Muco-Cutaneous Leishmaniasis in the New World: the Ultimate Subversion Catherine Ronet University of Lausanne

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Muco-Cutaneous Leishmaniasis in the New World: the Ultimate Subversion Catherine Ronet University of Lausanne Washington University School of Medicine Digital Commons@Becker Open Access Publications 2011 Muco-cutaneous leishmaniasis in the New World: The ultimate subversion Catherine Ronet University of Lausanne Stephen M. Beverley Washington University School of Medicine in St. Louis Nicolas Fasel University of Lausanne Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Recommended Citation Ronet, Catherine; Beverley, Stephen M.; and Fasel, Nicolas, ,"Muco-cutaneous leishmaniasis in the New World: The ultimate subversion." Virulence.2,6. 547-552. (2011). https://digitalcommons.wustl.edu/open_access_pubs/2631 This Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in Open Access Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact [email protected]. ARTICLE ADDENDUM ARTICLE ADDENDUM Virulence 2:6, 547-552; November/December 2011; © 2011 Landes Bioscience Muco-cutaneous leishmaniasis in the New World The ultimate subversion Catherine Ronet,1 Stephen M. Beverley2 and Nicolas Fasel1,* 1Department of Biochemistry; University of Lausanne; Epalinges, Switzerland; 2Department of Molecular Microbiology; Washington University School of Medicine; St. Louis, MO USA nfection by the human protozoan par- Additionally, host factors are thought to Iasite Leishmania can lead, depending play significant roles in determining the primarily on the parasite species, to either clinical course of the disease as well. cutaneous or mucocutaneous lesions, or Leishmania parasites exist as free- fatal generalized visceral infection. In living promastigotes in the sand fly vector. the New World, Leishmania (Viannia) Following differentiation to the infective species can cause mucocutaneous leish- metacyclic form, parasites are deposited in maniasis (MCL). Clinical MCL involves the skin of vertebrate host by the sand fly a strong hyper-inflammatory response bite. There promastigotes encounter sev- ©2011Landes Bioscience. and parasitic dissemination (metastasis) eral host cell types including neutrophils, from a primary lesion to distant sites, dendritic cells and skin macrophages, leading to destructive metastatic second- ultimately transiting and differentiating Donot distribute. ary lesions especially in the nasopha- into amastigotes which go on to repli- ryngal areas. Recently, we reported that cate within the phagolysosome of macro- metastasizing, but not non-metastatic phages. Leishmania parasites must change strains of Leishmania (Viannia) guya- their metabolism and adapt themselves to nensis, have high burden of a non-seg- this new environment, and resist the oxi- mented dsRNA virus, Leishmania RNA dative and other attacks activated by the Virus (LRV). Viral dsRNA is sensed by innate immune system of the host. the host Toll-like Receptor 3 (TLR3) Leishmania species of the L. (Viannia) thereby inducing a pro-inflammatory subgenus, including mainly L. brazilien- response and exacerbating the disease. sis, L. guyanensis and L. panamensis, give The presence of LRV in Leishmania rise to CL but are also responsible for Key words: leishmaniasis, Leishmania opens new perspectives not only in basic MCL in up to 5–10% of cases. MCL is RNA virus, hyperinflammation, TLR-3, understanding of the intimate relation clearly distinguishable from other cuta- IFNβ between the parasite and LRV, but also neous leishmaniases by its chronic, latent in understanding the importance of the and metastatic behavior. It is character- Submitted: 07/08/11 inflammatory response in MCL patients. ized by the dissemination of parasites and Revised: 08/22/11 secondary distant lesions development Accepted: 08/23/11 Leishmania are human protozoan para- (metastasis), especially in the oral and sites endemic in 88 countries, with a nasopharyngeal areas of the face, and is http://dx.doi.org/10.4161/viru.2.6.17839 disease prevalence of 12 million cases accompanied by extensive tissue destruc- *Correspondence to: Nicolas Fasel; accompanied by 80,000 annual fatalities. tion concomitant with high immune cell Email: [email protected] These infections induce a large spectrum infiltration, intense activation of inflam- of clinical pathologies, mainly cutane- matory cells and parasite presence (albeit Addendum to: Ives A, Ronet C, Prevel F, Ruzzante ous (CL), mucosal (MCL) and visceral at low levels).1 MCL can appear con- G, Fuertes Marraco S, Schutz F, et al. Leishmania RNA Virus controls the severity of mucocuta- leishmaniasis (VL). The differences comitantly, several years after the initial neous leishmaniasis. Science 2011; 331:775–8; arise primarily from infection by differ- infection, or even in patients without PMID:21311023; http://dx.doi.org/10.1126/ ent Leishmania species, such as L. major, any CL history. MCL lesions are not self- science.1199326. L. braziliensis and L. infantum respectively. healing and are more resistant to antimony www.landesbioscience.com Virulence 547 treatment than the primary lesions, with Th1/Th2 phenotype and elevated cyto- RNAi machinery was recently shown frequent relapses. The factors responsible toxic T cell activity. However, cells from to be functional in L. braziliensis and in for these relapses are not known; both MCL patients display impaired control of L. guyanensis.17 A second remarkable feature the emergence of antimony resistance as the immune response due to a defect in the presence of Leishmania RNA viruses well as differences among the infecting their ability to respond to IL-10.7-10 The in many isolates of the L. (Viannia) spe- L. (Viannia) species and its virulence have production of the different inflammatory cies. These Leishmaniaviruses have been been suggested.2,3 cytokines by the host is likely to increase classified as Totiviridae, which includes Reactivation of L. (Viannia) infection cellular recruitment and contribute to the RNA viruses detected in other protozoa can occur following stress or immuno- pathology of the disease. Thus by these such as Trichomonas vaginalis and Giardia suppression at a site of local inflammation, and potentially other mechanisms, immu- lamblia and a variety of fungi including raising the challenging question of how nological hyperactivity contributes to Saccharomyces cerevisiae. Totiviruses have these factors interact with slow-growing MCL pathology. In turn measures dimin- a small unsegmented dsRNA genome or dormant parasites and the immune ishing uncontrolled inflammation could between 5–7 kb in length, which encodes system to favor the reemergence of disease be one promising alternative or comple- a capsid protein and a capsid-RNA depen- pathology. Thus far, little is known about ment to the conventional drug therapy. dent RNA polymerase (RDRP) fusion the pathogenesis of MCL, especially fac- Interestingly, treatment with the anti- protein essential for replication. tors involved in the immune response of inflammatory TNFα inhibitor pentoxy- The existence of cytosolic dsRNA the host, in the parasite dissemination, phylline in combination with antimony viruses within Leishmania was first shown or in reactivation. It is likely that both was effective in MCL patients unrespon- in two L. guyanensis strains: MHOM/ L. (Viannia) oxidative stress and antimony sive to antimonial therapy alone.11 SR/81/CUMC1A and MHOM/BR/75/ resistance as well as genetic background of The susceptibility of the golden ham- M4147.18,19 Currently Leishmania the host (e.g., particular alleles encoding ster to infection with species of the viruses are given arbitrary identifiers at TNFα, TNFβ, IL-6, CXCR1 and CCL2/ L. (Viannia) subgenus has provided a the time of discovery, namely LRV1-1 MCP1) and particular species and/or iso- useful experimental model of mucocuta- and LRV1–4 for the viruses of the late specific virulence factors are impor- neous leishmaniasis. Hamsters infected L. guyanensis CUMC-1 and L. guyanen- tant parameters ©2011in the development of Landeswith L. (Viannia) guyanensis Bioscience. isolated sis M4147 strain respectively. These two MCL. The definition of such factors and from human MCL lesions reproduce the viruses share an overall 76% nucleotide of the immune response of the host could metastatic phenotype with primary and sequence identity.20,21 LRV1s have since be extremely useful, not only toDo predict metastaticnot lesion distribute. development.12 Different been identified in many isolates of New the outcome of the disease and diagnosis species and individual strains often differ World Leishmania (L. braziliensis and tools, but also to understand the meta- in their propensity to cause hyperinflam- L. guyanensis), but in just one isolate of Old static process and the inter-relationships matory cutaneous secondary metastatic World species L. major, which was showed of the parasite with its host. Currently the lesions.13 Diversity was even seen within a sufficient nucleotide sequence divergence immunological mechanisms of protection single strain, as infective clones from the to be termed LRV2-1 (compare taxonomy and factors controlling relapse and avoid- isolate of L. (Viannia) guyanensis (L.g.) browser at www.ncbi.nlm.nih.gov). LRV1 ing reactivation of the infection are not (WHI/BR/78/M5313) were either highly are present not only in laboratory strains well understood. metastatic, moderately metastatic or non- of L. guyanensis and L. braziliensis but In MCL, the immune response to metastatic in the hamster model. Non- importantly also in biopsies
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