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

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.

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

“…Comparing the degrees of connection from the bootstrap analysis highlighted the increased connectivity of CCL3, CCL4, and CXCL12 in co-infected granulomas, while IL-1b showed increased connectivity in mono-infected granulomas (Figure 2E). Such increased network density has previously been shown to reflect heightened inflammatory states (Bruyn et al, 2021;Tiburcio et al, 2021;Vinhaes et al, 2021). Interestingly, IFN-a 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 (Figure 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 (Kauffman et al, 2021;Vinhaes et al, 2021) to quantify the interconnectivity of these variables (Figure 2C). After SIV infection, multiple soluble mediators, in particular several chemokines, had increased numbers of correlations with each other, and the overall network density was significantly higher in co-infected granulomas (Figure 2D).…”

A systematic review and meta-analysis of blood interleukin-4 levels concerning malaria infection and severity

“…The difference in IL-4 levels between uncomplicated malaria and healthy controls was reported in 24 studies [ 8 – 15 , 19 , 21 , 22 , 35 – 40 , 43 , 45 – 50 ]. Higher IL-4 levels in uncomplicated malaria than in healthy controls were reported in 14 studies (58.3%) [ 8 – 10 , 21 , 22 , 36 – 39 , 43 , 45 , 47 , 48 , 50 ]. Meanwhile, lower IL-4 levels in uncomplicated malaria than in healthy controls were reported in four studies (16.7%) [ 11 , 12 , 40 , 46 ].…”

“…Then, 92 full-text articles were excluded for the following reasons; 18 were IL-4 in uncomplicated malaria only, 13 were IL-4 in pregnancy, 12 with IL-4 data were unavailable, 11 were in vitro studies of IL-4, ten were full-text unavailable, eight reported IL-4 in cord blood, five with IL-4 gene expression, five were conference abstracts, three reported IL-4 in asymptomatic malaria, two were animal studies, two reported IL-4 in tissue section, one study using the same group of participants, one was a review, and one reported IL-4 receptor. Twenty-nine studies [ 8 – 15 , 18 , 20 , 30 – 48 ] that met the inclusion criteria were included. From the reference lists of the included studies, seven studies [ 19 , 21 , 22 , 49 – 52 ] were identified and were included in the review.…”

“…Next, the difference in IL-4 levels between uncomplicated malaria (635 cases) and healthy controls (674 cases) was estimated from 11 studies that reported quantitative data (mean and SD, or median and range) of IL-4 levels [9,11,19,21,22,35,39,40,[48][49][50]. The meta-analysis results showed no difference in mean IL-4 levels between uncomplicated and healthy controls (P = 0.57, pooled MD 0.79 pg/mL, 95% CI −1.92 to 3.50 pg/mL, I 2 99.89%, 11 studies, Fig.…”