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https://www.arca.fiocruz.br/handle/icict/50243
DISSECTING DISEASE TOLERANCE IN PLASMODIUM VIVAX MALARIA USING THE SYSTEMIC DEGREE OF INFLAMMATORY PERTURBATION
Author
Affilliation
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative, Salvador, Brazil / Escola Bahiana de Medicina e Saúde Pública. Salvador, BA, Brasil.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative, Salvador, Brazil / Universidade Salvador. Laureate Universities. Curso de Medicina. Salvador, BA, Brasil.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative, Salvador, Brazil.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative, Salvador, Brazil / Centro Universitário Facultade de Tecnologia e Ciências. Curso de Medicina. Salvador, BA, Brasil.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative, Salvador, Brazil / Universidade Federal da Bahia. Faculdade de Medicina. Salvador, BA, Brasil.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative, Salvador, Brazil / Universidade Federal da Bahia. Faculdade de Medicina. Salvador, BA, Brasil.
Fundação de Medicina Tropical Dr Heitor Vieira Dourado. Instituto de Pesquisa Clínica Carlos Borborema. Manaus, AM, Brasil / Fundação Oswaldo Cruz. Instituto Leônidas & Maria Deane. Manaus, AM, Brasil.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Medicina. Salvador, BA, Brasil / Instituto Nacional de Ciência e Tecnologia. Instituto de Investigação em Imunologia. São Paulo, SP, Brasil.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative, Salvador, Brazil / Escola Bahiana de Medicina e Saúde Pública. Salvador, BA, Brasil / Universidade Salvador. Laureate Universities. Curso de Medicina. Salvador, BA, Brasil / Centro Universitário Faculdade de Tecnologia e Ciências. Curso de Medicina. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Medicina. Salvador, BA, Brasil.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative, Salvador, Brazil / Universidade Salvador. Laureate Universities. Curso de Medicina. Salvador, BA, Brasil.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative, Salvador, Brazil.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative, Salvador, Brazil / Centro Universitário Facultade de Tecnologia e Ciências. Curso de Medicina. Salvador, BA, Brasil.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative, Salvador, Brazil / Universidade Federal da Bahia. Faculdade de Medicina. Salvador, BA, Brasil.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative, Salvador, Brazil / Universidade Federal da Bahia. Faculdade de Medicina. Salvador, BA, Brasil.
Fundação de Medicina Tropical Dr Heitor Vieira Dourado. Instituto de Pesquisa Clínica Carlos Borborema. Manaus, AM, Brasil / Fundação Oswaldo Cruz. Instituto Leônidas & Maria Deane. Manaus, AM, Brasil.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Medicina. Salvador, BA, Brasil / Instituto Nacional de Ciência e Tecnologia. Instituto de Investigação em Imunologia. São Paulo, SP, Brasil.
Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil / Multinational Organization Network Sponsoring Translational and Epidemiological Research Initiative, Salvador, Brazil / Escola Bahiana de Medicina e Saúde Pública. Salvador, BA, Brasil / Universidade Salvador. Laureate Universities. Curso de Medicina. Salvador, BA, Brasil / Centro Universitário Faculdade de Tecnologia e Ciências. Curso de Medicina. Salvador, BA, Brasil / Universidade Federal da Bahia. Faculdade de Medicina. Salvador, BA, Brasil.
Abstract
Homeostatic perturbation caused by infection fosters two major defense strategies, resistance
and tolerance, which promote the host’s survival. Resistance relates to the ability of
the host to restrict the pathogen load. Tolerance minimizes collateral tissue damage without
directly affecting pathogen fitness. These concepts have been explored mechanistically in
murine models of malaria but only superficially in human disease. Indeed, individuals
infected with Plasmodium vivax may present with asymptomatic malaria, only mild symptoms,
or be severely ill. We and others have reported a diverse repertoire of immunopathological
events that potentially underly susceptibility to disease severity in vivax malaria.
Nevertheless, the combined epidemiologic, clinical, parasitological, and immunologic features
associated with defining the disease outcomes are still not fully understood. In the
present study, we perform an extensive outlining of cytokines and inflammatory proteins in
plasma samples from a cohort of individuals from the Brazilian Amazon infected with P.
vivax and presenting with asymptomatic (n = 108) or symptomatic (n = 134) disease (106
with mild presentation and 28 with severe malaria), as well as from uninfected endemic controls
(n = 128) to elucidate these gaps further. We employ highly multidimensional Systems
Immunology analyses using the molecular degree of perturbation to reveal nuances of a
unique profile of systemic inflammation and imbalanced immune activation directly linked to
disease severity as well as with other clinical and epidemiologic characteristics. Additionally,
our findings reveal that the main factor associated with severe cases of P. vivax infection
was the number of symptoms, despite of a lower global inflammatory perturbation and parasitemia.
In these participants, the number of symptoms directly correlated with perturbation
of markers of inflammation and tissue damage. On the other hand, the main factor associated with non-severe infections was the parasitemia values, that correlated only with
perturbation of inflammatory markers, such as IL-4 and IL-1β, with a relatively lower number
of symptoms. These observations suggest that some persons present severe vivax regardless
of pathogen burden and global inflammatory perturbation. Such patients are thus little
tolerant to P. vivax infection and show higher susceptibility to disrupt homeostasis and consequently
exhibit more clinical manifestations. Other persons are capable to tolerate higher
parasitemia with lower inflammatory perturbation and fewer symptoms, developing nonsevere
malaria. The analytical approach presented here has capability to define in more
details the determinants of disease tolerance in vivax malaria.
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