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.
