Abstract
Although inhalation of infected aerosols is a frequent route for Brucella infection in humans, it rarely causes pulmonary clinical manifestations, suggesting a mild or nearly absent local inflammatory response. The goal of this study was to characterize the early innate immune response to intratracheal infection with Brucella abortus in mice and to evaluate whether it is modulated by this pathogen. After infection with 106 CFU of B. abortus, the pulmonary bacterial burden at 7 days post-infection (p.i.) was comparable to the initial inoculum, despite an initial transient decline. Brucella was detected in spleen and liver as early as 1 day p.i. IL-1β and MCP-1 increased at 3 days p.i., whereas IL-12, KC, TNF-α, and IFN-γ only increased at 7 days p.i. Histological examination did not reveal peribronchial or perivascular infiltrates in infected mice. Experiments were conducted to evaluate if the limited inflammatory lung response to B. abortusis caused by a bacterial mechanism of TLR signaling inhibition. Whereas inoculation of E. coli LPS to control mice [phosphate-buffered saline (PBS)/LPS] caused lung inflammation, almost no histological changes were observed in mice preinfected intratracheally with B. abortus (WT/LPS). We speculated that the Brucella TIR-containing proteins (Btps) A and B, which impair TLR signaling in vitro, may be involved in this modulation. After LPS challenge, mice preinfected with the B. abortus btpAbtpB double mutant exhibited a stronger pulmonary polymorphonuclear infiltrate than WT/LPS mice, although milder than that of the PBS/LPS group. In addition, lungs from B. abortus btpAbtpB-infected mice presented a stronger inflammatory infiltrate than those infected with the WT strain, and at day 7 p.i., the pulmonary levels of KC, MCP-1, and IL-12 were higher in mice infected with the mutant. This study shows that B. abortus infection produces a mild proinflammatory response in murine lungs, partially due to immune modulation by its Btp proteins. This may facilitate its survival and dissemination to peripheral organs.
Highlights
Brucellosis is a worldwide-distributed zoonotic disease caused by Brucella species that affects over 500,000 people annually [1]
Mice were intratracheally infected with B. abortus WT, and CFU numbers were determined in lung, liver, and spleen homogenates at different times within the first week p.i
To assess the early pulmonary cytokine response induced by the intratracheal infection with B. abortus WT, levels of IL-1β, TNF-α, IFN-γ, IL-12, MCP-1, and KC were measured in lung homogenates from infected mice
Summary
Brucellosis is a worldwide-distributed zoonotic disease caused by Brucella species that affects over 500,000 people annually [1]. The infection can be transmitted to humans by several ways, among which inhalation of infected aerosols is one of the most frequent. Several reports place airborne transmission as the cause of outbreaks of human brucellosis in bovine and porcine slaughterhouses, vaccine production laboratories, and rural areas [2,3,4,5]. Aerosols have been implicated in most cases of laboratory-acquired brucellosis, which is considered the most common laboratory-acquired infection [6]. Due to its easy aerosolization, high infectivity and airb orne transmission, Brucella species are considered potential biological weapons [1] and are classified by the CDC and NIAID as category B bioterrorism agents
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