|FACE TO FACE
|Year : 2019 | Volume
| Issue : 2 | Page : 133-137
Face to face: Leishmaniasis and its changing patterns
|Date of Acceptance||13-Aug-2019|
|Date of Web Publication||18-Sep-2019|
|How to cite this article:|
. Face to face: Leishmaniasis and its changing patterns. Trop Parasitol 2019;9:133-7
1. Being one of the leading parasitology researchers from India, could you please explain how would your research findings made an impact on National Leishmania Control Programme?
In India, visceral leishmaniasis (VL) or commonly known as kala-azar is endemic for centuries. It is caused by Leishmania donovani, a kinetoplastid protozoan parasite, which is transmitted from one patient to another through a tiny insect known as sand-fly (Phlebotomus argentipes). Rarely, the disease can be transmitted through infected blood, solid organs transplantation, through shared injection needles, and very rarely, from mother to child via placenta. The disease is most commonly seen in poorest of the poor population due to more vulnerability of these people to insect bites. Mainly affects the reticuloendothelial system of the patient that includes the spleen, bone marrow, and other hematopoietic systems, and therefore, this form is also known as visceral of leishmaniasis. There are at least two other forms of the infection. These are cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (MCL). The conventional methods of diagnosing VL such as bone marrow, splenic and lymph node aspirations, or biopsies were painful, often hazardous and less sensitive. My team realized these limitations, and we worked to innovate a new diagnostic method. Therefore, we cloned a novel antigen from a clinical isolate of L. donovani (KE16), and the rights to commercialize this recombinant antigen were given to an Indian manufacturing company. The company in collaboration prepared rapid diagnostic immunochromatographic kits based on flow-through and lateral flow principles of antibody detection kits. These kits were taken up by the Government of India in its Kala-azar Control (elimination) Programme, and the Government of India saved millions of dollars by using our indigenous kits. The cost-effective and highly sensitive and specific kits thus helped the early detection and control of kala-azar from India.
2. What is the current scenario of vector-borne diseases in your region with special reference to malaria and leishmaniasis?
In India, traditionally, VL has remained endemic in Gangetic Plains. The disease reported originally in the 19th century in Assam, Bengal, and Tamil Nadu, has changed its epidemiological course in the last 50 years. The Tamil Nadu has become completely VL free, while very few cases are reported now from Assam. However, the disease has migrated upward, becoming endemic in West Bengal, Bihar, Uttar Pradesh, and Uttarakhand. Nevertheless, in the last 15 years with the unprecedented active case finding and treatment initiative, the number of VL has come down drastically with only few deaths. Similarly, cases of malaria have also reduced significantly, but some pockets of vivax malaria are still high. However, cases of CL are being reported more frequently, particularly in Rajasthan which is endemic region, and also in nonendemic regions. Sporadic cases are reported from Kerala, Karnataka, and Himachal Pradesh. The manifestations are more severe in AIDS patients.
3. As eminent expert member of various organizations, please share your views on research progress in developing countries with respect to neglected tropical diseases (NTDs)?
As the title given to these diseases itself, it suggests that several diseases prevalent in the tropical world remain neglected in terms of research, treatment, and prevention. Some of the prominent diseases are vector-borne disease such as leishmaniasis, soil transmitted helminthic parasites, and intestinal parasitosis. However, in the last few decades, the World Health Organization (WHO) and other international agencies have given emphasis on combating these diseases. This includes several initiatives such as Deworm the World, Leishmania Elimination Programme, and Malaria Eradication Programme. The Government of India has also initiated several funding opportunities to work on these diseases directly or through National Vector Borne Diseases Control Programme. At international level, sufficient funding has been arranged by European Commission, WHO (NTD), Medecins Sans Frontieres (MSF), etc., several publishing houses have also realized the importance of these diseases in the form of special calls for publications in the form of special issues, or editor's collection, and various other forms of comprehensive publications on these diseases. Earlier, only one journal was published by the Royal Society of Tropical Medicine, but now, the American Society of Tropical Medicine and Hygiene has also started a monthly journal for the last more than three decades. Public Library of Science (PLoS) started a special journal only to cover these diseases known as PLoS NTDs, which publishes huge quality articles and reviews. Similarly, lancet also published several special issues on these diseases in the last two decades. Currently, sufficient funding and publication opportunities are available in the field of NTDs. I believe that many of these diseases are no more neglected.
4. Leishmaniasis has been linked to environmental changes such as deforestation, building of dams, irrigation schemes, and urbanization. How far it is true in Indian scenario?
Climate is changing alarmingly in the last 50 years mainly due to urbanization and motorization of the entire world. The concentration of carbon dioxide and temperature both are continuously increasing, and it is expected that if no innovative methods are adopted to mitigate these changes, approximately the global temperature will raise up to 40°C by 2050. This is a huge increase and will lead to devastating impact on our life. Most significant impact will be in the tropical belt mainly the Southeast Asia. This global warming and increased CO2 concentration in our environment will have more rains, more famines, intense Tsunami-like storms. These changes will lead to more humidity and precipitation with increased vector-borne, air-borne, and water-borne diseases, food shortage, worsening pollution with severe respiratory illness, and social unrest. We can expect more outbreaks of malaria, dengue, chikungunya, all forms of leishmaniasis, schistosomiasis, helminthiasis, Lyme disease, Hantavirus, rift valley fever, and many more similar diseases. India will be hardest hit from it because most of these diseases engulf India.
5. Could you please elaborate on your work related to Leishmania and other works related to immunological models for this infection?
My main research has been on developing more sensitive and cost-effective diagnostic methods for infectious diseases, particularly those that are difficult to diagnose and treat. Toward this goal, my team has made several ground-breaking discoveries in the field of pathophysiology of VL or kala-azar. I was the first to develop and patent a rapid and highly cost-effective diagnostic test for this disease. A novel recombinant antigen (Ld-KE16) was prepared from an Indian strain of L. donovani (Singh and Sivakumar 2003; Sivakumar et al., 2006) ((PCT/IN2003/000400) and the commercial rights of the test were transferred to the M/s Span Diagnostic Pvt Ltd., through the Department of Biotechnology (DBT), Government of India. The company has made rapid diagnostic test (RDT) kits in various test formats, which were dedicated to the nation by the Honorable Minister of Science and technology, Government of India, Shri. Kapil Sibal on February 6, 2006, in a glittering ceremony at the Press Club of India. These RDTs have made the invasive and hazardous methods such as bone marrow and splenic aspiration dispensable at a very affordable price (Singh 2006). It is a matter of pride that the diagnosis of kala-azar can now be made at a cost of <Rs. 50/patient in India using these trailblazing “Made in India” kits. These test kits are exceptionally accurate with 100% specificity and 98% sensitivity.
The disease kala-azar mainly affects the poor and down-trodden section of our society (Singh et al., 2000). Till rapid tests were made available, thousands of poor in the states of Bihar, West Bengal, and Uttar Pradesh were dying due to this disease because of nonavailability of sensitive, cost-effective, and point-of-care diagnostic methods. It may be mentioned that with the availability of this revolutionary test, the number of kala-azar deaths has come down significantly, thanks to the Government of India for their active surveillance, and free treatment combined with the RDT kit developed by Dr. Singh that played a pivotal role in the National Kala-azar Elimination Program. This cutting-edge technology is also saving millions of dollars of the Indian Government every year on foreign exchange. This is the first ever-indigenous invention by a medical scientist, which is become an integral part of any National Disease Elimination Programme. This invention received high appreciation and applauds from the WHO (WR-India, as chair of the award selection committee) in theBMJ Research and Innovation excellence award distribution ceremony while announcing the award to me.
Beside the above, this work has been recognized by the prominent science agencies of India, notably the DBT (Product, process, and Commercialization award); Indian Council of Medical Research (Dr. BK Aikat Award); Medical Council of India (Dr. BC Roy Award); Government of Uttar Pradesh (Vigyan Ratna Award); Indian Medical Association (Med-Achiever Award); Delhi Medical Association (Chikitsa Ratna Award); Indian Society of Parasitology (Dr. BP Pandey Oration Award); Indian Association of Tropical Parasitology (Outstanding Researcher in Parasitology); Indus Foundation (Innovation Excellence Award); Society for Immunology and Immunopathology (Life Time achievement Award), and many more.
The issue of reservoirs of VL in India has remained dogmatic. The dictum has been that only postkala-azar dermal leishmanias is (PKDL) patients serve as reservoirs and there are no animal reservoirs in India, in contrast to the well-known animal reservoirs worldwide. In several studies, our work has shown that where there are no PKDL cases, the outbreaks or sporadic cases of VL do occur. Furthermore, using novel polymerase chain reaction primers (PCT/IN2004/000395), my team also found that VL and PKDL strains are genetically different and both strains have differences in the antileishmanial drug susceptibility pattern. Therefore, in a radical approach, my team investigated thousands of animals in endemic areas as well as in nonendemic areas and found that goats are very potent animal reservoirs of VL in India. These findings are bound to make drastic deviation in the Kala-azar Elimination Programme of India.
The whole genome sequence (WGS) of several isolates of L. donovani from VL patients has been sequenced, but my laboratory became the first in the world to carry out the WGS of the PKDL strain of Leishmani a. The sequence alignment data showed significant differences in the genome of PKDL strain as compared to VL strains. The WGS also revealed a revolutionary finding that a major portion of a saprophytic bacterial (Parvibaculum lavamentivorans DS-1) genome gets integrated into the genome of PKDL strain. On the basis of this discovery new biological phenomenon has been postulated, thereby this integration could be the triggering factor to manifest the two strains differently (the viscerotropic form becoming dermotropic). This landmark discovery also proved my old hypothesis, that L. donovani undergoesin vivo hybridization to manifest as PKDL. These findings will go a long way in the eradication of old dogma about PKDL.
India has distinction of having maximum cases of HIV, tuberculosis (TB) and Leishmaniasis. In an in-depth invited review in International Journal of Infectious Diseases, I have discussed the current scenario of HIV-leishmania coinfection and factors that contributed to help quell this duo, in contrast to the other coendemic countries. However, the Leishmania and TB both are coendemic in several parts of Eastern India. It is also known that approximately 20% VL patients will have concomitant or subsequent TB, but there is no effective vaccine for these infections. Considering this as a major research challenge, for the first time, my team prepared a self-cleaving chimeric DNA vaccine which can be used against both TB and VL. This cutting edge innovation has been patented globally (PCT/IN2009/000093). DBT who funded and licensed this work, observed this invention as of high commercial value.
Miltefosine is a new drug approved for the treatment of VL in 2004 only, but within few years of its introduction, the efficacy has gone down. To understand the mechanism of resistance, in an Avant-Garde study my team has discovered novel mutations in the genes of Leishmania; which impart resistance to miltefosine. These mutations can now be used as molecular markers to diagnose and predict miltefosine resistance in circulating strains at an initial stage (Srivastava et al., 2016).
6. It has been a major concern that, in recent decade or so Plasmodium vivax malaria is turning out to be severe like Plasmodium falciparum, what is your take on this issue?
This is important question. However, this needs to be addressed in proper context. There are ample evidences that vivax malaria is turning out to be more severe and increasing number of drug resistance are also being reported from Africa and South Asia. A detailed analysis needs to be done, most preferably on archived sample, whether we were misdiagnosing many viva malaria or mixed cases as falciparum malaria using conventional microscopic methods or actually a new crop of mutant strain of P. vivax has come up. With the help of more sensitive and species specific RDTs and molecular methods, nowadays correct diagnosis could also be reason of more reported cases of severe vivax malaria.
7. What you would like to suggest the young aspirants who would like to take up parasitology as a research interest?
Every medical or surgical subspecialty has its own charm. Parasitology is a branch of microbiology and as such the MD in Microbiology is not considered a lucrative specialty. It is mainly attached stigma that microbiologist can be a medico as well as a nonmedico unlike a pediatrician, a gynecologist or a neurosurgeon, or gastroenterologist etc., However, I strongly believe that excellence is most important than any superspecialty. Those who want to pursue academics and research, are at much advantageous position if they decide early and take up such paramedical subjects. However, if the aim is to earn wealth these subjects may not be the best option. In MBBS course, microbiology was my weakest subject, while surgery was my favorite subject. But destiny added with then situations made me a microbiologist. In fact in 1984, I was doing my junior residency in orthopedic surgery and was preparing for 1 + 2 year MS in orthopedics. Unfortunately, same time, Mrs. Indira Gandhi, the then Prime Minister of India was assassinated leading to communal rites. These victims admitted in my unit had high rate of secondary wound infections, and this was the first time that I got attracted toward infectious diseases. Rest is history. However, after getting MD from one prestigious institution (Chandigarh) and getting senior residency at All India Institute of Medical Sciences, New Delhi, I never looked back. During my residency itself I developed interest in research and publications. Thanks to my thesis supervisor Prof. Rakesh Kochhar. By the time, my senior residency was over I already had 11 publications, including two communications in Lancet. During the same time (late 1980s), new epidemic peak of leishmaniasis was going on and I became favorite of clinical colleagues by virtue of sitting late in the laboratory, communicating the results on phone, going to the patient bedside, etc., By that time, during only senior residency I was part of a new clinical trial of ketoconazole which gave me coauthorship in two important publications, one in lancet and another Journal of Infectious Diseases. In the meantime, I attended a short course in epidemiology of Infectious diseases at University of Michigan, Ann Arbor from my own pocket and partially supported by CSIR travel award. After return from Ann Arbor, I actively started participating in Leishmania research and DBT selected me for overseas fellowship to learn molecular biology. In conclusion, this specialty gave me speedy opportunities to excel and contribute to the society. I feel privileged and satisfied that the innovative research my team carried out, served the poorest of the poor in particular and the country in general. What else one would expect from a human life.
8. You have been working all over the world, what is your opinion on research approach in developing countries when compared to developed nations?
The major differences in the research approach in developed and developing world are funding and the resultant resources. The perception of government and in general public in developing world about research and researchers is not high. This is most probably due to their inherent issues of general concern such as poverty alleviation, political compulsions, and lack of vision. The grant spent on research in developed countries ranges 2%–4% of gross domestic products, while in developing countries, it is <1%. The highest spending is by South Korea followed by Japan and USA. China is picking up very rapidly other developed world, but in India, the signs of improved spending on research are not encouraging. Second, most of the funding agencies and project reviewers ask for proof of concept at the tile of project evaluation. That means if somebody in the developed world has done a fundamental research, duplication, or nominal enhancement in such results are accomplished by the research done in developing countries. The out of box research was most often not funded by most of the funded agencies, until recently, when Biotechnology Industry Research Assistance Council in association with other international agencies and nongovernmental organizations (NGOs) started funding innovative research. However, the results of such funding will come in future years. Third, most researchers in developing countries do research for promotion in their career instead of passion. Often this yields in falsification and fudging of data. Because of this, most of the developed world does not give due importance to the research done in developing countries. The other facet of this is that results are often doubted and high impact journal will not publish results from developing countries. This is not always, though, due to doubt in methodology and results but also racial biases.
9. Different novel strategies are being publicized globally for Leishmania control, which of these do you consider would be practically feasible?
I think no single approach will be sufficient enough to eliminate kala-azar, which is most severe and concerning form. States need to adopt multipronged strategies, which should include vector control, active cases detection and treatment, vaccine, and tracing the nonhuman reservoirs. I also think that awareness about the modes of infection and preventive strategies is equally important, as the disease often affects the poor and uneducated population, who do not adopt vector control and preventive methods, so easily due to lack of awareness. Government and NGOs should work hand-in-hand to accomplish the target of eliminating leishmaniasis from the globe.
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