Abstract
Evasion of host immune responses is a prerequisite for chronic bacterial diseases; however, the underlying mechanisms are not fully understood. Here, we show that the persistent intracellular pathogen Brucella abortus prevents immune activation of macrophages by inducing CD4+CD25+ T cells to produce the anti-inflammatory cytokine interleukin-10 (IL-10) early during infection. IL-10 receptor (IL-10R) blockage in macrophages resulted in significantly higher NF-kB activation as well as decreased bacterial intracellular survival associated with an inability of B. abortus to escape the late endosome compartment in vitro. Moreover, either a lack of IL-10 production by T cells or a lack of macrophage responsiveness to this cytokine resulted in an increased ability of mice to control B. abortus infection, while inducing elevated production of pro-inflammatory cytokines, which led to severe pathology in liver and spleen of infected mice. Collectively, our results suggest that early IL-10 production by CD25+CD4+ T cells modulates macrophage function and contributes to an initial balance between pro-inflammatory and anti-inflammatory cytokines that is beneficial to the pathogen, thereby promoting enhanced bacterial survival and persistent infection.
Highlights
Persistent bacterial infections have a significant impact on public health [1]
To further investigate if IL-10 plays a role in modulating the inflammatory response during acute brucellosis, C57BL/6 wildtype and Il10-deficient mice (IL-102/2) were infected IP with 56105 CFU of B. abortus 2308 and responses were evaluated at 9 d.p.i
This balance appears to shift in the case of persistent pathogens such as Brucella spp., which are able to evade toll-like receptors (TLRs) signaling during the early stages of infection, thereby preventing development of an immune response that is appropriate to clear the infection [28]
Summary
Persistent bacterial infections have a significant impact on public health [1]. While evasion of host immune responses is a prerequisite for these chronic infections, the underlying mechanisms are not fully understood. Human brucellosis, caused by the intracellular gram-negative coccobacilli Brucella spp., is considered one of the most important zoonotic diseases worldwide, with more than 500,000 new human cases reported annually [2]. The disease is characterized by a long incubation period that leads to a chronic, sometimes lifelong, debilitating infection with serious clinical manifestations such as fever, arthritis, hepatomegaly, and splenomegaly [3,4]. The use of animal models such as mice has been an important tool to better characterize the immune response to Brucella infection that leads to long-term bacterial persistence and chronic disease
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