Neuroinvasive microbes include a wide variety of microorganisms that can enter the Central Nervous System (CNS). They are capable of exerting influences on the autonomic nervous system of the host by releasing extracellular metabolites that may cause alterations in the biochemical and neurophysiological environment. Consequently, the host’s synaptic, neuroendocrine, peripheral immune, neuroimmune and behavioral response facilitate the progression of infection. The present study was conducted to screen and characterize bioactive peptides produced by neuroinvasive bacteria i.e. Listeria monocytogenes (Lm), Bacillus cereus (Bc), Neisseria meningitidis (Nm) and Clostridium tetani (Ct) that are commonly involved in CNS infections. Bacterial peptides were used to correlate the neurological, biochemical, immunological and neuroimmunolgical aspects of pathogenesis of CNS infections. Lm and Nm were isolated from cerebrospinal fluid (CSF) samples collected from 92 mentally compromised patients. Bc and Ct were also included in the study. All bacterial strains were identified by standard biochemical procedures. Collected CSF samples were also screened for the presence of herpes simplex virus (HSV) by polymerase chain reaction (PCR). Bacteria were cultured and filter sterilized cell free cultural broths (SCFBs) were prepared. Behavioral study and neurotransmitter analysis were performed after giving interaperitonieal (i.p.) shot of each bacterial SCFB to 4 groups (Test; n=7) of Sprague Dawely (SD) rats whereas 2 groups each (Control; n=7) received nutrient broth (NB) control and sterile physiological saline control respectively. Motor and behavioral activities were observed and biogenic amines were extracted from whole brain and analyzed by high performance liquid chromatography with electrochemical detection (HPLC-EC). Biogenic amines were detected in SCFBs of each bacterium. Extracellular bioactive peptides of these bacteria were screened and purified. Neuropathogenic effects of purified peptides were studied on BALB/c mice cohorts and correlated with CSF biogenic amines. BALB/c mice hippocampal neurons were cultured as per standard protocols and effects of bacterial peptides on the voltage dependent K+ and Na+ channels of these neurons were studied by patch clamp. Human peripheral blood mononuclear cells (PMBCs) and BALB/c mice microglial cells were separately cultured for comparative analysis, exposed to bacterial peptides and were observed for the cytopatheic effects (CPEs). Cellular RNA was extracted, purified and quantified. Reverse transcriptase polymerase chain reaction (RT-PCR) was done to study the expression of immunocytokines and toll like receptors (TLRs). Signal transduction precursors were also detected. Comparative analysis was done with the cellular RNA extracted from glial cells. Present study concludes with the detection of NO production induced by peptides both in immune and neuroimmune cells. The results indicated that Nm was found in 22% of the collected samples. Presence of HSV along with the co-infection of HSV1 and HSV2 was confirmed in most of the negative bacterial culture samples. Co-infection of both bacterial and viral etiology was also detected in some samples. Our study indicated that bacterial SCFBs shots induced promising behavioral changes including fever, swelling and hind paw paralysis in respective Sprague Dawely (SD) rat cohorts. Biogenic amine profile of SD rats revealed enhanced concentration of dopamine (DA) in the brains of all SD rat cohorts whereas profound elevation was found exclusively in rats treated with Lm SCFB. Comparative analysis of biogenic amines in SCFB with plain media control revealed that Bc, Ct and Nm showed the complete degradation of DA into its metabolic products whereas Lm showed negligible degradation of DA. Purified bacterial peptides of all bacteria used in present study elicited marked changes in behavior along with enhanced concentration of DA in the brains of BALB/c mice cohorts. Comparative analysis with CSF biogenic amines indicated the presence of DA, Dihydroxyphenyl acetic acid (DOPAC), Homovanillic acid (HVA) and 5-hydroxy Indol acetic acid (5HIAA) in HSV infected CSF samples exclusively whereas increased amount of DA was found in Lm. Extracellular peptides of Lm and Bc caused the irreversible blockage of both K+ and Na+ channels of BALB/c mice hippocampal neurons. Peptides of Bc, Ct, Lm and Nm caused aggregation leads to distortion of immune and neuro-immune cells. RT-PCR profile revealed that TLR2 and TLR4 were commonly expressed in PMBCs and microglial cells. However, TLR3 was additionally expressed in microglial cells which is an alternative to TLR9 of the PMBCs. Expression of the range of proinflammatory cytokines i.e. Interleukin 1 β (IL1β), Interleukin 6 (IL6) and Tumor necrosis factor alpha (TNFα) were found to be mediated via MyD88 dependent pathway. Production of Nitric Oxide (NO) was mainly found in Lm peptides. The most important finding is that the detection and diagnosis of neurological infections on the basis of clinical signs are unsatisfactory. Therefore, existence of both viral and bacterial etiological agents must be checked to avoid the misdiagnosis and wrong treatment of the CNS infections. The sequence indicated the small size of extracellular peptides of Bc, Ct, Lm and Nm. Our study demonstrated the intervention of these peptides in the biochemical, neurological, immunological and neuro-immunological processes of the host. Therefore, bacterial peptides would have far reaching implications in disease progression. It is significant to note that these peptides definitely carry certain pattern which is complimentary to the TLRs of PMBCs and microglial cells as both cells recognized and induced immune and neuro-immune processes. Present study initiates a new venue of research for screening and characterization of such bioactive peptides in other pathogens.