How black fever parasite develops drug resistance
BLACK FEVER or kala-azar is the second biggest killer in the world after malaria. In India, over 160 million people are at a risk from the disease widespread in Jhar-khand, Bihar, Uttar Pradesh and West Bengal. Worse, the parasite that causes it, Leishmania donovani, has grown increasingly drug resistant in recent years.
But there is some good news. A joint research team from Indian Institute of Chemical Biology (IICB), Kolkata, Indian Institute of Science, Bengaluru, Banaras Hindu University, Varanasi, and Institute of Tropical Medicine and University of Antwerp in Belgium has deciphered how the parasite develops drug resistance. Their study, published in PNAS on February 12, shows L donovani produces a complex sugar molecule to remove drugs from the host cells. “This observation can help design new therapeutics against this dreaded disease,” says co-author Syamal Roy of IICB.
In previous studies, the researchers had shown drug-resistant parasites have a much higher concentration of a cell surface complex sugar molecule, glycan, than drug-sensitive ones. They have also observed that host cells infected with drug-resistant parasites started producing a multidrug-resistant protein, MDR1. How this happened was unclear.
To pin down the exact mechanism of drug resistance, the researchers first silenced a gene in parasites that aids glycan synthesis. They then infected cultured macrophages (immune cells that kill bacteria) with three types of parasites: drug-resistant, drug-sensitive and drug-resistant with silenced glycan gene.
After 24 hours, the number of parasites per 100 macrophages was significantly higher on infection with drug-resistant parasites compared to others. The researchers found that glycan molecules on the surface of drug-resistant parasites manipulated the host cells to produce a protein that revs up the levels of drug-resistant protein MDR1 and cripples the host’s immune defense. This scavenges out the drug from host cells.
“This is the first report to show that drug-resistant Leishmania parasite has evolved a new mechanism to outwit immune defense mechanism of the infected host,” says Roy.