New insights on leishmaniasis in immunosuppressive conditions

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1 New insights on leishmaniasis in immunosuppressive conditions Javier Moreno Immunoparasitology Unit WHO Collaborative Center for Leishmaniasis Centro Nacional de Microbiología INSTITUTO DE SALUD CARLOS III

2 Clinical forms of leishmaniasis Cutaneous leishmaniasis Recidivant cutaneous leishmaniasis Mucocutaneus leishmaniasis Visceral leishmaniasis Difuse cutaneous leishmaniasis Post-kala azar dermal leishmaniasis

3 Leishmaniasis is distributed worldwide

4 The incidence and geographical distribution of leishmaniasis has increased as a result of social, environmental and health factors.

5 The incidence and geographical distribution of leishmaniasis has increased as a result of social, environmental and health factors. Risk factors associated with the emergence of leishmaniasis : Environmental changes Demographic and habits changes Travel, immigration and war conflicts: imported leishmaniasis Emergence of drug resistance Immunosuppression

6 Leishmaniasis and immunosuppression. Leishmaniasis has been associated with different immunosuppressive conditions: HIV/AIDS MALNUTRITION ORGAN TRANSPLANT LEUKEMIA AND OTHER MALIGNANCIES IMMUNOSUPPRESSIVE TREATMENTS

7 HIV-Leishmania coinfection Coinfection Leishmaniasis

8 HIV-Leishmania coinfection Number of coinfection cases in Spain 100 HAART year Madrid Andalucía Islas Baleares Total

9 HIV-Leishmania coinfection HIV-1 infection increases the risk of developing leishmaniasis by 100 to 2320 times and modifies the clinical spectrum of leishmaniasis - Increased parasite load in peripheral blood and bone marrow (uncontrolled replication of the parasite) - Parasitatization of unusual localizations (digestive tract, lung) - Low levels of parasite specific serum antibodies - High rate of cutaneous dissemination and visceralization despite the specie of Leishmania involved - High rate of treatment failure and recurrences (100% 12 months after treatment)

10 HIV-Leishmania coinfection Leishmania infection induces the replication of HIV-1 and AIDS progression. - Leishmania infection induces a chronic immune activation that produce the activation of latent virus and the increase of viral load. - Leishmania parasite can upregulate virus expression in HIV-1 infected monocytes. - LPG can also interact with the HIV-1 infected T cells to induce virus replication -Leishmania infection affects the life cycle of the virus through cytokine and induction of specific chemokine receptors.

11 [p24] ng/ml HIV-Leishmania coinfection In vitro infection of monocytoid U1 cells with L. infantum promastigotes induces HIV replication No infect 1:1 1:2 1:5 1:10 1:20 1:50 Ratio U1 cell/parasite

12 HIV-Leishmania coinfection Introduction of HAART by the end of 1990s has produced a clear decrease in the incidence of coinfection -HIV-1 protease inhibitors directly affect Leishmania proteases - Immune reconstitution inflammatory syndrome (IRIS) has been reported in coinfected patients after initiation of HAART. - IRIS associated leishmaniasis has a dermatologic presentation and has been described as diffuse cutaneous leishmaniasis or PKDL.

13 HIV-Leishmania coinfection The treatment of coinfected patients presents: -Reduced number of therapeutics options. Pentav. antimonials AMB0 Miltefosine Paramomycin Pentamidine COMBINATIONS -These patients have significant lower cure rates. Repeated exposure to single antileishmanial drug will inevitable generate resistance. -Higher drug toxicity -Higher relapse rates -Few clinical trials -Conventional treatment increases viral load

14 Malnutrition Protein Energy Malnutrition (PEM) is a major public health problem in developing countries (>30%) PEM is also the main cause of immunodeficiency in the world and a major determinant of both progression and severity of infections. Malnutrition is associated with the 60% of infant deaths caused by infections Malnutrition causes lymphoid organs atrophy and affects innate and adaptive (humoral and cellular) immune responses

15 Malnutrition and Leishmaniasis The ratio of asymptomatic/subclinical to clinical infection varies between the different endemic countries Asymptomatic CLINICAL SUDAN ,6-1 KENYA 4 1 ETHIOPIA 6 1 IRAN 13 1 BRAZIL SPAIN 50 1

16 Malnutrition and Leishmaniasis Malnourished individuals are more susceptible to VL, CL and MCL. Percentages of VL patientes with underweight ranges from 21,4% in Brazil to 92,6% in Sudan. PEM is a determinant factor for progression to clinical VL and it is associated with more severe forms of VL. Malnutrition is a major risk for poor treatment outcomes, Treatment is a 20% less effective in these patients.

17 Leishmaniasis and malnutrition in Amhara State, Ethiopia

18 Leishmaniasis and malnutrition in Amhara State, Ethiopia ASYMPTOMATIC LEISHMANIA INFECTION Cross-sectional survey (N = 567) Técnica n positivos % DAT 45 7,9 IFI 2 0,4 rk ,9 PCR 0 0 LST 35 6,2 Combined 73 12,9

19 Leishmaniasis and malnutrition in Amhara State, Ethiopia LEVELS OF MALNUTRITION Cross-sectional survey (N = 458) n % Acute Malnutrition ,9 BMI for Age Zscore < -2 Cronic Malnutrition ,7 Height for Age Zscore < -2

20 Leishmaniasis and malnutrition in Amhara State, Ethiopia Immunological findings: Malnourished children showed lower levels of lymphocytes (CD4+, CD8+ and B cells) than nonmalnourished children. Cytokine production was reduced in PBMCs after stimulation with PHA. Mean serum levels of PGE2 were higher in malnourished children compared to non-malnourished. Higher levels of IFN-g were detected in DAT+ nonmalnourished compared to DAT+ malnourished children

21 Models of experimental leishmaniasis on immunodeficient host ATHIMYC MICE High susceptibility to parasitic infections Excellent models for drug assay under immunosuppressive conditions

22 Models of experimental leishmaniasis on immunodeficient host Intradermal infection with L. major promastigotes in NMRI-nu/nu athymic mice - Cutaneous lesions appeared 10 weeks p.i. - Parasites are detected in liver and spleen by PCR and culture

23 Models of experimental leishmaniasis on immunodeficient host Skin-humanized mice as a model for human CL Human skin equivalent are grafted in the back of immunodeficient mice. Graft is inoculated with 5x10 6 L. major promastigotes

24 Models of experimental leishmaniasis on immunodeficient host Lesions in skin humanized mice were apparent from week 5 onwards

25 Models of experimental leishmaniasis on immunodeficient host Topic treatment was able to heal the lesion after 3 weeks

26 Models of experimental leishmaniasis on immunodeficient host SKIN-HUMANIZED MICE MODEL Skin-humanized mice develop skin ulcers at the inoculated human area This model reproduces the lesion pattern observed in infected human individuals This model allows assays on a larger number of individuals with an uniform genetic background This human-skin mouse chimera represents a first step fully valid to test CL drugs under immunosuppressive conditions.