Abstract
Ly6C+ inflammatory monocytes are essential to host defense against Toxoplasma gondii, Listeria monocytogenes and other infections. During T. gondii infection impaired inflammatory monocyte emigration results in severe inflammation and failure to control parasite replication. However, the T. gondii factors that elicit these monocytes are unknown. Early studies from the Remington laboratory showed that mice with a chronic T. gondii infection survive lethal co-infections with unrelated pathogens, including L. monocytogenes, but a mechanistic analysis was not performed. Here we report that this enhanced survival against L. monocytogenes is due to early reduction of bacterial burdens and elicitation of Ly6C+ inflammatory monocytes. We demonstrate that a single TLR11/TLR12 ligand profilin (TgPRF) was sufficient to reduce bacterial burdens similar to T. gondii chronic infection. Stimulation with TgPRF was also sufficient to enhance animal survival when administered either pre- or post-Listeria infection. The ability of TgPRF to reduce L. monocytogenes burdens was dependent on TLR11 and required IFN-γ but was not dependent on IL-12 signaling. TgPRF induced rapid production of MCP-1 and resulted in trafficking of Ly6Chi CCR2+ inflammatory monocytes and Ly6G+ neutrophils into the blood and spleen. Stimulation with TgPRF reduced L. monocytogenes burdens in mice depleted with the Ly6G specific MAb 1A8, but not in Ly6C/Ly6G specific RB6-8C5 depleted or CCR2−/− mice, indicating that only inflammatory monocytes are required for TgPRF-induced reduction in bacterial burdens. These results demonstrate that stimulation of TLR11 by TgPRF is a mechanism to promote the emigration of Ly6Chi CCR2+ monocytes, and that TgPRF recruited inflammatory monocytes can provide an immunological benefit against an unrelated pathogen.
Highlights
Toxoplasma gondii is an obligate intracellular Apicomplexan parasite that can infect nearly any nucleated cell of all warm blooded animals
We show that stimulation of the rodent specific Toll-like receptor TLR11 by the T. gondii ligand profilin can recruit inflammatory monocytes, and that these monocytes can protect the host against L. monocytogenes
We show that T. gondii profilin (TgPRF) induces production of MCP-1, which results in the trafficking of Ly6Chi CCR2+ inflammatory monocytes into the blood and spleen, and that CCR2-dependent recruitment of these cells is essential to the TgPRF-induced antibacterial response
Summary
Toxoplasma gondii is an obligate intracellular Apicomplexan parasite that can infect nearly any nucleated cell of all warm blooded animals. One of the T. gondii proteins known to stimulate IL-12 production is T. gondii profilin (TgPRF), which is required for parasite actin remodeling during host cell invasion and egress, and is a ligand for TLR11 and TLR12 [4,5,6,7]. Another critical factor for innate defenses are a class of Gr-1+ Ly6C+ monocytes that produce nitric oxide (NO) and TNF-a, and are recruited in a CCR2 dependent manner in response to both oral and parenteral T. gondii infections [8,9,10,11]. Ly6Chi monocytes are recruited during infections with other protozoan and bacterial pathogens, including Listeria monocytogenes [12,13,14,15,16]
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