34-35: Malaria Flashcards
history of malaria
1902: ronald ross demonstrated malaria is transmitted from human to human by mosquitos
1907: charles laceran proposed that it was caused by a protozoan organism, plasmodium
1948: Paul muller discovered DDT and its use on insects was critical in malaria eradication
2015: tu youyou extracted artemisinin from wormwood to improve malaria outcomes
malaria worldwide statistics
3.2B at risk
219M cases and 435K deaths in 2017
sub-saharan african had 89% of cases and 93% of deaths
- disease of children with deaths in children
why is malaria a leading cause of death from infectious disease?
socioeconomic conditions
- costs of treatment are very expensive
vector that is found primarily in Africa
malaria mosquito vector
anopheles as the only mosquito genus capable of spreading malaria
- only the female transmits
20 species of anopheles worldwide transmit parasites but certain species transmit better
malaria seasonality
peaks during or just after rainy season based on increased mosquito replication in standing water
malaria in the US statistics
600K cases in the US in 1914 primarily in louisiana and florida
CDC says there are 1700 imported cases annually
malaria mosquito vector control
DDT discovered after WWII in 1939
first insecticide that when applied to houses could kill mosquitos for up to a month
- only killed adults and larvae, but nothing else
malaria eradication in the US (1947-1951)
by the end of 1949, over 4.6M house spray applications performed
by the end of 1950, only 2K cases reported
by 1951, malaria considered eradicated
- huge success of DDT
global malaria eradication campaign (1947-1955)
combined systematic spraying of DDT and treatment of infected individuals with chloroquine
very effective in some countries
- Sri Lanka went from 1M cases in 1955 to just 18 cases in 1963
eradication in sub-saharan Africa never fully implemented
why did the first global malaria eradication campaign end?
financial issues
- cost too high and in 1964, Congress withdrew funding
drug resistance with chloroquine
DDT problems
- widespread use in agriculture led to resistance
- DDT also a devastating environmental pollutant causing severe damage to wildlife and non-harmful insects
global malaria control strategy in the 1990s
new control rather than eradication strategy
prompt treatment of all episodes of disease (within 24h)
- less symptoms, less parasites, less transmission
bednet use combined with insecticides
indoor residual spraying to kill mosquitos
malaria as an intracellular protozoan parasite
caused by 4 species
- focus on plasmodium falciparum, which causes the most disease and deaths
other species-specific plasmodium
what does the malaria parasite do?
infects RBCs
- easy to find
living in RBCs means that it evades key adaptive immune mechanisms (CTLs)
- CTLs require MHC and there’s no MHC in blood cells since there is no nucleus
malaria parasite in the body
sporozoites come from the mosquito through their bite
- each sporozoite infects a liver cell
liver cells are very large
- infected cells can release 10-30k merozoites
first cycle in the liver (7-14 days)
- disease only started when parasite replicates in RBCs
- takes longer than viruses
merozoites then produce gametocytes which are taken up by mosquitos
merozoite form of malaria
in the merozoite form, kill RBCs and cause inflammation
- cause systemic inflammation and fever when released
can have many rounds of replication in RBCs
- hemoglobin is the food source for malaria parasites
- eat hemoglobin, replicate and lyse RBCs
plasmodium falciparum parasites can infect as many as 60% of the RBCs
where does malaria disease come from?
merozoite form
cyclic fevers with the release of parasites every 48-72 hours from RBCs
malaria is well adapted because it can cause these fevers and release parasites at night
- specific mosquitos like to bite at night
clinical diagnosis of malaria
similar to other infections
plasmodium falciparum typically associated with higher levels of infected RBCs and have a different periodicity of fever than other species
malaria statistics
in endemic areas, 100% of children have yearly symptomatic malaria
- only 1-2% have severe complications from cerebral malaria
p. falciparum causes most deaths from malaria brain infections
- cerebral malaria has a mortality of 20%
- causes 95% of deaths and most people who die are children
immune response to malaria
innate immunity does very little
- activates inflammation and disease but doesn’t stop malaria
adaptive immunity
- enough immune response to keep from getting cerebral malaria and dying, but not enough to prevent infection and leads to more transmission
- IgG as the most important antibody for RBCs and liver cells
why is malaria such a successful antigen?
well-adapted for humans with no animal reservoir
evolved for transmission only in Anopheles mosquitos
plasmodium parasites are god at evading adaptive immune response
what is partial immunity with regards to malaria?
reduces symptoms but if parasite replicates in blood, mosquito transmission still occurs
people who are repeatedly infected with malaria develop partial immunity which does not prevent infection but prevents severe disease
how does malaria evade antibodies?
parasite expresses key antigens on the surface of infected RBCs but can also change these
infected RBCs have knobs which help with attachment so no elimination in the liver and spleen
- infected RBCs with knobs and malaria proteins are the best targets for antibodies
malaria immune evasion - changes in surface antigens and knobs
knobs are antigens and act as targets for antibodies
expression of variant surface antigens (VSAs) which are the primary targets of antibodies on the surface of infected RBCs
- key family of VSAs are Pfemp1 antigens which encode 60 different possibilities for what can be expressed
VSAs provide binding of RBCs to the vascular endothelium to evade degradation in the spleen and liver
important form of antigenic variation that makes it difficult for people to develop more than partial immunity
protective vs. sterilising immunity
with sterilising immunity, you have no infection/replication and cannot transmit
protective immunity just means you block disease but not infection
- partial immunity as less than protective
anti-malarial drugs
original drug was chloroquinine which was established as effective and safe in 1946
chloroquinine thought to inhibit heme-polymerisation, where heme in hemoglobin becomes toxic to malaria
other drugs targeting heme have been developed and used since 1970s
- drug resistance by parasites found against all of them
non-medical prevention of malaria
mosquito control
insecticide-treated bednets that is affordable and effective
natural resistance to malaria
individuals heterozygous for sickle-cell hemoglobin have some protective advantage
- if a sickle cell gets infected with malaria, it gets killed right away and cannot attach to the endothelium
blood type also identified as potentially protective
- uninfected RBCs can come in and attach to protect the infected one (rosette)
- happens more with A and B blood types since they are carbohydrates as opposed to O
issues with malaria vaccine design
no way to know what would provide full immunity since humans mostly don’t have full immunity
most vaccines target sporozoites (95%)
new recombinant vaccine against pre-liver stage
RTS,S composed of plasmodium falciparum sporozoite protein fused with hepatitis B virus surface antigen
recombinant protein vaccine
phase III trials found 50-56% reduction in first case of malaria when given to 5-17 month old children
requires 4 doses for protection
