Abstract
Brucella spp. cause undulant fever in humans and brucellosis in variety of other animals. Both innate and adaptive immunity have been shown to be important in controlling Brucella infection. Toll-like receptors (TLRs) represent a group of pattern recognition receptors (PRRs) that play critical roles in the host innate immune response, as well as development of adaptive immunity. In the current report, we investigated the role of TLR signaling in the clearance of Brucella and development of adaptive immunity in TLR2−/−, TLR4−/−, or MyD88−/− mice following aerosol exposure to B. melitensis 16 M. Consistent with previous reports, MyD88 is required for efficient clearance of Brucella from all three organs (lung, spleen, and liver). The results reveal Th2-skewed immune responses in TLR2−/− mice late in infection and support a TLR2 requirement for efficient clearance of Brucella from the lungs, but not from the spleen or liver. Similarly, TLR4 is required for efficient clearance of Brucella from the lung, but exhibits a minor contribution to clearance from the spleen and no demonstrable contribution to clearance from the liver. Lymphocyte proliferation assays suggest that the TLRs are not involved in the development of cell-mediated memory response to Brucella antigen. Antibody detection reveals that TLR2 and 4 are required to generate early antigen-specific IgG, but not during the late stages of infection. TLR2 and 4 are only transiently required for IgM production and not at all for IgA production. In contrast, MyD88 is essential for antigen specific IgG production late in infection, but is not required for IgM generation over the course of infection. Surprisingly, despite the prominent role for MyD88 in clearance from all tissues, MyD88-knockout mice express significantly higher levels of serum IgA. These results confirm the important role of MyD88 in controlling infection in the spleen while providing evidence of a prominent contribution to protection in other tissues. In addition, although TLR4 and TLR2 contribute little to control of spleen infection, a significant contribution to clearance of lung infection is described.
Highlights
The genus Brucella is a group of Gram-negative, facultative intracellular bacteria that cause brucellosis, a reproductive disease in ruminants, and undulating fever in humans
We investigated the role of Toll-like receptors (TLRs) signaling in the clearance of Brucella and development of adaptive immunity in TLR2−/−, TLR4−/−, or myeloid differentiation factor 88 (MyD88)−/− mice following aerosol exposure to B. melitensis 16 M
A significant difference in bacterial burden is detectable by week 4 and extends through week 10, indicating that the contribution of TLR2, TLR4, and MyD88 to the control of Brucella infection in the lungs occurs via adaptive immunity (Figure 1)
Summary
The genus Brucella is a group of Gram-negative, facultative intracellular bacteria that cause brucellosis, a reproductive disease in ruminants, and undulating fever in humans. Brucellosis is one of the most important worldwide zoonotic diseases. Ten species have been identified to date, three of which, including B. melitensis, B. abortus, and B. suis are virulent in humans and represent a significant threat to public health (Atluri et al, 2011). Humans often become infected following inhalation of particles carrying the bacteria or consumption of dairy products contaminated with the organism. Vaccination is used to successfully reduce the spread of disease, the risk remains high in underdeveloped nations. There are currently no vaccines available that are safe for use in humans, and generally effective, antibiotic treatments do not always prevent disease recrudescence. As a result of these factors and concern over their potential weaponization, NIH and the CDC/USDA have classified these three species as category B agents
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