Tolerance May Be More Appropriate Than Immunity When Describing Chronic Malaria Infections

Shanks, G. Dennis

doi:10.4269/ajtmh.18-0906

Cited by 11 publications

(15 citation statements)

References 17 publications

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“…This immune tolerance is also supported by the rst series of experimental malaria infections in humans, which revealed that the risk of fever decreases with the number of infections [49]. According to Shanks [50], parasites in asymptomatic carriage bene t from relative immune tolerance and adults exercise better control over parasite density and genotypic uctuations. Indeed, antibodies can be classi ed into two groups, those acquired during early childhood, resulting from the primary infection, short-lived in nature, considered as marker of exposure and those with a long lifespan acquired through repeated infections and associated with protection [51,52,53].…”

Section: Discussionmentioning

confidence: 88%

Immune tolerance to asymptomatic submicroscopic Plasmodium falciparum infections in adults living in malaria endemic areas

Diouf

Diop

Dièye

et al. 2020

Preprint

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Background Combined malaria control interventions have reduced mortality rate, number of clinical cases and parasite prevalence across Africa between 2000 and 2015. As a consequence, Plasmodium infections have become mostly asymptomatic and often sub-microscopic in many endemic areas. The present study aims to evaluate the contribution of asymptomatic sub-microscopic P. falciparum carriage on antibody responses against malaria antigens. Methods A total of 353 samples from a cross-sectional sampling conducted in Ndiop (Senegal) in 2016 were tested by qPCR and microscopy to determine parasite prevalence. Plasmodium falciparum positive samples were genotyped using msp-2 marker. The IgG seroprevalence against crude schizont antigen of a local P. falciparum strain, tested by ELISA, was compared to parasite prevalence. An age-matched, under 10 years, 10-15 and over 15 years cohort of 110 positive and negative qPCR samples were used to determine the impact of sub-microscopic carriage on IgG and IgM antibody responses against schizont extract and MSP3 recombinant antigen. Results The microscopic diagnosis was negative for all thick smears defining a study cohort of submicroscopic asymptomatic individuals with an overall parasite prevalence of 22.37% (79/353) by qPCR. Submicroscopic infections were associated with significant lower IgG responses in qPCR positive samples for individuals over 15 years of age, for both crude schizont (p=0.021) and MSP3 recombinant antigen (p=0.035). IgM responses were significantly higher (p=0.034) in children under 10 years, showing their susceptibility to primary infection. Above 15 years of age, a significant difference was found between parasite prevalence of 9.3% (33/353) and IgG seroprevalence of 23.8% (84/353) (p=0.01). The overall genetic diversity detected is characterized by a complexity of infection (COI) and a number of genotypes of 2.4 and 17, respectively.Conclusion Asymptomatic submicroscopic P. falciparum carriage is prevalent in the study area and is associated with immune tolerance to parasites in adults. The difference between parasite prevalence and IgG seroprevalence results from long-lived IgG in adults point out attention for elders in endemic areas as a stable parasite reservoir. In this context, mass molecular detection followed by treatment could be a valuable method for achieving elimination.

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Section: Discussionmentioning

confidence: 88%

Immune tolerance to asymptomatic submicroscopic Plasmodium falciparum infections in adults living in malaria endemic areas

Diouf

Diop

Dièye

et al. 2020

Preprint

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“…Chronic and subclinical as well as low-parasitemic Plasmodium infections do not induce strong inflammatory responses in endemic settings ( 8 , 25 ). Upon repeat exposure to the parasite, anti-disease immunity develops first, followed by anti-parasitic immunity that can be highly effective ( 26 – 28 ) – up to sterile immunity in a small percentage of individuals ( 29 , 30 ). In contrast to sterile immunity, anti-disease immunity is characterized by developing tolerance to parasitemia ( 31 ), which can be associated with a more general immunosuppression ( 32 ).…”

Section: Introductionmentioning

confidence: 99%

Expansion of Functional Myeloid-Derived Suppressor Cells in Controlled Human Malaria Infection

et al. 2021

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Malaria can cause life-threatening complications which are often associated with inflammatory reactions. More subtle, but also contributing to the burden of disease are chronic, often subclinical infections, which result in conditions like anemia and immunologic hyporesponsiveness. Although very frequent, such infections are difficult to study in endemic regions because of interaction with concurrent infections and immune responses. In particular, knowledge about mechanisms of malaria-induced immunosuppression is scarce. We measured circulating immune cells by cytometry in healthy, malaria-naïve, adult volunteers undergoing controlled human malaria infection (CHMI) with a focus on potentially immunosuppressive cells. Infectious Plasmodium falciparum (Pf) sporozoites (SPZ) (PfSPZ Challenge) were inoculated during two independent studies to assess malaria vaccine efficacy. Volunteers were followed daily until parasites were detected in the circulation by RT-qPCR. This allowed us to analyze immune responses during pre-patency and at very low parasite densities in malaria-naïve healthy adults. We observed a consistent increase in circulating polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) in volunteers who developed P. falciparum blood stage parasitemia. The increase was independent of preceding vaccination with a pre-erythrocytic malaria vaccine. PMN-MDSC were functional, they suppressed CD4+ and CD8+ T cell proliferation as shown by ex-vivo co-cultivation with stimulated T cells. PMN-MDSC reduced T cell proliferation upon stimulation by about 50%. Interestingly, high circulating PMN-MDSC numbers were associated with lymphocytopenia. The number of circulating regulatory T cells (Treg) and monocytic MDSC (M-MDSC) showed no significant parasitemia-dependent variation. These results highlight PMN-MDSC in the peripheral circulation as an early indicator of infection during malaria. They suppress CD4+ and CD8+ T cell proliferation in vitro. Their contribution to immunosuppression in vivo in subclinical and uncomplicated malaria will be the subject of further research. Pre-emptive antimalarial pre-treatment of vaccinees to reverse malaria-associated PMN-MDSC immunosuppression could improve vaccine response in exposed individuals.

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“…The capacity to restrict the infection burden and control inflammation and immune activation are major determinants of the malaria clinical outcomes (reviewed in [9, 10]). The ability to control parasite load results from anti-microbial immune responses and leads to pathogen elimination and resistance to infection [11].…”

Section: Introductionmentioning

confidence: 99%

“…The capacity to restrict the infection burden and control inflammation and immune activation are major determinants of the malaria clinical outcomes (reviewed in [9,10]).…”

Section: Introductionmentioning

confidence: 99%

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

Vinhaes

Carmo

Queiroz

et al. 2021

Preprint

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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.

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Tolerance May Be More Appropriate Than Immunity When Describing Chronic Malaria Infections

Cited by 11 publications

References 17 publications

Immune tolerance to asymptomatic submicroscopic Plasmodium falciparum infections in adults living in malaria endemic areas

Immune tolerance to asymptomatic submicroscopic Plasmodium falciparum infections in adults living in malaria endemic areas

Expansion of Functional Myeloid-Derived Suppressor Cells in Controlled Human Malaria Infection

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

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