Induction of autophagy through CLEC4E in combination with TLR4: an innovative strategy to restrict the survival of Mycobacterium tuberculosis |
| |
Authors: | Susanta Pahari Shikha Negi Mohammad Aqdas Eusondia Arnett Larry S. Schlesinger |
| |
Affiliation: | 1. Immunology Division, CSIR-Institute of Microbial Technology , Chandigarh, India;2. Host-Pathogen Interactions Program, Texas Biomedical Research Institute , San Antonio, TX, USA;3. Immunology Division, CSIR-Institute of Microbial Technology , Chandigarh, India |
| |
Abstract: | ABSTRACT Host-directed therapies are gaining considerable impetus because of the emergence of drug-resistant strains of pathogens due to antibiotic therapy. Therefore, there is an urgent need to exploit alternative and novel strategies directed at host molecules to successfully restrict infections. The C-type lectin receptor CLEC4E and Toll-like receptor TLR4 expressed by host cells are among the first line of defense in encountering pathogens. Therefore, we exploited signaling of macrophages through CLEC4E in association with TLR4 agonists (C4.T4) to control the growth of Mycobacterium tuberculosis (Mtb). We observed significant improvement in host immunity and reduced bacterial load in the lungs of Mtb-infected mice and guinea pigs treated with C4.T4 agonists. Further, intracellular killing of Mtb was achieved with a 10-fold lower dose of isoniazid or rifampicin in conjunction with C4.T4 than the drugs alone. C4.T4 activated MYD88, PtdIns3K, STAT1 and RELA/NFKB, increased lysosome biogenesis, decreased Il10 and Il4 gene expression and enhanced macroautophagy/autophagy. Macrophages from autophagy-deficient (atg5 knockout or Becn1 knockdown) mice showed elevated survival of Mtb. The present findings also unveiled the novel role of CLEC4E in inducing autophagy through MYD88, which is required for control of Mtb growth. This study suggests a unique immunotherapeutic approach involving CLEC4E in conjunction with TLR4 to restrict the survival of Mtb through autophagy. |
| |
Keywords: | Anti-TB drugs atg5 knockout autophagy Becn1 knockdown CLEC4E/Mincle host-directed immunotherapy macrophages Mycobacterium tuberculosis TLR4 tuberculosis |
|
|