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 non-severe malaria. The analytical approach presented here has capability to define in more details the determinants of disease tolerance in vivax malaria.
Highlights
Malaria remains a major global cause of morbidity and mortality, with devasting impact over the last 10 years, estimated by more than 200 million cases and 400,000 deaths reported per year worldwide [1]
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
Summary
Malaria remains a major global cause of morbidity and mortality, with devasting impact over the last 10 years, estimated by more than 200 million cases and 400,000 deaths reported per year worldwide [1]. In contrast to the burden of Plasmodium falciparum infection in African countries, Plasmodium vivax represents the predominant parasite in American regions, with noticeable incidence within the Brazilian Amazon, responsible for the vast majority of malaria cases in this area [1,2]. Infection with P. vivax is historically thought to result in milder disease presentation than that caused by P. falciparum, mostly because the latter commonly results in high parasitemia, intense hemolysis and inflammation associated with cytoadherence to small capillaries (reviewed in [3]). We and others have described that older individuals who live for many years in a highly endemic area, and those who are highly exposed and had several previous malaria episodes, tend to develop asymptomatic P. vivax infection, which is associated with very low parasitemia and diminished inflammatory responses [7,8,9,10,11,12,13].
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