Immunotherapy for visceral leishmaniasis: A trapeze of balancing counteractive forces

The protozoan parasite Leishmania donovani, residing and replicating within the cells of the monocyte-macrophage (mono-mac) lineage, causes visceral leishmaniasis (VL) in humans. While, Leishmania infantum, is the main causative agent for zoonotic VL, where dogs are the main reservoirs of the disease. The chemotherapy is a serious problem because of restricted repertoire of drugs, drug-resistant parasites, drug-toxicity and the requirement for parenteral administration, which is a problem in resource-starved countries. Moreover, immunocompromised individuals, particularly HIV-1 infected are at higher risk of VL due to impairment in T-helper cell and regulatory cell responses. Furthermore, HIV-VL co-infected patients report poor response to conventional chemotherapy. Recent efforts are therefore directed towards devising both prophylactic and therapeutic immunomodulation. As far as prophylaxis is concerned, although canine vaccines for the disease caused by Leishmania infantum or Leishmania chagasi are available, no vaccine is available for use in humans till date. Therefore, anti-leishmanial immunotherapy triggering or manipulating the host's immune response is gaining momentum during the last two decades. Immunomodulators comprised of small molecules, anti-leishmanial peptides, complex ligands for host receptors, cytokines or their agonists and antibodies have been given trials both in experimental models and in humans. However, the success of immunotherapy in humans remains a far-off target. We, therefore, propose that devising a successful immunotherapy is an act of balancing enhanced beneficial Leishmania-specific responses and deleterious immune activation/hyperinflammation just as the swings in a trapeze.