Pointer to how kala azar trumps drugs

New Delhi, Jan. 22: Scientists in Calcutta say they have deciphered the molecular chicanery the parasite that causes kala azar unleashes to hijack the human body's immune system and evade drugs used to treat this potentially fatal infection.

The researchers at the Indian Institute of Chemical Biology, Calcutta, and their collaborators say their findings suggest that the challenge posed by drug-resistant versions of the kala azar parasite may be even more formidable than hitherto believed.

India's foci of kala azar ' an infection caused by a parasite called Leishmaniasis donovani that spreads through the bites of tiny sandflies ' are primarily scattered across parts of Bengal, Bihar, Jharkhand and eastern Uttar Pradesh.

In recent years, public health experts have been concerned at the emergence of relapses or resistance of the infection to two drugs widely used against kala azar.

Now, IICB immunologist Syamal Roy and his colleagues have unravelled the sequence of molecular and genetic events that could explain how drug-resistant versions of the kala azar parasite are able to outwit the human immune system and evade at least one class of drugs, and possibly another drug too. Their findings appear today in the US journal Proceedings of the National Academy of Sciences.

"This is a big advance in our understanding of drug-resistant parasites," said Nirmal Kumar Ganguly, a biotechnology professor at the National Institute of Immunology, New Delhi, not directly associated with the study.

The research team has shown that kala azar parasites that are drug-resistant take over the genetic machinery of human immune cells called macrophages and force them to produce excess levels of a protein called interleukin-10.

This surge in interleukin-10 activates a molecular pump in the cells that expels drugs called antimonials, the primary therapy for kala azar for decades since its discovery by a Calcutta physician Upendranath Brahmachari in 1921.

Doctors say kala azar, which leads to anaemia, fever, weight loss, a swollen spleen, and pigmentation on the skin, is usually fatal if untreated.

India had to abandon the use of antimonials after the widespread emergence of parasites resistant to this class of drugs. Medical studies during the late-1990s suggested that 65 per cent of patients in India who had received antimonials would not respond to treatment.

Public health experts estimate that many tens of thousands of people are infected with kala azar in India each year and several hundred patients die either because of treatment failure, lack of access to timely treatment or incomplete treatment.

About a decade ago, India introduced an alternative drug for kala azar called miltefosine, but doctors say there are signals that about 10 per cent patients who have received miltefosine have a relapse.

The researchers say the discovery of how the drug-resistant parasite harnesses the molecular pump is particularly worrying because both antimonials and miltefosine seem to be expelled from cells through the action of this pump.

"The challenge of drug-resistant forms of this parasite seems to be getting more complicated than it was thought to be," said Dipshikha Chakravortty, an associate professor at the Centre for Infectious Diseases Research at the Indian Institute of Science, Bangalore, and a team member.

Scientists believe a superior understanding of molecular mechanisms of drug resistance will help in the design of new drugs. "This study provides new and important targets for (the design of) anti-leishmanial compounds," said Shyam Sundar, a professor of medicine at the Institute of Medical Sciences, Banaras Hindu University, Varanasi, another team member.

"Kala azar is primarily a disease that affects the poor and those whose habitat overlaps with that of the sandflies," said Ganguly, former director-general of the Indian Council of Medical Research. "Using molecular information to design new drugs will be a long-term goal ' right now, given the concerns about drug resistance, standard treatment should involve a combination of two drugs."

Indian drug regulators have approved two more drugs for kala azar ' amphotericin-B and paromomycin. The current standard treatment, Ganguly said, is typically a two-drug combination using two of these three drugs.

But Roy and his colleagues at the IICB are also looking for new drugs. They have just completed a set of animal studies that suggest that a known anti-psychotic drug named imipramine is more effective than miltefosine.

In a research paper last month in the journal PLoS Neglected Diseases, the IICB scientists said imipramine should be considered a candidate inexpensive and highly effective drug.

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