title: Studies in the mouse model identify strain variability as a major determinant of disease outcome in Leishmania infantum infection.
abstract: BACKGROUND
  Visceral leishmaniasis is a severe and potentially fatal disease caused by protozoa of the genus Leishmania, transmitted by phlebotomine sandflies. In Europe and the Mediterranean region, L. infantum is the commonest agent of visceral leishmaniasis, causing a wide spectrum of clinical manifestations, including asymptomatic carriage, cutaneous lesions and severe visceral disease. Visceral leishmaniasis is more frequent in immunocompromised individuals and data obtained in experimental models of infection have highlighted the importance of the host immune response, namely the efficient activation of host's macrophages, in determining infection outcome. Conversely, few studies have addressed a possible contribution of parasite variability to this outcome.
  
  
  METHODS
  In this study, we compared three isolates of L. infantum regarding their capacity to grow in the organs of mice, the way they activate the host's macrophages and other components of the immune response and also their capacity to cope with host's antimicrobial mechanisms, namely reactive oxygen and nitrogen species.
  
  
  RESULTS
  We found that the three parasite strains significantly differed regarding the degree to which they induced nitric oxide synthase (NOS2) and arginase expression in infected macrophages and the pattern of cytokine production they induced in the host, resulting in different degrees of inflammatory response in infected livers. Additionally, the three strains also significantly differed in their in vitro susceptibility to reactive oxygen and nitrogen species. This variability was reflected in the capacity of each strain to persist and proliferate in the organs of wild-type as well as NOS2- and phagocyte oxidase- deficient mice.
  
  
  CONCLUSIONS
  The results obtained in this study show that parasite strain variability is an important determinant of disease outcome in L. infantum visceral leishmaniasis, with relevant implications for studies on host-pathogen interaction and also for leishmanicidal drug development.
authors.affiliation: Instituto de Investigação e Inovação em Saúde and IBMC, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal. Filipe.Marques@ibmc.up.pt.
authors.forename: Filipe
authors.initials: F
authors.lastname: Marques
authors.affiliation: Instituto de Investigação e Inovação em Saúde and IBMC, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal. svcosta@igc.gulbenkian.pt.|Present address: Cell Biology of Viral Infection Lab, Instituto Gulbenkian de Ciência, Oeiras, Portugal. svcosta@igc.gulbenkian.pt.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Vale-Costa
authors.affiliation: Instituto de Investigação e Inovação em Saúde and IBMC, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal. TCruz@ibmc.up.pt.
authors.forename: Tânia
authors.initials: T
authors.lastname: Cruz
authors.affiliation: Instituto de Investigação e Inovação em Saúde and IBMC, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal. joana.amc.marques@gmail.com.
authors.forename: Joana Moreira
authors.initials: JM
authors.lastname: Marques
authors.affiliation: Instituto de Investigação e Inovação em Saúde; IBMC, Instituto de Biologia Molecular e Celular, and ICBAS, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal. Tania.Silva@ibmc.up.pt.
authors.forename: Tânia
authors.initials: T
authors.lastname: Silva
authors.affiliation: Instituto de Investigação e Inovação em Saúde and IBMC, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal. JNeves@ibmc.up.pt.
authors.forename: João Vilares
authors.initials: JV
authors.lastname: Neves
authors.affiliation: GHTM, Global Health and Tropical Medicine, IHMT, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Lisbon, Portugal. SCortes@ihmt.unl.pt.|Present Address: Molekularbiologie und Funktionelle Genomik, Technische Hochschule Wildau, Wildau, Germany. SCortes@ihmt.unl.pt.
authors.forename: Sofia
authors.initials: S
authors.lastname: Cortes
authors.affiliation: ICBAS, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal. anaisabelmfernandes@gmail.com.
authors.forename: Ana
authors.initials: A
authors.lastname: Fernandes
authors.affiliation: ICBAS, Instituto de Ciências Biomédicas Abel Salazar, and CIIMAR, Centro Interdisciplinar de Investigação Marinha e Ambiental, Universidade do Porto, Porto, Portugal. erocha@icbas.up.pt.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Rocha
authors.affiliation: Instituto de Investigação e Inovação em Saúde; IBMC, Instituto de Biologia Molecular e Celular, and ICBAS, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal. rappelb@ibmc.up.pt.
authors.forename: Rui
authors.initials: R
authors.lastname: Appelberg
authors.affiliation: Instituto de Investigação e Inovação em Saúde; IBMC, Instituto de Biologia Molecular e Celular, and ICBAS, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal. prodrigu@ibmc.up.pt.
authors.forename: Pedro
authors.initials: P
authors.lastname: Rodrigues
authors.affiliation: Instituto de Investigação e Inovação em Saúde; IBMC, Instituto de Biologia Molecular e Celular, and ICBAS, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal. atomas@ibmc.up.pt.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Tomás
authors.affiliation: Instituto de Investigação e Inovação em Saúde; IBMC, Instituto de Biologia Molecular e Celular, and ICBAS, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal. sgomes@ibmc.up.pt.
authors.forename: Maria Salomé
authors.initials: MS
authors.lastname: Gomes
mesh_terms: D000825:Animal Structures / Q000469:parasitology / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D014644:Genetic Variation; D054884:Host-Pathogen Interactions; D018314:Leishmania infantum / Q000145:classification / Q000235:genetics* / Q000276:immunology / Q000472:pathogenicity*; D007898:Leishmaniasis, Visceral / Q000469:parasitology* / Q000473:pathology*; D008262:Macrophage Activation; D051379:Mice; D026361:Reactive Nitrogen Species / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D016896:Treatment Outcome; D014774:Virulence
chemical_list: D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species