Orientia tsutsugamushi is an obligately intracellular bacterium and the etiological agent of scrub typhus. Human studies and animal models of scrub typhus have shown robust type 1-skewed proinflammatory responses during severe infection. Macrophages (Mφ) play a critical role in initiating such responses, yet mechanisms of innate recognition for O. tsutsugamushi remain unclear. In this study, we investigated whether Syk-dependent C-type lectin receptors (CLRs) contribute to innate immune recognition and the generation of proinflammatory responses. To validate a role of CLRs in scrub typhus, we infected murine bone marrow-derived (Mφ) with O. tsutsugamushi in the presence of selective Syk inhibitors and analysed a panel of CLRs and proinflammatory markers via qRT-PCR. We found that Mincle/Clec4a and Clec5a transcription was significantly abrogated upon Syk inhibition at 6 hours of infection. The effect of Syk inhibition on Mincle protein expression was validated via western blot. Syk-inhibited Mφ had diminished expression of type 1 cytokines/chemokines (Il12p40, Tnf, Il27p28, Cxcl1) during infection. Additionally, expression of innate immune cytosolic sensors (Mx1 and Oas1-3) was highly induced in the brain of lethally infected mice. We established that Mx1 and Oas1 expression was reduced in Syk-inhibited M, while Oas2, Oas3, and MerTK were not sensitive to Syk inhibition. This study reveals that Syk-dependent CLRs contribute to inflammatory responses to O. tsutsugamushi. It also provides the first evidence for Syk-dependent activation of intracellular defenses during infection, suggesting a role of pattern recognition receptor crosstalk in orchestrating macrophage-mediated responses to this poorly studied bacterium.

Background: Colorectal cancer is considered the third most fetal among all type of cancer. Spleen tyrosine kinase (SYK) is a non-receptor type tyrosine-protein that plays crucial role in signaling mediated via immune receptor. We adopted an onco-informatics analysis to evaluate the SYK expression and prognostic value of SYK in colorectal cancer, and identification of potential phytochemicals which may inhibit overexpression of SYK protein as well as minimized colorectal cancer. Materials & Methods: Differential expression of SYK gene was analyzed using the several transcriptomic databases including Oncomine, UALCAN, GENT2 and GEPIA2. The server, cBioPortal was used to analyze mutation and copy number alterations whereas GENT2, GEPIA, OncoLnc and PrognoScan were employed to examine the survival rate. A protein-protein interaction network of SYK and co-expressed genes of SYK was conducted via GeneMANIA. Considering SYK gene encoding protein as drug target, selected phytochemicals were assessed by molecular docking using PyRx 0.8 packages. YASARA molecular dynamics simulators were applied for the post validation of the molecular docking data. Results: We have observed significant overexpression of mRNA expression levels of SYK gene colorectal adenocarcinoma (COAD) samples compared with normal tissues. Significant methylation level and various genetic alterations are assembled in SYK gene which can lead to the development of colorectal cancer. As a result, lower level of SYK expression was related to the more chances of patients’ survival by which all the outcomes from the multiple bioinformatics platforms and web resources have demonstrated the significant evidences that the SYK kinsase can possess as a potential biomarker for the treatment of colorectal cancer. Here, aromatic phytochemicals namely, Kaempferol and Glabridin targeting SYK showed more stability compared to controls and may be useful for the treatment of colorectal cancer. Conclusion: Our study showed dysregulated expression of SYK in colorectal cancer and potentiality to act as a biomarker for the prognosis of CRC. Moreover, we have shown phytochemicals (Kaempferol and Glabridin) target SYK as potential treatment strategies and drug repositioning potentiality in colorectal cancer.

The proliferation and survival signals emanating from the B-cell receptor (BCR) constitute a crucial aspect of mature lymphocyte’s life. Dysregulated BCR signaling is considered a potent contributor to tumor survival in different subtypes of B cell non-Hodgkin lymphomas (B-NHLs). In the last decade, emergence of BCR-associated kinases as rational therapeutic targets has led to the development and approval of several small molecule inhibitors targeting either Bruton's tyrosine kinase (BTK), spleen tyrosine kinase (SYK), or phosphatidylinositol 3 kinase (PI3K), offering alternative treatment options to standard chemoimmunotherapy, and making some of these drugs valuable assets in the anti-lymphoma armamentarium. Despite their initial effectiveness, these precision medicine strategies are limited by primary resistance in aggressive B-cell lymphoma like diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), especially in the case of first generation BTK inhibitors. In these patients, BCR-targeting drugs often fail to produce durable responses, and nearly all cases eventually progress with a dismal outcome, due to secondary resistance. This review will discuss our current understanding of the role of antigen-dependent and antigen-independent BCR signaling in DLBCL and MCL and will cover both approved inhibitors and investigational molecules being evaluated in early preclinical studies. We will discuss how the mechanisms of action of these molecules, and their off/on-target effects can influence their effectiveness and lead to toxicity, and how our actual knowledge supports the development of more specific inhibitors and new, rationally based, combination therapies, for the management of MCL and DLBCL patients.