (PA)-based anthrax vaccines acting on toxins are less effective than live attenuated vaccines, suggesting that additional antigens may contribute to protective immunity. Several reports indicate that capsule or spore-associated antigens may enhance the protection afforded by PA. Addition of formaldehyde-inactivated spores (FIS) to PA (PA-FIS) elicits total protection against cutaneous anthrax. Nevertheless, vaccines that are effective against cutaneous anthrax may not be so against inhalational anthrax. The aim of this work was to optimize immunization with PA-FIS and to assess vaccine efficacy against inhalational anthrax. We assessed the immune response to recombinant anthrax PA from Bacillus anthracis (rPA)-FIS administered by various immunization protocols and the protection provided to mice and guinea pigs infected through the respiratory route with spores of a virulent strain of B. anthracis. Combined subcutaneous plus intranasal immunization of mice yielded a mucosal immunoglobulin G response to rPA that was more than 20 times higher than that in lung mucosal secretions after subcutaneous vaccination. The titers of toxin-neutralizing antibody and antispore antibody were also significantly higher: nine and eight times higher, respectively. The optimized immunization elicited total protection of mice intranasally infected with the virulent B. anthracis strain 17JB. Guinea pigs were fully protected, both against an intranasal challenge with 100 50% lethal doses (LD 50 ) and against an aerosol with 75 LD 50 of spores of the highly virulent strain 9602. Conversely, immunization with PA alone did not elicit protection. These results demonstrate that the association of PA and spores is very much more effective than PA alone against experimental inhalational anthrax.

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Middle ear sensory information has never been localized in the homunculus of the somatosensory cortex (S1). We investigated the somatosensory representation of the middle ear in 15 normal hearing subjects. We applied small air pressure variations to the tympanic membrane while performing a 3T fMRI study. Unilateral stimulations of the right ear triggered bilateral activations in the caudal part of the postcentral gyrus in Brodmann area 43 (BA 43) and in the auditory associative areas 42 (BA 42) and 22 (BA 22). BA 43 has been found to be involved in activities accompanying oral intake, and could be more largely involved in pressure activities in the oropharynx area. The tympanic membrane is indirectly related to the pharynx area through the action of tensor tympani, which is a Eustachian tube muscle. The Eustachian tube muscles have a role in pressure equalisation in the middle ear and also have a role in the pharyngeal phase of swallowing. Activation of BA 42 and BA 22 could reflect activations associated with the bilateral acoustic reflex triggered prior to selfvocalization to adjust air pressure in the oropharynx during speech. We propose that BA 43, 42 and 22 are the cortical areas associated with middle ear function. We did not find representation of tympanic membrane movements due to pressure in S1, but its representation in the postcentral gyrus in BA 43 seems to suggest that at least part of this area conveys pure somatosensory information. inserm-00638231, version 1 -4 Nov 2011Agnès JOB 3

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