T Cells from Programmed Death-1 Deficient Mice Respond Poorly to Mycobacterium tuberculosis Infection

Programmed Death-1 (PD-1; CD279) receptor molecule is widely believed to be a negative regulator predominantly expressed by exhausted/activated mouse T cells. Upon interaction with its ligands, PD-L1 and PD-L2, PD-1 inhibits activation of T cells and cytokine production, which has been documented in various viral and fungal infections as well as in vitro studies. Therefore, inhibition of T cell responses by PD-1 resulted in disease resistance in a variety of mouse infection models studied heretofore.Here, we report that PD-1 deficient (PD-1(-/-)) mice infected with Mycobacterium tuberculosis (M. tb) H37Rv by the aerosol route have increased susceptibility as compared with their wild type littermates. Surprisingly, M. tb antigen-specific T cell proliferation was dramatically reduced in PD-1 deficient animals compared with wild-type littermates, and this was due to increased numbers of regulatory T cells (Tregs) and recruitment of mesenchymal stem cells. Furthermore, PD-1(-/-) mice exhibited decreases in the autophagy-induced LC3-B marker protein in macrophages.Our findings suggest that PD-1 does not play an inhibitory role during M. tb infection and instead promotes mycobacterial clearance in mice

Early secretory antigenic target-6 of Mycobacterium tuberculosis: enigmatic factor in pathogen–host interactions

T helper (Th) 1 and 17 cells play important roles in host protective responses against tuberculosis. Early Secretory Antigenic Target 6; a Region of Difference 1 (RD1) encoded protein, mounts Th17-responses in the lung. Therefore, lack of RD-1 region makes Bacillus Calmette–Guérin (BCG) less vaccine efficacious than parent strains

Sex distribution of bacterial isolates from septic wounds.

<p>Sex distribution of bacterial isolates from septic wounds.</p

Percentage of multi-drug resistance against a variety of antibiotics in septic wound causing bacteria.

<p>Percentage of multi-drug resistance against a variety of antibiotics in septic wound causing bacteria.</p

Spot assay of lytic phages on the MDR-bacteria from septic wounds.

<p><b>Spot assay of lytic phages on the lawn of MDR-bacterial isolates</b>. A. Spot assay of phage MDR-SA1 on the lawn of multi-drug resistant <i>S</i>. <i>aureus</i>. B. Spot assay of phage MDR-PA4 on the lawn of multi-drug resistant <i>P</i>. <i>aeruginosa</i>. C. Spot assay of phage MDR-KP1 on the lawn of multi-drug resistant <i>K</i>. <i>pneumoniae</i>. D. Spot assay of phage MDR-EC3 on the lawn of multi-drug resistant <i>E</i>. <i>coli</i>.</p

Predominant bacterial isolates from septic wound patients.

<p>Predominant bacterial isolates from septic wound patients.</p

Isolation and <i>in vitro</i> evaluation of bacteriophages against MDR-bacterial isolates from septic wound infections

<div><p>Multi-drug resistance has become a major problem for the treatment of pathogenic bacterial infections. The use of bacteriophages is an attractive approach to overcome the problem of drug resistance in several pathogens that cause fatal diseases. Our study aimed to isolate multi drug resistant bacteria from patients with septic wounds and then isolate and apply bacteriophages <i>in vitro</i> as alternative therapeutic agents. Pus samples were aseptically collected from Rajiv Gandhi Institute of Medical Science (RIMS), Kadapa, A.P., and samples were analyzed by gram staining, evaluating morphological characteristics, and biochemical methods. MDR-bacterial strains were collected using the Kirby-Bauer disk diffusion method against a variety of antibiotics. Bacteriophages were collected and tested <i>in vitro</i> for lytic activity against MDR-bacterial isolates. Analysis of the pus swab samples revealed that the most of the isolates detected had <i>Pseudomonas aeruginosa</i> as the predominant bacterium, followed by <i>Staphylococcus aureus</i>, <i>Klebsiella pneumoniae</i> and <i>Escherichia coli</i>. Our results suggested that gram-negative bacteria were more predominant than gram-positive bacteria in septic wounds; most of these isolates were resistant to ampicillin, amoxicillin, penicillin, vancomycin and tetracycline. All the gram-positive isolates (100%) were multi-drug resistant, whereas 86% of the gram-negative isolates had a drug resistant nature. Further bacteriophages isolated from sewage demonstrated perfect lytic activity against the multi-drug resistant bacteria causing septic wounds. <i>In vitro</i> analysis of the isolated bacteriophages demonstrated perfect lysis against the corresponding MDR-bacteria, and these isolated phages may be promising as a first choice for prophylaxis against wound sepsis, Moreover, phage therapy does not enhance multi-drug resistance in bacteria and could work simultaneously on a wide variety of MDR-bacteria when used in a bacteriophage cocktail. Hence, our results suggest that these bacteriophages could be potential therapeutic options for treating septic wounds caused by <i>P</i>. <i>aeruginosa</i>, <i>S</i>. <i>aureus</i>, <i>K</i>. <i>pneumoniae</i> and <i>E</i>. <i>coli</i>.</p></div

Wound type with significant bacterial type.

<p>Wound type with significant bacterial type.</p

γδ T cell mediated immune responses in Disease and Therapy

The role of γδ T cells in immunotherapy has gained specific importance in the recent years because of their prominent function involving directly or indirectly in the rehabilitation of the diseases. γδ T cells represent a minor population of T cells that express a distinct T cell receptor(TCR) composed of γδ chains instead of αβ chains. Unlike αβ T cells, γδ T cells display a restricted TCR repertoire and recognize mostly unknown non-peptide antigens. γδ T cells act as a link between innate and adaptive immunity, because they lack precise MHC restriction and seize the ability to recognize ligands that are generated during affliction. Skin epidermal γδ T cells recognize antigen expressed by damaged or stressed keratinocytes and play an indispensable role in tissue homeostasis and repair through secretion of distinct growth factors. γδ T cell based immunotherapy strategies possess great prominence in the treatment because of the property of their MHC-independent cytotoxicity, copious amount of cytokine release, and a immediate response in infections. Understanding the role of γδ T cells in pathogenic infections, wound healing, autoimmune diseases and cancer might provide knowledge for the successful treatment of these diseases using γδ T cell based immunotherapy. Enhancing the γδ T cell functions by administration of aminobisphosphonates like zoledronate, pamidronate and bromohydrin pyrophosphate along with cytokines and monoclonal antibodies shows a hopeful approach for treatment of tumors and infections. The current review summarizes the role of γδ T cells in various human diseases and immunotherapeutic approaches using γδ T cells

Age distribution of patients with significant bacterial growth.

<p>Age distribution of patients with significant bacterial growth.</p