Innate and Adaptive Immune Responses to Malaria Flashcards
(52 cards)
Overall, how does the body respond to malaria?
body prioritises host fitness over parasite clearance
What is so unique about the Parasite Burden and “Severity of Malaria in Tanzanian Children (2014)” paper?
large scale study in which nearly 900 children were examined at birth, once every two weeks during infancy, once every month after infancy, and during any illness
– blood smears collected at all visits, regardless of whether symptoms were present
this is a large scale study that was able to study the effects in v young children over a long period of time
cannot be performed again as current guidelines say that if someone in study is ill w malaria, they have to be treated
this data is only piece of its kind
In the Tanzania study, how many children had severe malaria?
102 had severe malaria
87 (85.3%) had only one severe episode
70 (68.6%) had severe malaria during their first, second, or third infection of life
In the Tanzania study, what was the trend of percentage of those who got severe malaria compared to infection number?
risk of severe malaria exponentially declines as the number of infections they previously has increases
engagement of tolerance, not resistance mechanisms
What is the relationship between parasitaemia and severe malaria?
high parasite density is needed to progress to sever malaria
but high parasite density does not always cause severe malaria
What is the relationship between parasite density and symptoms?
there is a weak correlation
What is the difference in gene expression between the first and second exposure to malaria?
decrease of pro-inflammatory cytokine production in second exposure
Do innate cells have memory?
experiments show when monocytes previously exposed to malaria in vivo are exposed to parasite lysate show a decrease in the amount of pro inflammatory cytokines released (Portugal 2014)
in addition, experiments on prisoner volunteers involved to exposure to endotoxin before and after they were infected with malaria
– there was a significant decrease in clinical illness
– although this study was unethical and potentially v dangerous
Innate immune cells have a short lifespan so how would they form memory?
it has been shown that exposure of HSCs in the BM to the BCG vaccine (against M. tuberculosis) changes their transcriptional landscape
– leading to enhanced myelopoiesis at the expense of lymphopoiesis
– BCG-educated HSCs generate epigenetically modified macrophages that provide increased protection to M. tuberculosis compared to naive macrophages
What functions do monocytes perform upon secondary infection to malaria, if not the pro-inflammatory response?
do not downregulate everything
– upregulation of blood vessel creation
– glucose uptake
– deal w stress of malaria infection
– no hypoxia –> no acidosis
in addition, there is an expansion of innate blood cells during first infection
– does not occur on second
BCG induces epigenetic change, what about malaria?
experiment took place over 100 days, much longer than a monocyte lifespan, looking at epigenetic differences
no differences between unexposed and expose mice, so no innate memory?
there are functional differences however, influenced by this tissue microenvironment
– changes in liver structure due to hemozoin
How is the NLRP3 inflammasome activated during malaria infection?
exposure to hemozoin activates it though Lyn and Syk kinases
How are macrophages impaired during malaria infection?
impairment of macrophage function after ingestion of P. falciparum infected RBCs or hemozoin
What is clinical immunity to malaria and how does it develop?
immunity that develops to the clinical symptoms of malaria, not the parasite itself
develops after years of constant exposure in hyper- or holo-endemic areas
in some areas of favourable malaria transmission, one person can be infected more than 1000 times per year
lost without re-exposure (lasts at least 5 years)
How is it hypothesised that people eventually become immune?
- immunity is due to acquisition of a repertoire of responses to many different isolates
and/or
- the development of cross-protective responses to shared antigens
–> an understanding of both immune mechanisms and antigen targets is needed to understand vaccine-mediated immunity
Is passive transfer of human malaria immunity effective?
12 children (4mo -2y) w malaria received IgG by injection every 8-24h for 3 days
using gambian vs UK sera - can Ab alone protect?
trophozoite counts were considerably lower using sera from ‘protected’ adults than UK adults
How are babies protected from malaria at birth?
children remain v resistant to high parasitaemia, fever, SM, and death until 6 months
- susceptibility begins at 3-4 mo
protection may be associated w presence of maternal IgG –. debated, other mechanisms? eg lactoferrin
levels of these decrease over first year of life
Why is it significant that transplacental transfer of IgG increases exponentially during final month of term pregnancy (40 weeks)?
any change in when baby is born could drastically change how many protective Abs they have
How is IgG transferred during pregnancy?
maternal IgG Abs transferred to foetus via active transport mechanism mediated by FcRn
– neonatal Fc receptor
– selectively transports IgG
transfer efficiency highest for IgG1
– then IgG4 –> IgG3 –> IgG2
Is there evidence to support a protective role of maternally transferred Ab?
not much
previous analysis based on total IgG levels
recently, however, evidence shows IgG3 should be the best IgG subclass at protecting against malaria
–> better at fixing complement + engaging FcR on phagocytes
however is transferred to foetus at low efficiency
How can Abs block different stages of the Plasmodium lifecycle?
- sporozoites
– block trafficking to liver - erythrocytic stages
– targeting merozoites and infected RBCs - gametocytes
– blocking transmission
What is the function of Abs against PfEMP1?
opsonic phagocytosis activity is reduced in PfEMP1 knock down
– may also block cytoadherence
no difference in function of Abs between SM and UM
therefore the amount of IgG present in an experienced host may be important for clinical presentation of disease
Why is Ab binding to the right spot on PfEMP1 variant important?
PfEMP1 is large protein that contains functional binding sites
targeting these sites allows Abs to inhibit function of PfEMP1 eg binding site of EPCR and/or CD36
adults recognise PfEMP1 peptides > children
What is the function of repetitive interspersed repeats?
RIFIN
like PfEMP1, highly antigenically varied
– encoded by set of 150-200 genes
– 1 expressed per parasite
function
– bind to erythrocytes (prefer group A) to from rosettes and induce cytoadherence
