Leishmania RNA Virus Controls the Severity of Mucocutaneous Leishmaniasis

An RNA virus of a parasite binds to human Toll-like receptor 3 and modulates host immune responses to the parasite. Mucocutaneous leishmaniasis is caused by infections with intracellular parasites of the Leishmania Viannia subgenus, including Leishmania guyanensis. The pathology develops after parasite dissemination to nasopharyngeal tissues, where destructive metastatic lesions form with chronic inflammation. Currently, the mechanisms involved in lesion development are poorly understood. Here we show that metastasizing parasites have a high Leishmania RNA virus–1 (LRV1) burden that is recognized by the host Toll-like receptor 3 (TLR3) to induce proinflammatory cytokines and chemokines. Paradoxically, these TLR3-mediated immune responses rendered mice more susceptible to infection, and the animals developed an increased footpad swelling and parasitemia. Thus, LRV1 in the metastasizing parasites subverted the host immune response to Leishmania and promoted parasite persistence.

[1]  B. Travi,et al.  Behavior of Leishmania braziliensis s.l. in golden hamsters: evolution of the infection under different experimental conditions. , 1988, The Journal of parasitology.

[2]  Lena Alexopoulou,et al.  Detrimental Contribution of the Toll-Like Receptor (TLR)3 to Influenza A Virus–Induced Acute Pneumonia , 2006, PLoS pathogens.

[3]  K. Stuart,et al.  Leishmania RNA viruses in Leishmania of the Viannia subgenus. , 1996, The American journal of tropical medicine and hygiene.

[4]  B. Travi,et al.  Evidence for leishmania (viannia) parasites in the skin and blood of patients before and after treatment. , 2006, The Journal of infectious diseases.

[5]  J. Patterson,et al.  Detection of Leishmania RNA virus 1 proteins , 1993, Journal of virology.

[6]  E. Ullu,et al.  Retention and Loss of RNA Interference Pathways in Trypanosomatid Protozoans , 2010, PLoS pathogens.

[7]  Alba,et al.  Haemoculture of Leishmania (Viannia) braziliensis from two cases of mucosal leishmaniasis: re-examination of haematogenous dissemination. , 1992, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[8]  P. Myler,et al.  Distribution and sequence divergence of LRV1 viruses among different Leishmania species. , 1992, Molecular and biochemical parasitology.

[9]  D. Wirth,et al.  Characterization of a RNA virus from the parasite Leishmania. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[10]  T. Beaty,et al.  IL6 -174 G/C promoter polymorphism influences susceptibility to mucosal but not localized cutaneous leishmaniasis in Brazil. , 2006, The Journal of infectious diseases.

[11]  J. Louis,et al.  TLR9-Dependent Activation of Dendritic Cells by DNA from Leishmania major Favors Th1 Cell Development and the Resolution of Lesions1 , 2009, The Journal of Immunology.

[12]  L. Guizani-Tabbane,et al.  Leishmania initially activates but subsequently down-regulates intracellular mitogen-activated protein kinases and nuclear factor-kappaB signaling in macrophages. , 2008, Molecular immunology.

[13]  Benjamin S. Bloom,et al.  A Taxonomy for Learning, Teaching, and Assessing: A Revision of Bloom's Taxonomy of Educational Objectives , 2000 .

[14]  C. Pirmez,et al.  Cytokine patterns in the pathogenesis of human leishmaniasis. , 1993, The Journal of clinical investigation.

[15]  S. Gaze,et al.  Mucosal Leishmaniasis Patients Display an Activated Inflammatory T‐cell Phenotype Associated with a Nonbalanced Monocyte Population , 2006, Scandinavian journal of immunology.

[16]  N. Fasel,et al.  Resistance to oxidative stress is associated with metastasis in mucocutaneous leishmaniasis. , 2006, The Journal of infectious diseases.

[17]  R. Corrêa-Oliveira,et al.  Short report: quantification of leishmaniavirus RNA in clinical samples and its possible role in pathogenesis. , 2003, The American journal of tropical medicine and hygiene.

[18]  F. Tuon,et al.  Mucosal leishmaniasis . Current scenario and prospects for treatment. , 2008, Acta tropica.

[19]  S. Reed,et al.  Transforming growth factor-beta in human cutaneous leishmaniasis. , 1995, The American journal of pathology.

[20]  J. Blackwell,et al.  Tumour necrosis factor alpha and mucocutaneous leishmaniasis. , 1999, Parasitology today.

[21]  C. Bogdan,et al.  The role of nitric oxide in innate immunity , 2000, Immunological reviews.

[22]  F. Chappuis,et al.  Influence of Leishmania (Viannia) species on the response to antimonial treatment in patients with American tegumentary leishmaniasis. , 2007, The Journal of infectious diseases.

[23]  L. O’Neill,et al.  Toll-like receptors: from the discovery of NFkappaB to new insights into transcriptional regulations in innate immunity. , 2006, Biochemical pharmacology.

[24]  N. Saravia,et al.  Natural history, clinical evolution, and the host-parasite interaction in New World cutaneous Leishmaniasis. , 1996, Clinics in dermatology.

[25]  S. Akira,et al.  Immunoprivileged status of the liver is controlled by Toll-like receptor 3 signaling. , 2006, The Journal of clinical investigation.

[26]  Haitao Wen,et al.  TLR3 is an endogenous sensor of tissue necrosis during acute inflammatory events , 2008, The Journal of experimental medicine.

[27]  N. Saravia,et al.  CLONAL DIVERSITY IN THE EXPRESSION AND STABILITY OF THE METASTATIC CAPABILITY OF LEISHMANIA GUYANENSIS IN THE GOLDEN HAMSTER , 2000, The Journal of parasitology.

[28]  J. Patterson,et al.  Hygromycin B resistance mediates elimination of Leishmania virus from persistently infected parasites , 1997, Journal of virology.

[29]  A. Llanos-Cuentas,et al.  CXCL10 Production by Human Monocytes in Response to Leishmania braziliensis Infection , 2009, Infection and Immunity.

[30]  B. Travi,et al.  Infectivity of the subspecies of the Leishmania braziliensis complex in vivo and in vitro. , 1990, The American journal of tropical medicine and hygiene.

[31]  L. Carvalho,et al.  Decreased In Situ Expression of Interleukin-10 Receptor Is Correlated with the Exacerbated Inflammatory and Cytotoxic Responses Observed in Mucosal Leishmaniasis , 2005, Infection and Immunity.

[32]  E. Carvalho,et al.  Lymphadenopathy as the first sign of human cutaneous infection by Leishmania braziliensis. , 1995, The American journal of tropical medicine and hygiene.