David L. Sacks

National Institute of Allergy and Infectious Diseases

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Nathan C. Peters

University of Calgary

Susanne Nylén

Karolinska Institutet

Shyam Sundar

Banaras Hindu University

Tiago Rodrigues Ferreira

National Institute of Allergy and Infectious Diseases

Yasmine Belkaid

National Institute of Allergy and Infectious Diseases

Shaden Kamhawi

National Institute of Allergy and Infectious Diseases

Phillip G. Lawyer

Brigham Young University

Salvatore J. Turco

University of Kentucky

Susana Méndez

Universidad de La Frontera

Om Prakash Singh

Institute of Medical Sciences

Cooperative Institutions

National Institutes of Health

161

National Institute of Allergy and Infectious Diseases

158

Banaras Hindu University

Fundação Oswaldo Cruz

Institute of Medical Sciences

Harvard University

Universidade de São Paulo

QIMR Berghofer Medical Research Institute

Johns Hopkins University

National Cancer Institute

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The Role of Interleukin (IL)-10 in the Persistence of Leishmania major in the Skin after Healing and the Therapeutic Potential of Anti–IL-10 Receptor Antibody for Sterile Cure

The Journal of Experimental Medicine (2001)

Yasmine Belkaid Karl F. Hoffmann Susana Méndez Shaden Kamhawi Mark C. Udey

Some pathogens (e.g., Mycobacterium tuberculosis, Toxoplasma gondii, Leishmania spp) have been shown to persist in their host after clinical cure, establishing the risk of disease reactivation. We analyzed the conditions necessary for the long term maintenance of Leishmania major in genetically resistant C57BL/6 mice after spontaneous healing of their dermal lesions. Interleukin (IL)-10 was found to play an essential role in parasite persistence as sterile cure was achieved in IL-10-deficient and IL-4/IL-10 double-deficient mice. The requirement for IL-10 in establishing latency associated with natural infection was confirmed in IL-10-deficient mice challenged by bite of infected sand flies. The host-parasite equilibrium was maintained by CD4+ and CD8+ T cells which were each able to release IL-10 or interferon (IFN)-gamma, and were found to accumulate in chronic sites of infection, including the skin and draining lymph node. A high frequency of the dermal CD4+ T cells released both IL-10 and IFN-gamma. Wild-type mice treated transiently during the chronic phase with anti-IL-10 receptor antibodies achieved sterile cure, suggesting a novel therapeutic approach to eliminate latency, infection reservoirs, and the risk of reactivation disease.

10.1084/jem.194.10.1497

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Citations (551)

Vaccination with DNA Encoding the Immunodominant LACK Parasite Antigen Confers Protective Immunity to Mice Infected with Leishmania major

The Journal of Experimental Medicine (1997)

Sanjay Gurunathan David L. Sacks Daniel R. Brown Steven L. Reiner Hughes Charest

To determine whether DNA immunization could elicit protective immunity to Leishmania major in susceptible BALB/c mice, cDNA for the cloned Leishmania antigen LACK was inserted into a euykaryotic expression vector downstream to the cytomegalovirus promoter. Susceptible BALB/c mice were then vaccinated subcutaneously with LACK DNA and challenged with L. major promastigotes. We compared the protective efficacy of LACK DNA vaccination with that of recombinant LACK protein in the presence or absence of recombinant interleukin (rIL)-12 protein. Protection induced by LACK DNA was similar to that achieved by LACK protein and rIL-12, but superior to LACK protein without rIL-12. The immunity conferred by LACK DNA was durable insofar as mice challenged 5 wk after vaccination were still protected, and the infection was controlled for at least 20 wk after challenge. In addition, the ability of mice to control infection at sites distant to the site of vaccination suggests that systemic protection was achieved by LACK DNA vaccination. The control of disease progression and parasitic burden in mice vaccinated with LACK DNA was associated with enhancement of antigen-specific interferon-γ (IFN-γ) production. Moreover, both the enhancement of IFN-γ production and the protective immune response induced by LACK DNA vaccination was IL-12 dependent. Unexpectedly, depletion of CD8+ T cells at the time of vaccination or infection also abolished the protective response induced by LACK DNA vaccination, suggesting a role for CD8+ T cells in DNA vaccine induced protection to L. major. Thus, DNA immunization may offer an attractive alternative vaccination strategy against intracellular pathogens, as compared with conventional vaccination with antigens combined with adjuvants.

10.1084/jem.186.7.1137

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Citations (360)

Type I Interferons Suppress Anti-parasitic Immunity and Can Be Targeted to Improve Treatment of Visceral Leishmaniasis

Cell Reports (2020)

Rajiv Kumar Patrick T. Bunn Siddharth Singh Susanna S. Ng Marcela Montes de

Parasitic Disease

10.1016/j.celrep.2020.01.099

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Citations (51)

Contributors

Elsevier eBooks (2016)

Rafi Ahmed Roy M. Anderson Daniel Bakken Jeffrey M. Bethony Barry R. Bloom

10.1016/b978-0-12-802174-3.00037-0

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Efficient Capture of Infected Neutrophils by Dendritic Cells in the Skin Inhibits the Early Anti-Leishmania Response

PLoS Pathogens (2012)

Flávia Lima Ribeiro-Gomes Nathan C. Peters Alain Debrabant David L. Sacks

Neutrophils and dendritic cells (DCs) converge at localized sites of acute inflammation in the skin following pathogen deposition by the bites of arthropod vectors or by needle injection. Prior studies in mice have shown that neutrophils are the predominant recruited and infected cells during the earliest stage of Leishmania major infection in the skin, and that neutrophil depletion promotes host resistance to sand fly transmitted infection. How the massive influx of neutrophils aimed at wound repair and sterilization might modulate the function of DCs in the skin has not been previously addressed. The infected neutrophils recovered from the skin expressed elevated apoptotic markers compared to uninfected neutrophils, and were preferentially captured by dermal DCs when injected back into the mouse ear dermis. Following challenge with L. major directly, the majority of the infected DCs recovered from the skin at 24 hr stained positive for neutrophil markers, indicating that they acquired their parasites via uptake of infected neutrophils. When infected, dermal DCs were recovered from neutrophil depleted mice, their expression of activation markers was markedly enhanced, as was their capacity to present Leishmania antigens ex vivo. Neutrophil depletion also enhanced the priming of L. major specific CD4+ T cells in vivo. The findings suggest that following their rapid uptake by neutrophils in the skin, L. major exploits the immunosuppressive effects associated with the apoptotic cell clearance function of DCs to inhibit the development of acquired resistance until the acute neutrophilic response is resolved.

Ex vivo

Neutrophil Extracellular Traps

Priming (agriculture)

10.1371/journal.ppat.1002536

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Citations (191)

Splenic accumulation of IL-10 mRNA in T cells distinct from CD4+CD25+ (Foxp3) regulatory T cells in human visceral leishmaniasis

The Journal of Experimental Medicine (2007)

Susanne Nylén Radheshyam Maurya Liv Eidsmo Krishna Das Manandhar Shyam Sundar

Visceral leishmaniasis (VL) is a life-threatening disease characterized by uncontrolled parasitization of the spleen, liver, and bone marrow. Interleukin (IL)-10 has been implicated in the suppression of host immunity in human VL based on the elevated levels of IL-10 observed in plasma and lesional tissue, and its role in preventing clearance of Leishmania donovani in murine models of VL. The aim of this study was to identify the cellular source of IL-10 in human VL and determine if CD4+CD25+ (Foxp3high) regulatory T (T reg) cells are associated with active disease. We analyzed surface marker and gene expression in peripheral blood mononuclear cells and splenic aspirates from Indian VL patients before and 3–4 wk after treatment with Amphotericin B. The results did not point to an important role for natural CD4+CD25+ (Foxp3high) T reg cells in human VL. They did not accumulate in and were not a major source of IL-10 in the spleen, and their removal did not rescue antigen-specific interferon γ responses. In contrast, splenic T cells depleted of CD25+ cells expressed the highest levels of IL-10 mRNA and were the predominant lymphocyte population in the VL spleen. The elevated levels of IL-10 in VL plasma significantly enhanced the growth of L. donovani amastigotes in human macrophages. The data implicate IL-10–producing CD25−Foxp3− T cells in the pathogenesis of human VL.

10.1084/jem.20061141

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Citations (324)

Expression of a stage-specific lipophosphoglycan in Leishmania major amastigotes

Molecular and Biochemical Parasitology (1991)

Salvatore J. Turco David L. Sacks

Lipophosphoglycan

Amastigote

Glycoconjugate

10.1016/0166-6851(91)90030-a

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Citations (93)

Development of Infective Stage Leishmania Promastigotes within Phlebotomine Sand Flies

American Journal of Tropical Medicine and Hygiene (1985)

David L. Sacks Peter V. Perkins

Midgut promastigotes were obtained from Phlebotomus papatasi and Lutzomyia longipalpis on days 3-7 after infection with cloned isolates of Leishmania major and Leishmania mexicana amazonensis, respectively, and examined as to their ability to initiate cutaneous infections in BALB/c mice. Sequential development of midgut promastigotes from a noninfective to an infective stage was confirmed for both the New World and Old World species. The generation of infective promastigotes from rapidly dividing avirulent populations occurred as early as day 3 and was well under way by day 4 after infective feed. Optimally infective promastigotes were recovered from midguts shortly after bloodmeal passage, coinciding with the time at which another bloodmeal is sought by the fly.

10.4269/ajtmh.1985.34.456

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Citations (176)

Thermosensitivity Patterns of Old vs. New World Cutaneous Strains of Leishmania Growing within Mouse Peritoneal Macrophages in Vitro

American Journal of Tropical Medicine and Hygiene (1983)

David L. Sacks Aldina Barral Franklin A. Neva

Infection of mouse peritoneal macrophages in vitro was used to examine the effect of elevated temperature on the intracellular replication of various strains of Leishmania. Of eight cutaneous strains examined, all grew optimally at 35 degrees C. At 37 degrees C the reduction in growth was most pronounced for the New World cutaneous strains, and at 39 degrees C three of four New World cutaneous strains were completely destroyed whereas all of the L. tropica strains survived and exhibited at least 100% growth after 3 days. The results of these in vitro studies correlate closely with the outcome of heat therapy on two patients with cutaneous disease, suggesting that, in general, cutaneous lesions due to L. tropica strains might be less responsive to heat therapy than lesions due to L. mexicana and related strains.

Leishmania tropica

Amastigote

10.4269/ajtmh.1983.32.300

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Citations (60)

Complement binding by two developmental stages of Leishmania major promastigotes varying in expression of a surface lipophosphoglycan.

The Journal of Experimental Medicine (1988)

S M Puentes David L. Sacks R P da Silva Keith A. Joiner

The binding of complement by two developmentally distinct stages of Leishmania major has been studied. Noninfective log phase growth (LOG) promastigotes (serum sensitive) activate complement with deposition of covalently bound C3b onto the surface of the parasite. Infective, peanut agglutinin (PNA-) metacyclic stage promastigotes (serum resistant) also bear mainly C3b after incubation in serum, but a major portion of deposited C3 is present as a 110 X 10(3) mol wt C3 fragment. Whereas deposition of C3b on LOG promastigotes is mediated through the alternative pathway. PNA- parasites are unable to activate the alternative pathway in nonimmune serum. C3 is released from the parasite surface by proteolytic cleavage, at a rate which is nearly threefold greater for LOG than for PNA- promastigotes. Immunoprecipitation experiments show that the developmentally regulated lipophosphoglycan is a major C3 acceptor on both LOG and PNA- parasites. These experiments, which are the first to compare the form and processing of complement on infective and noninfective promastigotes of Leishmania, provide a framework for further definition of the differential C3 receptor-dependent uptake and survival of these parasites within mononuclear phagocytes.

Lipophosphoglycan

C3-convertase

Immunoprecipitation

10.1084/jem.167.3.887

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Citations (202)