Contribution of the murine and primate models to thestudy of arenaviral diseases and hemorrhagic fevers / Contribución de los modelos murino y primate al estudio de las enfermedades porarenavirus y fiebres hemorrágicas / Contribuição dos modelos murinos e primatas ao estudo de doenças por arenavirus efebre hemorrágica

This manuscript is an inedited part of my PhD dissertation, based on historical and recent findingson animal models, that was presented as part of the requirements to fulfill the conditions to become aphilosophical doctor on Veterinary Sciences at the University of Wisconsin on October of 2003.The currentmini-review written on a free-version style, underlines some of the cornerstones of immunology as ascience, understood thanks to the use of the Lymphocytic Choriomeningitis virus (LCMV) experimentallyand naturally infected mouse model. It should suffice to say that there have been two Nobel prices ofMedicine for discoveries made through the employment of this animal model, in order to recognize theright importance to it. In addition, several laboratories, Dr. Salvato´s among them, have also employed theLCMV-infected Rhesus monkey model as a tool to unravel the mysteries of arenaviral hemorrhagic fever,and particularly the physiopathology of Lassa disease in humans. Here I show some of the knowledgegenerated through the study of both animal infections.

El siguiente manuscrito, es un capítulo inédito de mi tesis doctoral, basado en hallazgos históricos yrecientes sobre modelos animales, que fue presentado como parte de los requisitos para obtener el títulode Ph.D. en Ciencias veterinarias en la Universidad de Wisconsin, en Octubre de 2003.La actual minirevisiónescrita en estilo de versión libre, subraya algunas de las piedras angulares de la inmunología comociencia, entendidas gracias al uso del modelo murino infectado natural y experimentalmente con el virusde Coriomeningitis Linfocítica (LCMV). Sería suficiente mencionar que han existido dos premios Nóbelde Medicina por descubrimientos realizados a través del empleo de este modelo animal, para reconocer lareal importancia del mismo. Adicionalmente, varios laboratorios, el de la Dra. Salvato entre ellos, tambiénhan empleado el modelo del mono Rhesus como un instrumento para desvelar los misterios de las fiebreshemorrágicas por arenavirus, y particularmente la fisiopatología de la enfermedad de Lassa en humanos.Aquí yo muestro alo del conocimiento generado a través del estudio de ambas infecciones animales.

O seguinte manuscrito é um capítulo inédito da minha tese doutoral, baseado em casos históricose recentes sobre modelos animais, que foram apresentados na defesa da tese de Ph.D. em CiênciasVeterinárias da Universidade de Wisconsin, em outubro de 2003. A atual mini revisão escrita em estilode versão livre, enfatiza em algumas pedras angulares da inmunologìa como ciência. Graças ao usodo modelo murino infectado natural e experimentalmente com o vírus da Coriomeningitis Linfocítica(LCMV). Seria suficiente mencionar que foram outorgados dois prêmios Nobel de Medicina pelosdescobrimentos realizados a través do uso deste modelo, para reconhecer a real importância do mesmo.Adicionalmente, vários laboratórios, entre eles o da Dra. Salvato, tem utilizado o modelo macaco Rhesuscomo um instrumento para desvelar os mistérios das febres hemorrágicas por arenavirus, e particularmentea fisiologia e patologia da doença de Lassa em humanos. Aqui eu indico algo do conhecimento gerado através do estudo das duas infecções animais.

Circulating natural killer and γδ T cells decrease soon after infection of rhesus macaques with lymphocytic choriomeningitis virus

Rhesus macaques infected with the WE strain of lymphocytic choriomeningitis virus (LCMV-WE) serve as a model for human infection with Lassa fever virus. To identify the earliest events of acute infection, rhesus macaques were monitored immediately after lethal infection for changes in peripheral blood mononuclear cells (PBMCs). Changes in CD3, CD4, CD8 and CD20 subsets did not vary outside the normal fluctuations of these blood cell populations; however, natural killer (NK) and γδ T cells increased slightly on day 1 and then decreased significantly after two days. The NK subsets responsible for the decrease were primarily CD3-CD8+ or CD3-CD16+ and not the NKT (primarily CD3+CD56+) subset. Macaques infected with a non-virulent arenavirus, LCMV-Armstrong, showed a similar drop in circulating NK and γδ T cells, indicating that this is not a pathogenic event. V³9 T cells, representing the majority of circulating γδ T cells in rhesus macaques, displayed significant apoptosis when incubated with LCMV in cell culture; however, the low amount of cell death for virus-co-cultured NK cells was insufficient to account for the observed disappearance of this subset. Our observations in primates are similar to those seen in LCMV-infected mice, where decreased circulating NK cells were attributed to margination and cell death. Thus, the disappearance of these cells during acute hemorrhagic fever in rhesus macaques may be a cytokine-induced lymphopenia common to many virus infections.

Tales of mice and men: Natural History of Arenaviruses

Nowadays, Arenaviruses are among  the most feared viruses due to their potential as weapons for bioterrorism purposes. This potential is based on their increasing diversity and the fact that they are carried by rodentswhose biologic success compares only wit insects and humans. The prototype of this family is  Lymphocytic Choriomeningitis Virus which has been and excellent tool for a myriad of discoveries in immunology. Arenaviruses have been known for over 70 years but the number of members of the family is growing thanks to their insidious subsistence in third world countries and to the nature of their   genome, that makes of them sorts of skilful machines for evolution This review collects some of the work of the authors about the best-known features described for this group of viruses, among the many still-to-be discovered characteristics of this puzzling, and hard-to-study, group of zoonotic viruses.