Dissecting Disease Tolerance in Plasmodium vivax Malaria Using the Systemic Degree of Inflammatory Perturbation

Abstract

Homeostatic perturbation caused by infection fosters two major defense stratagems, resistance and tolerance, which promote the survival of the infected host. 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. The findings mapped the relationships between the systemic degree of inflammatory perturbation and parasitemia values to define the disease tolerance in vivax malaria.

CD4 T cells are rapidly depleted from tuberculosis granulomas following acute SIV co-infection

“…2e). Such increased network density has previously been shown to reflect heightened inflammatory states [25][26][27] . Interestingly, IFNa was not detected in the granulomas from either group of animals, so we are unable to implicate virus-induced type IFN response in these changes in the granuloma inflammatory milieu after SIV infection (Fig 2f).…”

“…To further characterize the impact of early SIV infection on the inflammatory milieu of granulomas, we next used network density analysis of Spearman correlations 24,25 to quantify the interconnectivity of these variables (Fig. 2c).…”