NIAID funds extramural research on the molecular biology of Leishmania parasites to better understand disease transmission and pathogenesis. These efforts include:
- studies of the mechanisms of gene expression to guide the development of specific inhibitors against the parasites
- research on the novel membrane defense system used by Leishmania to support the development of effective novel treatments
NIAID-supported researchers are also examining the role of RNA viruses on the pathogenesis of Leishmania. How the parasite causes disease of varying severity is not well understood. Investigators are examining whether at least two novel RNA viruses that infect the parasite may be in part responsible for this, as the viral presence appears to confer elevated pathology and metastasis.
Patients with cutaneous and visceral leishmaniasis are seen on a natural history protocol by the Clinical Parasitology team. This protocol allows for patients to be diagnosed and treated by experts in the field using state of the art tools. Clinical data and specimens are collected over the course of treatment to allow us to better understand the host and parasite factors that shape the course of disease.
Intracellular Parasite Biology
David L. Sacks, Ph.D., of the Laboratory of Parasitic Diseases, Intracellular Parasite Biology Section, oversees research projects that address the immunology and cell biology of leishmanial infections and the biology of Leishmania parasites within their mammalian hosts and sand fly vectors. The ultimate goal is to develop new strategies to treat and prevent leishmanial infections and to potentially apply these insights to diseases caused by other intracellular pathogens, such as tuberculosis, or to other vector-borne diseases, such as malaria.
Dr. Sacks and his collaborators seek to define the role of sand fly saliva in modulating the host response to Leishmania parasites. The lab uses experimental mouse models to define how the host acquires resistance to Leishmania infection, as well as to uncover the immunoregulatory mechanisms that control persistent infection after treatment, which is a hallmark of the infection in humans.
Yasmine Belkaid, Ph.D., of the Laboratory of Parasitic Diseases, Mucosal Immunology Unit, heads a research program investigating the immunologic mechanisms induced by parasites to promote their survival within their human and animal hosts. Her studies and others like them have found that natural regulatory T (Treg) cells help limit collateral tissue damage caused by vigorous immune responses, but these cells also can limit the magnitude of the immune response, resulting in a failure to adequately contain infection.
These findings have led Dr. Belkaid and her colleagues to explore how natural Treg cells mediate the immune response during infection by single-cell parasites, such as Leishmania. By focusing their attention on immune regulatory mechanisms within mammalian hosts, scientists in her lab hope to uncover and unleash potent immune responses against such parasites, potentially leading to new treatments against diseases such as leishmaniasis and toxoplasmosis.
NIAID supports extramural research on sand fly biology and populations. Reference genomes are important tools to help understand genetic diversity and mechanisms of insecticide resistance, and to assist in the development of novel tools and strategies for the prevention of disease transmission. NIAID-funded researchers are generating new, high quality reference genome sequences for two critical sand fly species: Lutzomyia longipalpis, a primary vector of American visceral leishmaniasis, and Phlebotomus papatasi, a vector of cutaneous leishmaniasis found in areas including northern Africa, the Middle East and India. These genomes will aid efforts to monitor and control disease transmission.
Scientists at NIAID laboratories are also studying the biology of leishmaniasis vectors. These include:
- José M.C. Ribeiro, M.D., Ph.D., of Laboratory of Malaria and Vector Research, Vector Biology Section, directs a research program that explores the biochemical and pharmacological properties found in the salivary glands of blood-feeding insects and ticks. Dr. Ribeiro and his team have deciphered the genetic makeup of substances found in sand fly saliva and discovered several novel anti-clotting, anti-platelet, and vasodilatory agents that help the sand fly evade the mammalian host’s immune system when feeding.
Scientists in his lab seek to improve the understanding of how blood-feeding behavior in insects and ticks evolved and, at the same time, identify new compounds in the saliva of these insects and ticks that can be used to help develop treatments or vaccines
Vector Molecular Biology
Jesus G. Valenzuela, Ph.D., of Laboratory of Malaria and Vector Research, Vector Molecular Biology Unit, leads a research program that studies the molecular aspects of salivary and midgut proteins in disease-transmitting vectors such as sand flies. Dr. Valenzuela and his team aim to improve understanding of the molecular interactions between vector, parasite, and mammalian host, and to identify targets for transmission-blocking vaccines and vector-based salivary vaccines for leishmaniasis and other vector-borne diseases.
The lab develops tools to study the immune responses to proteins in sand fly saliva and to understand how cellular immune responses to these proteins can protect against Leishmania infection. It investigates how Leishmania parasites interact with midgut proteins in the sand fly to survive and multiply and how the parasites can influence expression of certain midgut proteins. The lab also conducts epidemiologic studies of leishmaniasis in Mali, Africa, to advance scientific understanding of Leishmania infection and of cellular immune responses to sand fly salivary proteins in humans.