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Figure 4: Putative host signaling pathway induced by Y. pestis bacterial effectors, LPS and Lpp. TLR-2, TLR-4, CD14, and INF- were transcriptionally upregulated in host tissues in response to WT Y. pestis infection. Binding of TLR-4 by LPS and TLR-2 by Lpp is inferred from literature and canonical pathway databases (e.g., Biocarta). Myd88 and IRAK, which are TLR adaptor molecules, were upregulated by WT. Y. pestis, resulting in the activation of mitogen-activated protein kinases (MAPKs), three of which (Map3k6, Map3k8, and Map4k5) were transcriptionally upregulated in WT Y. pestis-infected mice based on microarray analysis results. MAPKs are known to phsophorylate and activate nemo-like kinase (Nik), which was upregulated in WT bacteria-infected mice but not in animals infected with the lpp mutant. Phosphorylation of Nik is known to cause activation of NF- B, which was also transcriptionally upregulated in WT Y. pestis-infected mice. Engagement of IFN- to its receptor also leads to NF- B activation via STAT 2 and 3, which were upregulated in WT Y. pestis-infected animals. NF- B activation results in transcription of proinflammatory cytokines, which were indeed upregulated based on microarray analysis (examples are listed in the diagram). The three MAPKs that were transcriptionally upregulated based on microarray analysis are known activators of c-jun N-terminal kinases (JNK) which leads to activation of Elk-1 and AP-1 transcription factors. AP-1 is composed of c-Jun and Fos subunits, both of which were upregulated in WT infected mice. Leukemia inhibitory factor (Lif) was uniquely upregulated in mice infected with the mutant and thus is likely inhibited in the presence of lpp, as shown. Cyclin D3 (Ccnd3) was uniquely upregulated in the spleen of WT-infected mice and the lung of lpp mutant infected mice and leads to increased cell proliferation. Prostaglandin E synthase (Ptges), Bak1, Bcl2l1, and hexokinase 1 (Hk1) are all known to regulate apoptosis. Each of the genes encoding these proteins was differentially expressed in lpp mutant-infected animals, compared to those infected with WT Y. pestis. Most likely, Lpp contributes to inhibition of host cell apoptosis and modulates inflammatory responses in coordination with LPS [22].