Sepsis and meningitis are life-threatening diseases with a high incidence in neonates, infants and in the immunocompromized and older-aged patients in which E. coli is one of the most important pathogens [26, 27]. Immunocompromized patients, in particular, are susceptible to sepsis and meningitis from a variety of bacteria and fungi. For many of these pathogens, no vaccines are commercially available. Moreover, the effectiveness of vaccination in these patients is often reduced, since most vaccines are less immunogenic in the older age group because of age-related changes in the immune system .
For these reasons, infectiologists are highly interested in epitopes shared by several serotypes of the same species or even different species, which are suitable for the simultaneous vaccination against multiple pathogens. Since bacterial DNA, unlike eukaryotic DNA contains a high rate of unmethylated cytosine-guanine (CpG) motifs , recent attention has focused on this epitope, which is a ligand of Toll-like receptor (TLR)-9. Stimulation of microglial cells with CpG oligonucleotides increased phagocytosis of E. coli, Streptococcus pneumoniae and Cryptococcus neoformans and intracellular killing of these pathogens by microglial cells [30–32]. In various animal models, CpG ODN pre-treatment conferred protection against a variety of bloodstream and other extracerebral bacterial infections [33–35]. Another epitope shared by many pathogens is muramyl dipeptide (MDP), the smallest peptidoglycan constituent of both Gram-positive and Gram-negative bacteria. It is a ligand of the nucleotide-binding oligomerization domain-like receptor 2 (NOD2), moderately activates microglial cells leading to an increased phagocytosis of bacteria and acts in an additive or synergistic way with TLR agonists . MDP is known to be an adjuvant for vaccination, which induces antigen-specific T and B cell responses, delayed-type hypersensitivity and antibody production. Thirty-five years ago, it was shown that MDP enhances the non-specific immunity to Klebsiella pneumoniae infections in adult and newborn mice . Parenteral MDP and two of its analogs protected mice against Pseudomonas aeruginosa or Candida albicans infections . MDP conjugated with the neoglycoprotein mannosyl human serum albumin (mannose-HSA), in a murine model of visceral leishmaniasis, strongly reduced splenic parasite burden, whereas free MDP at a similar dose had very little effect . Prophylactic treatment with MDP protected mice against E. coli, Streptococcus pneumoniae, Salmonella typhimurium, Salmonella enteritidis and Toxoplasma gondii infections [40, 41]. The synthetic MDP derivate romurtide, given orally or subcutaneously, also enhanced the nonspecific resistance against microbial infections in mice .
Prophylactic administration of TLR or NOD ligands can lead to an unspecific inflammatory state characterized by the release of proinflammatory cytokines by immune cells and elevated cytokine concentrations in the systemic circulation. This may be a severe disadvantage for an organism attempting to combat an infection, because activated phagocytes are not only able to efficiently eliminate pathogens, but can also acutely damage host tissue or lead to chronic autoimmune diseases [43, 44]. This phenomenon is most devastating in the CNS [45, 46]. There, it probably contributes to neuronal and axonal injury in the course of meningitis, encephalitis and septic encephalopathy . It probably also is the pathophysiological basis of the deterioration of patients with neurodegenerative diseases during infections. The functional outcome of TLR-induced activation of microglia in the CNS depends on a subtle balance between protective and harmful effects [48–50]. For this reason, activation of the TLR or NOD system aiming at increasing the resistance to infections bears the risk of inducing collateral damage to the vessels, the nervous system or other organs.
PEA, an endogenous compound found in most mammalian tissues, has well-known anti-inflammatory, neuroprotective and analgesic properties . Moreover, oral PEA pre-treatment (optimum dose 50 mg/kg/day for 12 consecutive days) increased the resistance of mice against challenge with Shigella dysenteriae toxin and streptolysin O, but also against intravenous infection with live group A streptococci . Unlike TLR or NOD agonists, PEA does not induce the release of TNFα, IL-6 and CXCL1 by microglial cells . It therefore cannot be considered a mere immunostimulant, but a true immunomodulator .
PEA is known for its anti-inflammatory activity and effect on interleukins. PEA was shown to attenuate the factors of intestinal injury during inflammation and to inhibit proinflammatory cytokine production (TNFα, IL-1β), adhesion molecules (ICAM-1, P-selectin) expression, and NF-κB expression .
Many effects of PEA have been shown to be dependent on the peroxisome proliferator-activated receptor-α (PPARα) [11, 12]. In our study, the phagocytic rate in PEA-stimulated macrophages was not as strongly decreased by the PPARα inhibitor GW6471 as in macrophages stimulated by the PPARα agonists fenofibrate and palmitic acid. This suggests that the properties of PEA do not only depend on the stimulation of PPARα. In the present study, PEA administered ip did not only act at the site of infection, but also protected against injection of bacteria into the CNS. This compares well with the protection against intravenous infection by oral PEA administration . Since the immune system of the CNS is separated from the systemic circulation by the blood–brain and blood-CSF barrier, the CSF and by the glia limitans composed of astrocytic foot processes and a parenchymal basement membrane , our results suggest that PEA treatment influences the immune defense of the whole organism including the deep compartments. Early clinical trials with PEA in the 1970s, at that time under the trade name of Impulsin, demonstrated its potential of reducing the incidence and severity of acute respiratory infections . Unfortunately, since then, no other studies focusing on PEA as a prophylaxis or as an adjuvant therapy in the management of infections have been published. Concerning its safety, more than 3,600 patients have been successfully treated with PEA, with no adverse effects reported in any of the trials [51, 54].
In conclusion, PEA appears to increase the resistance of animals and humans against bacterial infections without inducing a chronic inflammatory state. Its efficacy should be studied in immunocompromized animals and with a broader range of pathogens. Because of the apparently low rate of adverse effects, PEA is a promising compound for a clinical trial in patients at a high risk of developing life-threatening infections.