Mycobacterium are important human pathogens and their strength lies in establishing acute infections, latent infections as well as co-existing with other dreadful infectious agents like HIV. The success of mycobacterium infection often relies in its ability to evade immune-surveillance mechanisms mediated by sentinels of host immunity by modulating host signal transduction pathways and expression of immune regulatory molecules. In this scenario, the role of pattern recognition receptors (PRRs) in orchestrating host immune responses assumes central importance. Of the PRRs, the Toll-like receptors (TLRs) or intracellular surveillance receptors such as retinoic acid-inducible gene 1 (RIG-I)-like receptors (RLRs) govern key immune-surveillance mechanisms in recognition as well as control of mycobacterial or viral infections. The first part of this study illustrates the role of SHH signaling in macrophage induced neutrophil recruitment during mycobacterial infections. The present investigation demonstrates that, in response to mycobacterium infection, macrophages displayed robust activation of TLR2 dependent SHH signaling. By utilizing the well-documented experimental air pouch model, we show that the ability of pathogenic mycobacterium infected macrophages to recruit polymorph nuclear leukocytes (PMNs) like neutrophils to the infected site was dependent on SHH signaling. The activated SHH signaling differentially regulated the expression of proteolytic enzymes, MMP-9 and MMP-12 that would contribute to PMN migration. Interestingly, SHH-responsive krüppel-like family (KLF) of transcription factors, KLF4 and KLF5 were found to modulate these chemokine effectors to regulate neutrophil recruitment. Subsequent chapters describe novel functions of SHH signaling during RIG-I mediated anti-viral immunity and RIG-I mediated modulation of TLR2 anti-inflammatory signature in mycobacteria infected macrophages. In this perspective, we demonstrate that RIG-I ligand robustly induces the activation of SHH signaling via the phosphatidylinositide 3-kinase (PI3K) pathway in macrophages. Furthermore, we show that the sustained inhibition of PKA-GSK-3β-SUFU negative regulatory axis upon RIG-I engagement with 5'3pRNA is critical for the activation of SHH signaling. Gain or loss of function studies implicate the necessity of RIG-I triggered MAVS-TBK1 canonical axis in the inhibition of PKA-GSK-3β-SUFU negative regulatory axis that contributes to SHH signaling activation. The RIG-I activated SHH signaling drives the production of anti-viral type 1 interferons leading to the inhibition Japanese encephalitis virus (JEV) replication. Further, RIG-I-mediated anti-viral type 1 interferon production and subsequent control of viral replication suggested the involvement of two transcriptional factors, IRF3 and YY1 in the response along a SHH axis. Further, mounting evidence clearly depicts a significant cross talk among the molecular events initiated by given TLRs and RLRs like RIG-I. Clearly, these studies present an interesting challenge in delineating the events during polymicrobial infection of host immune cells like macrophages or DCs. Altogether, our results improve our understanding of mycobacteria associated confections’ and may add significantly to the current knowledge of the delicate balance that determines a successful mycobacterial infection.