Associate Professor
Kwadwo Asamoah Kusi
Project Title
Clinical and immunopathological consequences of chronic HBV and Plasmodium falciparum co-infections
Project Objectives
Aim 1: To determine the effect of chronic HBV infection on the outcome of Plasmodium liver stage infection. Aim 2: To determine the cytokine expression profiles of white cells from chronic HBV patients with and without Plasmodium infection over a one year period.
Host Organisation
| Department | Institution | Country |
|---|---|---|
| University of Ghana | GH |
EDCTP Project
TMA2018SF-2456
EDCTP Program
EDCTP2
EDCTP Project Call
Senior Fellowship (SF)
Study Design
case-control design
Project Summary
Hepatitis B virus (HBV) and Plasmodium are very common pathogens in sub-Saharan Africa and sometimes occur as co-infections. Both pathogens infect liver cells and elicit pathogen-specific immune responses that may mediate both protection and immunopathology. HBV infection of the liver, even in an acute form, is usually long term, while Plasmodium liver infections are usually over a limited period after an infectious mosquito bite. Immune responses, especially against chronic HBV infections, can thus affect liver stage malaria-specific T cell responses. There is however no consensus on how HBV induced immune responses affect liver stage anti-malarial immunity. Plasmodium infection could also, in the reverse, contribute to liver pathology in chronic HBV-infected subjects. Malaria vaccine candidate trials usually exclude individuals infected with immune modulating pathogens such as HBV. However, vaccine induced responses could be compromised in HBV-infected persons if vaccines are later approved for routine immunization. Investigation of the potential impact of chronic HBV infection on malaria liver stage-specific immune response quality is therefore essential. This study will test the primary hypothesis that chronic HBV infections elicit a strong regulatory T cell environment that dampens induction of the needed pro-inflammatory response against liver stage malaria parasites. We will recruit chronic HBV-infected subjects from the Gastroenterology Clinic of the Korle Bu Teaching Hospital in Accra and followed up once a month over one year. Primary outcome measure will be Plasmodium liver stage infection, to be indirectly assessed by i) elevated antibody levels against the parasite circumsporozoite protein as evidence of infectious bite exposure, and ii) detection of asexual blood stage parasites as evidence of completed liver cycle. We will determine anti-CSP antibody seroprevalence and blood stage parasite infection every month by microscopy, RDTs and PCR. We will measure levels of selected cytokines and liver enzymes every three months and HBV viral load at study baseline and at seven months. We will also recruit a parallel cohort of healthy subjects as controls, follow up at similar time intervals and measure their anti-CSP antibody seroprevalence, parasite infection status, cytokine levels and liver enzymes for comparison. The study will provide useful data on the by-stander effects of chronic HBV infection on immunity and outcome of Plasmodium liver stage infections as well as the impact of liver stage Plasmodium infection on the clinical course of chronic HBV infection in co-infected individuals. The study will further be used to train three students at the PhD and MPhil levels.
Current Organisation
NOGUCHI MEMORIAL INSTITUTE FOR MEDICAL RESEARCH(NM
Current Job Title
Senior Research Fellow
Biography
Publications
Cerebral malaria (CM) may cause death or long-term neurological damage in children, and several host genetic risk factors have been reported. Malaria-specific immunoglobulin (Ig) G3 antibodies are crucial to human immune response against malaria. The hinge region of IgG3 exhibits length polymorphism (with long [L], medium [M], and short [S] alleles), which may influence its functionality. We studied IgG3 hinge region length polymorphisms in 136 Ghanaian children with malaria. Using logistic regression models, we found that children with the recessive MM allotype encoding medium IgG3 hinge region length had an increased risk of CM (adjusted odds ratio, 6.67 [95% confidence interval, 1.30–34.32]; P = .004) . This has implications for future epidemiological studies on CM.
Sterile protection against clinical malaria has been achieved in animal models and experimental human challenge studies involving immunization with radiation attenuated Plasmodium falciparum sporozoite vaccines as well as by live sporozoites under chloroquine prophylaxis. Parasite-specific IFN-c and granzyme B-secreting CD8 + T cells have been identified as key mediators of protection. Although the exact parasite targets of protective CD8 + T cell responses are not fully defined, responses against a handful of vaccine candidate antigens have been associated with protection. Identifying the T cell targets in these antigens will facilitate the development of simpler, costeffective, and efficacious next generation multi-epitope vaccines. The aim of this study was to identify immunodominant portions of four malaria vaccine candidate antigens using peripheral blood mononuclear cells (PBMCs) from adults with life-long exposure to malaria parasites. Cryopreserved PBMCs from 291 HLA-typed subjects were stimulated with pools of overlapping 15mer peptides spanning the entire sequences of P. falciparum circumsporozoite protein (CSP, 9 pools), apical membrane antigen 1 (AMA1, 12 pools), thrombospondin related anonymous protein (TRAP, 6 pools) and cell traversal for ookinetes and sporozoites (CelTOS, 4 pools) in FluoroSpot assays. 125 of 291 subjects made IFN-c responses to 30 of the 31 peptide pools tested and 22 of 291 made granzyme B responses, with 20 making dual responses. The most frequent responses were to the CSP Cterminal region and the least frequent responses were to TRAP and CelTOS. There was no association between FluoroSpot responses and active malaria infection, detected by either microscopy, RDT, or PCR. In conclusion, CSP and AMA1 have relatively higher numbers of epitopes that trigger IFN-c and granzyme B-secreting T cells in adults with life-long malaria parasite exposure compared to the other two antigens tested, and highlights the continued relevance of these two antigens as vaccine candidates.