Naturally acquired immunity (NAI) to high-density parasitemia and clinical illness from P. falciparum (Pf) and P. vivax (Pv) infection develops slowly during childhood and wanes in the absence of periodic boosting from blood stage infection. Serum IgG antibodies are critical for development of this acquired immunity. The slow acquisition of NAI arises, in part, from an impaired ability to generate persisting malaria-specific memory 8 cells (MBC) and resulting long-lived Ab secreting plasma cells (LLPC) to a broad repertoire malaria Ags. Blood stage Pf and Pv may suppress generation and maintenance of malaria MBC and LLPC by virtue of their high Ag loads that elicit systemic pro-inflammatory responses, e.g. increased TNF-a, IFN-y which are eventually down-regulated (possibly explaining, in part, why many malaria infected children in endemic areas are asymptomatic). In the current proposal we examine the hypothesis that the inflammatory milieu elicited by repeated malaria infections among individuals with little or no NAI, e.g. young children and malaria naive adults, upregulates potent inhibitory feedback loops that impair generation and maintenance of MBC and LLPC. A central goal of research here is to establish a link between susceptibility to malaria infection and uncomplicated morbidity and the ability to generate and sustain malaria Ag-specific MBC. We will evaluate and compare these relationships with respect Pf and Pv since NAI to Pv develops more rapidly than to Pf under conditions of similar transmission in Papua New Guinea (PNG). The studies will be performed with collaborators from West Africa and NIH in order to determine whether these features of NAI are generalized across populations that diverge genetically and epidemiologically. While immune regulatory mechanisms will be considered broadly using gene microarray analysis of known or suspected feedback loops, inhibitory FcyRIIB that regulates the B cell receptor (BCR) activation threshold by binding malaria Ag immune complexes (IC) will be evaluated specifically. We will use biological samples and clinical/parasite data from children and adults exposed to Pv and Pf in PNG under the auspices of approved IRB protocols of the SW Pacific ICEMR. The specific objective of the project are: i) Correlate the degree of NAI with malaria Agspecific MBC frequency, breadth and durability; ii) Determine the immunoregulatory networks elicited by acute malaria and their relation to generation Pf MBC; (iii) Assess whether FCGR2B functional polymorphisms impact NAI and malaria Ag-specific MBC development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
3U19AI089686-03S1
Application #
8477355
Study Section
Special Emphasis Panel (ZAI1-AWA-M (M1))
Project Start
Project End
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$235,750
Indirect Cost
$74,416
Name
Case Western Reserve University
Department
Type
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Lerch, Anita; Koepfli, Cristian; Hofmann, Natalie E et al. (2017) Development of amplicon deep sequencing markers and data analysis pipeline for genotyping multi-clonal malaria infections. BMC Genomics 18:864
Messerli, Camilla; Hofmann, Natalie E; Beck, Hans-Peter et al. (2017) Critical Evaluation of Molecular Monitoring in Malaria Drug Efficacy Trials and Pitfalls of Length-Polymorphic Markers. Antimicrob Agents Chemother 61:
Fran├ža, Camila T; Li Wai Suen, Connie S N; Carmagnac, Amandine et al. (2017) IgG antibodies to synthetic GPI are biomarkers of immune-status to both Plasmodium falciparum and Plasmodium vivax malaria in young children. Malar J 16:386
Schofield, Louis; Ioannidis, Lisa J; Karl, Stephan et al. (2017) Synergistic effect of IL-12 and IL-18 induces TIM3 regulation of ?? T cell function and decreases the risk of clinical malaria in children living in Papua New Guinea. BMC Med 15:114
Hofmann, Natalie E; Karl, Stephan; Wampfler, Rahel et al. (2017) The complex relationship of exposure to new Plasmodium infections and incidence of clinical malaria in Papua New Guinea. Elife 6:
Jain, Aarti; Taghavian, Omid; Vallejo, Derek et al. (2016) Evaluation of quantum dot immunofluorescence and a digital CMOS imaging system as an alternative to conventional organic fluorescence dyes and laser scanning for quantifying protein microarrays. Proteomics 16:1271-9
Hupalo, Daniel N; Luo, Zunping; Melnikov, Alexandre et al. (2016) Population genomics studies identify signatures of global dispersal and drug resistance in Plasmodium vivax. Nat Genet 48:953-8
Koepfli, Cristian; Nguitragool, Wang; Hofmann, Natalie E et al. (2016) Sensitive and accurate quantification of human malaria parasites using droplet digital PCR (ddPCR). Sci Rep 6:39183
Guo, Suqin; He, Lishan; Tisch, Daniel J et al. (2016) Pilot testing of dipsticks as point-of-care assays for rapid diagnosis of poor-quality artemisinin drugs in endemic settings. Trop Med Health 44:15
de Assis, Rafael Ramiro; Ludolf, Fernanda; Nakajima, Rie et al. (2016) A next-generation proteome array for Schistosoma mansoni. Int J Parasitol 46:411-5

Showing the most recent 10 out of 69 publications