The role of heme oxygenase-1 in malaria-induced immunomodulation
Lead Research Organisation:
London School of Hygiene & Tropical Medicine
Department Name: Infectious and Tropical Diseases
Abstract
Malaria is a tropical disease that kills in its own right and weakens immune defences against other infections. Malaria-infected children are less responsive to vaccination and more susceptible to bacterial and viral infections.
Malaria infects red blood cells, causing them to burst, releasing parasites and parasite by-products. Heme is a breakdown product of red blood cell haemoglobin. Heme is degraded by an enzyme (heme oxygenase-1; HO-1) to produce molecules that can modify immune responses, and may account for the immunomodulation seen during malaria infection.
The aim of the research is to determine whether HO-1 modifies the immune response to malaria and to concomitant bacterial infections. This will be examined in experimentally-infected mice and in people with naturally-acquired malaria infections. Whether the outcome of infections can be modified by changing the activity of HO-1 will be assessed.
Drugs are already available for use in humans to either up- or down-regulate HO-1. These drugs could easily be used in malaria if altering HO-1 activity had beneficial effects. This research will be carried out in the UK and in The Gambia, where many thousands of children are severely affected by malaria every year.
Malaria infects red blood cells, causing them to burst, releasing parasites and parasite by-products. Heme is a breakdown product of red blood cell haemoglobin. Heme is degraded by an enzyme (heme oxygenase-1; HO-1) to produce molecules that can modify immune responses, and may account for the immunomodulation seen during malaria infection.
The aim of the research is to determine whether HO-1 modifies the immune response to malaria and to concomitant bacterial infections. This will be examined in experimentally-infected mice and in people with naturally-acquired malaria infections. Whether the outcome of infections can be modified by changing the activity of HO-1 will be assessed.
Drugs are already available for use in humans to either up- or down-regulate HO-1. These drugs could easily be used in malaria if altering HO-1 activity had beneficial effects. This research will be carried out in the UK and in The Gambia, where many thousands of children are severely affected by malaria every year.
Technical Summary
Background:
Severe human malaria results from direct damage by the parasite compounded by inflammatory immunopathology and bacterial co-infection. I propose that endogenous immunomodulators, whilst preventing immunopathology, simultaneously inhibit immune effector mechanisms required to clear malaria parasites and contain concurrent infections such as non-typhoidal salmonella. Heme oxygenase-1 (HO-1) - which degrades heme, producing immunomodulatory by-products, most notably carbon monoxide and iron - is one potential immunomodulator. HO-1 is induced during malaria infections but its role is unclear. Although it protects mice from experimental cerebral malaria, preliminary data from human studies suggest that upregulation of HO-1 predisposes to severe malaria. The possibility that the effects of HO-1 during malaria infections are mediated through modulation of the immune response and provision of iron acting as a growth factor for pathogens, has not been investigated.
Aim:
To investigate the role of HO-1 during malaria infection, particularly its potential role in immunomodulation
Objective:
To determine if the induction of HO-1 during malaria infection in mice and in humans modulates immune responses and thereby increases susceptibility to Salmonella sepsis.
Design:
Initially, the immunological and clinical effects of pharmacological induction and inhibition of HO-1, and of carbon monoxide administration, will be assessed in mice infected with various species and strains of rodent malaria parasites. The effect of HO-1 on susceptibility to co-infection with Salmonella typhimurium will also be assessed. Subsequently, the effect of HO-1 on immune function will be assessed in vitro/ex vivo in Gambian children acutely-infected with, and recovering from, Plasmodium falciparum infection. HO-1 levels in these children will be compared with clinical and immune parameters and evidence of co-infection.
Methodology:
HO-1 mRNA expression is assessed using qRT-PCR, protein expression determined by flow cytometry/western blot, and HO-1 activity measured by spectroscopy (bilirubin production). HO-1 activity will be induced by cobalt protopophyrin, inhibited by zinc protoporphyrin or mimicked by carbon monoxide releasing molecules. Myeloid and lymphoid cell activation and function will be assessed by flow cytometry (activation markers, cytokine secretion), ELISA (cytokines, antibodies) and proliferation assays. Bacterial infection and bacterial load will be assessed by blood culture. Standard clinical and laboratory procedures will be used to assess clinical and malariometric parameters.
Scientific and Medical Opportunities:
The study will reveal the role of HO-1 in modulating immune responses and predisposing to sepsis. Understanding the mechanisms of malaria-related immunomodulation may faciliate pharmacological reduction of direct and indirect morbidity/mortality of malaria, and enhance responses to vaccination in malaria endemic populations.
Severe human malaria results from direct damage by the parasite compounded by inflammatory immunopathology and bacterial co-infection. I propose that endogenous immunomodulators, whilst preventing immunopathology, simultaneously inhibit immune effector mechanisms required to clear malaria parasites and contain concurrent infections such as non-typhoidal salmonella. Heme oxygenase-1 (HO-1) - which degrades heme, producing immunomodulatory by-products, most notably carbon monoxide and iron - is one potential immunomodulator. HO-1 is induced during malaria infections but its role is unclear. Although it protects mice from experimental cerebral malaria, preliminary data from human studies suggest that upregulation of HO-1 predisposes to severe malaria. The possibility that the effects of HO-1 during malaria infections are mediated through modulation of the immune response and provision of iron acting as a growth factor for pathogens, has not been investigated.
Aim:
To investigate the role of HO-1 during malaria infection, particularly its potential role in immunomodulation
Objective:
To determine if the induction of HO-1 during malaria infection in mice and in humans modulates immune responses and thereby increases susceptibility to Salmonella sepsis.
Design:
Initially, the immunological and clinical effects of pharmacological induction and inhibition of HO-1, and of carbon monoxide administration, will be assessed in mice infected with various species and strains of rodent malaria parasites. The effect of HO-1 on susceptibility to co-infection with Salmonella typhimurium will also be assessed. Subsequently, the effect of HO-1 on immune function will be assessed in vitro/ex vivo in Gambian children acutely-infected with, and recovering from, Plasmodium falciparum infection. HO-1 levels in these children will be compared with clinical and immune parameters and evidence of co-infection.
Methodology:
HO-1 mRNA expression is assessed using qRT-PCR, protein expression determined by flow cytometry/western blot, and HO-1 activity measured by spectroscopy (bilirubin production). HO-1 activity will be induced by cobalt protopophyrin, inhibited by zinc protoporphyrin or mimicked by carbon monoxide releasing molecules. Myeloid and lymphoid cell activation and function will be assessed by flow cytometry (activation markers, cytokine secretion), ELISA (cytokines, antibodies) and proliferation assays. Bacterial infection and bacterial load will be assessed by blood culture. Standard clinical and laboratory procedures will be used to assess clinical and malariometric parameters.
Scientific and Medical Opportunities:
The study will reveal the role of HO-1 in modulating immune responses and predisposing to sepsis. Understanding the mechanisms of malaria-related immunomodulation may faciliate pharmacological reduction of direct and indirect morbidity/mortality of malaria, and enhance responses to vaccination in malaria endemic populations.
People |
ORCID iD |
| Aubrey Cunnington (Principal Investigator / Fellow) |