Particle-size dependent effects in the Balb/c murine model of inhalational melioidosis

Abstract

Deposition of Burkholderia pseudomallei within either the lungs or nasal passages of the Balb/c murine model resulted in different infection kinetics. The infection resulting from the inhalation of B. pseudomallei within a 12 μm particle aerosol was prolonged compared to a 1 μm particle aerosol with a mean time-to-death (MTD) of 174.7 ± 14.9 h and 73.8 ± 11.3 h, respectively. Inhalation of B. pseudomallei within 1 μm or 12 μm particle aerosols resulted in a median lethal dose (MLD) of 4 and 12 cfu, respectively. The 12 μm particle inhalational infection was characterized by a marked involvement of the nasal mucosa and extension of bacterial colonization and inflammatory lesions from the olfactory epithelium through the olfactory nerves (or tracts) to the olfactory bulb (100%), culminating in abscessation of the brain (33%). Initial involvement of the upper respiratory tract lymphoid tissues (nasal-associated lymphoid tissue (NALT) and cervical lymph nodes) was observed in both the 1 and 12 μm particle inhalational infections (80–85%). Necrotising alveolitis and bronchiolitis were evident in both inhalational infections, however, lung pathology was greater after inhalation of the 1 μm particle aerosol with pronounced involvement of the mediastinal lymph node (50%). Terminal disease was characterized by bacteraemia in both inhalational infections with dissemination to the spleen, liver, kidneys, and thymus. Treatment with co-trimoxazole was more effective than treatment with doxycycline irrespective of the size of the particles inhaled. Doxycycline was more effective against the 12 μm particle inhalational infection as evidenced by increased time to death. However, both treatment regimes exhibited significant relapse when therapy was discontinued with massive enlargement and abscessation of the lungs, spleen, and cervical lymph nodes observed.

Induction of Mouse Melioidosis with Meningitis by CD11b+ Phagocytic Cells Harboring Intracellular B. pseudomallei as a Trojan Horse

“…The BALB/c mouse, a model that reflects the clinical course of human acute melioidosis [3], [4], [6], [10], [19], [20], was used to obtain reproducible manifestations of neurological melioidosis that includes aspects of leptomeningitis, meningoencephalitis, encephalomyelitis and brain abscesses secondary to remote infected foci. After adoptive transfer of infected cells, the initial meningeal foci were localized in the regions surrounding cerebral superior sagittal sinus because, on day 2 post-transfer, macroscopic brain abscesses, encephalomyelitis, brain stem encephalitis and even neutrophil infiltration in another meningeal place were not found.…”

“…It has been reported that the bacteria colonizing the lungs, lymph nodes and brain disseminate locally from infected foci [7], [20]. The induction of interferon-γ (IFN-γ) and the activation of phagocytic cells are essential for the early control of B. pseudomallei in mice.…”

Particle size and pathogenicity in the respiratory tract

“…However, comparative studies in animal models have been conducted using experimental systems that can differentially deposit pathogens in the LRT and URT within small or large particle aerosols 69 - 77 . The general theme running through studies investigating the effects of aerosol particle size on infectivity is that greater numbers of pathogens need to deposit in the URT to produce lethal infection compared with the LRT (Tables 3 and 4).…”

Morphological Alteration and Survival of Burkholderia pseudomallei in Soil Microcosms

“…Thus, greater lung pathology occurred after the inhalation of the 1-μm aerosolized particles. 41 These findings have important implications for the risk of inhalational melioidosis in endemic countries during the monsoon season, which facilitates the aerosol transmission of melioidosis infections and leads to pneumonic infections.…”

“…The median length (0.606 μm) and median width (0.460 μm) of B. pseudomallei cells in the endemic soil microcosm demonstrated in this study (Table 1) suggest the possibility that this pathogen could be retained in the lungs and therefore highlights the risk of transmission of melioidosis by inhalation, as was previously suggested by Sagripanti and others 38 and Thomas and others. 41 The Balb/c murine model of inhalational melioidosis exhibited a shorter mean time to death when 1-μm B. pseudomallei aerosol particles were inhaled compared with when 12-μm particles were inhaled, as well as a lower median lethal dose of 4 and 12 CFU, respectively. Thus, greater lung pathology occurred after the inhalation of the 1-μm aerosolized particles.…”