Host Antimicrobial Peptides: the promise of new treatment strategies against Tuberculosis

Tuberculosis (TB) continues to be a devastating infectious disease and remerges as a global health emergency due to an alarming rise of antimicrobial resistance to its treatment. Despite of the serious effort that has been applied to develop effective antitubercular chemotherapies, the potential of antimicrobial peptides (AMPs) remains underexploited. A large amount of literature is now accessible on the AMP mechanisms of action against a diversity of pathogens; nevertheless, research on their activity on mycobacteria is still scarce. In particular, there is an urgent need to integrate all available interdisciplinary strategies to eradicate extensively drug-resistant Mycobacterium tuberculosis strains. In this context, we should not underestimate our endogenous antimicrobial proteins and peptides as ancient players of the human host defense system. We are confident that novel antibiotics based on human AMPs displaying a rapid and multifaceted mechanism, with reduced toxicity, should significantly contribute to reverse the tide of antimycobacterial drug resistance. In this review, we have provided an up to date perspective of the current research on AMPs to be applied in the fight against TB. A better understanding on the mechanisms of action of human endogenous peptides should ensure the basis for the best guided design of novel antitubercular chemotherapeutics

Eosinophil cationic protein is not only a distinctive eosinophil protein

We read with interest the article by Qiu et al (Thorax 2007;62:475–82). In this paper, neutrophils and eosinophils were identified using mouse anti-human neutrophil elastase and anti-eosinophil cationic protein (ECP), both monoclonal antibodies (mAbs). mAbs against ECP have been used to detect total eosinophils, but immunostaining techniques evidenced that the number of ECP+ cells was higher than the number of eosinophils.1 Recent studies show that ECP is not only a distinctive eosinophil protein, but has been found in neutrophils.1–3This work was supported by grants from the Junta de Andalucia (Ayudas Grupos de Investigación), Fundación de la Sociedad Española de Alergia e Inmunología Clínica, Fundación Sanitaria Virgen Macarena and Fundación Alergol, Spain. AV was supported by fellowships from the Ministerio de Ciencia y Tecnología, and Fundación Alergol. JM is under the Programa de Intensificación de la Actividad Investigadora del Sistema Nacional de Salud.Ye

Eosinophil cationic protein and histamine production by neutrophils from patients with periodontitis.

Periodontitis develops through an inflammatory process caused by an infection at the microbial biofilm, followed by tissue destruction mediated by leukocytes, which cause clinically significant destruction of connective tissue and bone. Several elements derived from the bacteria cause the inflammatory response and the release of mediators involved in destruction of the periodontium. There are number of inflammatory mediators released by leukocytes, mainly neutrophils, upon bacterial challenge. Neutrophils produce and release eosinophil cationic protein (ECP) and histamine, two important inflammatory mediators; however, their role has not been characterized in periodontal inflammation. Thus, the purpose of this study is to investigate whether neutrophils from patients with periodontitis can produce ECP and histamine in response to lipopolysaccharides (LPSs). ECP and histamine production in response to LPSs was analyzed by enzyme-linked immunosorbent assay. Expression of the histidine decarboxylase and ECP was also analyzed by flow cytometry and fluorescence microscopy in neutrophils from patients with periodontitis in response to LPS. It was found that neutrophils from patients with periodontitis express higher levels of histidine decarboxylase and ECP than those from healthy volunteers, and they also release higher levels of histamine. Findings described could represent new knowledge indicating neutrophils as a source of histamine and ECP in the progression of periodontitis

Expression of the transcription factor NFAT2 in human neutrophils: IgE-dependent, Ca2+- and calcineurin-mediated NFAT2 activation

NFAT (nuclear factors of activated T cells) proteins constitute a family of transcription factors involved in mediating signal transduction. The presence of NFAT isoforms has been described in all cell types of the immune system, with the exception of neutrophils. In the present work we report for the first time the expression in human neutrophils of NFAT2 mRNA and protein. We also report that specific antigens were able to promote NFAT2 protein translocation to the nucleus, an effect that was mimicked by the treatment of neutrophils with anti-immunoglobulin E (anti-IgE) or anti-Fc{epsilon}-receptor antibodies. Antigens, anti-IgE and anti-Fc{epsilon}Rs also increased Ca2+ release and the intracellular activity of calcineurin, which was able to interact physically with NFAT2, in parallel to eliciting an enhanced NFAT2 DNA-binding activity. In addition, specific chemical inhibitors of the NFAT pathway, such as cyclosporin A and VIVIT peptide, abolished antigen and anti-IgE-induced cyclooxygenase-2 (COX2) gene upregulation and prostaglandin (PGE2) release, suggesting that this process is through NFAT. Our results provide evidence that NFAT2 is constitutively expressed in human neutrophils, and after IgE-dependent activation operates as a transcription factor in the modulation of genes, such as COX2, during allergic inflammation.A.V. and P.C. were supported by fellowships from the Ministerio de Ciencia y Tecnología, and Fundación Alergol, Spain. R.E. is a recipient of a postdoctoral grant (Juan de la Cierva) (SAF2003-00200) from the Ministerio de Educación y Ciencia, Spain. This work was funded by grants from the Consejería de Salud, Junta de Andalucía (SAS-55/04 and SAS-74/04)

Angiotensin II induces CD62L shedding in human neutrophils

Studies indicate that both alterations in leukocyte and endothelial cell adhesion molecules and the renin angiotensin system are involved in the pathogenesis of atherosclerosis processes in human hypertension. The present work was undertaken to investigate whether angiotensin II (Ang II) regulates the expression of CD62L on human neutrophils. Human neutrophils were stimulated with Ang II in the presence of various AT1-receptor antagonists and protein kinase inhibitors, and CD62L cell surface expression was detected by flow cytometry. We report for the first time that Ang II down-regulated CD62L from the surface of human neutrophils, a process which was independent of neutrophil adhesion to endothelium since neutrophils were still able to adhere to human umbilical vein endothelial cells even under doses that almost completely release CD62L from the cell surface. This process occurred through pathways involving AT1 receptors, extracellular signal-regulated kinases 1 and 2 mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase, and calcineurin, ruling out a role for p38 MAPK and small GTPases in the process. © 2009 Elsevier Ireland Ltd.This work was funded by grants from the Consejería de Salud, Junta de Andalucía (SAS-55/04). J.M. is working within the Programa de Intensificación de la Actividad Investigadora en el Sistema Nacional de Salud.Peer Reviewe

Angiotensin II induces CD62L shedding in human neutrophils

Studies indicate that both alterations in leukocyte and endothelial cell adhesion molecules and the renin angiotensin system are involved in the pathogenesis of atherosclerosis processes in human hypertension. The present work was undertaken to investigate whether angiotensin II (Ang II) regulates the expression of CD62L on human neutrophils. Human neutrophils were stimulated with Ang II in the presence of various AT1-receptor antagonists and protein kinase inhibitors, and CD62L cell surface expression was detected by flow cytometry. We report for the first time that Ang II down-regulated CD62L from the surface of human neutrophils, a process which was independent of neutrophil adhesion to endothelium since neutrophils were still able to adhere to human umbilical vein endothelial cells even under doses that almost completely release CD62L from the cell surface. This process occurred through pathways involving AT1 receptors, extracellular signal-regulated kinases 1 and 2 mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase, and calcineurin, ruling out a role for p38 MAPK and small GTPases in the process