Dissecting disease tolerance in Plasmodium vivax malaria using the systemic degree of inflammatory perturbation

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 pathoge...

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Autores principales:	Caian L. Vinhaes, Thomas A. Carmo, Artur T. L. Queiroz, Kiyoshi F. Fukutani, Mariana Araújo-Pereira, María B. Arriaga, Marcus V. G. Lacerda, Manoel Barral-Netto, Bruno B. Andrade
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270
Acceso en línea:	https://doaj.org/article/433bd63dea5b4891b15c41708e8ba517
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id	oai:doaj.org-article:433bd63dea5b4891b15c41708e8ba517
record_format	dspace
institution	DOAJ
collection	DOAJ
language	EN
topic	Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270
spellingShingle	Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Caian L. Vinhaes Thomas A. Carmo Artur T. L. Queiroz Kiyoshi F. Fukutani Mariana Araújo-Pereira María B. Arriaga Marcus V. G. Lacerda Manoel Barral-Netto Bruno B. Andrade Dissecting disease tolerance in Plasmodium vivax malaria using the systemic degree of inflammatory perturbation
description	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 non-severe malaria. The analytical approach presented here has capability to define in more details the determinants of disease tolerance in vivax malaria. Author summary Plasmodium vivax infection can result in a broad spectrum of disease manifestations, ranging from asymptomatic malaria to severe life-threatening disease. Despite significant advances in the current understanding of the critical factors associated with the disease outcomes in vivax malaria, the immunopathological events responsible for the diversity of severe manifestations in the disease remain deeply unknown. Here, a large panel of cytokines/chemokines were assessed in plasma samples from a Brazilian cohort of P. vivax patients presenting with asymptomatic infection or symptomatic malaria at the time of diagnosis, as well as from uninfected endemic controls, to define the relationships between systemic inflammation, disease presentation, parasitemia, and epidemiologic characteristics. In-depth analyses using the molecular degree of perturbation were employed to reveal nuances of a unique profile of systemic inflammation and imbalanced immune activation directly linked to disease severity. Moreover, the discoveries diagrammed the occurrence of disease tolerance by narrowing down the interactions between the systemic degree of inflammatory perturbation and parasitemia values in vivax malaria patients.
format	article
author	Caian L. Vinhaes Thomas A. Carmo Artur T. L. Queiroz Kiyoshi F. Fukutani Mariana Araújo-Pereira María B. Arriaga Marcus V. G. Lacerda Manoel Barral-Netto Bruno B. Andrade
author_facet	Caian L. Vinhaes Thomas A. Carmo Artur T. L. Queiroz Kiyoshi F. Fukutani Mariana Araújo-Pereira María B. Arriaga Marcus V. G. Lacerda Manoel Barral-Netto Bruno B. Andrade
author_sort	Caian L. Vinhaes
title	Dissecting disease tolerance in Plasmodium vivax malaria using the systemic degree of inflammatory perturbation
title_short	Dissecting disease tolerance in Plasmodium vivax malaria using the systemic degree of inflammatory perturbation
title_full	Dissecting disease tolerance in Plasmodium vivax malaria using the systemic degree of inflammatory perturbation
title_fullStr	Dissecting disease tolerance in Plasmodium vivax malaria using the systemic degree of inflammatory perturbation
title_full_unstemmed	Dissecting disease tolerance in Plasmodium vivax malaria using the systemic degree of inflammatory perturbation
title_sort	dissecting disease tolerance in plasmodium vivax malaria using the systemic degree of inflammatory perturbation
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/433bd63dea5b4891b15c41708e8ba517
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spelling	oai:doaj.org-article:433bd63dea5b4891b15c41708e8ba5172021-11-18T09:15:51ZDissecting disease tolerance in Plasmodium vivax malaria using the systemic degree of inflammatory perturbation1935-27271935-2735https://doaj.org/article/433bd63dea5b4891b15c41708e8ba5172021-11-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8589215/?tool=EBIhttps://doaj.org/toc/1935-2727https://doaj.org/toc/1935-2735Homeostatic 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 non-severe malaria. The analytical approach presented here has capability to define in more details the determinants of disease tolerance in vivax malaria. Author summary Plasmodium vivax infection can result in a broad spectrum of disease manifestations, ranging from asymptomatic malaria to severe life-threatening disease. Despite significant advances in the current understanding of the critical factors associated with the disease outcomes in vivax malaria, the immunopathological events responsible for the diversity of severe manifestations in the disease remain deeply unknown. Here, a large panel of cytokines/chemokines were assessed in plasma samples from a Brazilian cohort of P. vivax patients presenting with asymptomatic infection or symptomatic malaria at the time of diagnosis, as well as from uninfected endemic controls, to define the relationships between systemic inflammation, disease presentation, parasitemia, and epidemiologic characteristics. In-depth analyses using the molecular degree of perturbation were employed to reveal nuances of a unique profile of systemic inflammation and imbalanced immune activation directly linked to disease severity. Moreover, the discoveries diagrammed the occurrence of disease tolerance by narrowing down the interactions between the systemic degree of inflammatory perturbation and parasitemia values in vivax malaria patients.Caian L. VinhaesThomas A. CarmoArtur T. L. QueirozKiyoshi F. FukutaniMariana Araújo-PereiraMaría B. ArriagaMarcus V. G. LacerdaManoel Barral-NettoBruno B. AndradePublic Library of Science (PLoS)articleArctic medicine. Tropical medicineRC955-962Public aspects of medicineRA1-1270ENPLoS Neglected Tropical Diseases, Vol 15, Iss 11 (2021)

Dissecting disease tolerance in Plasmodium vivax malaria using the systemic degree of inflammatory perturbation

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