34-35: Malaria

Question 1

history of malaria

Answer 1

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

Question 2

malaria worldwide statistics

Answer 2

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

Question 3

why is malaria a leading cause of death from infectious disease?

Answer 3

socioeconomic conditions
- costs of treatment are very expensive

vector that is found primarily in Africa

Question 4

malaria mosquito vector

Answer 4

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

Question 5

malaria seasonality

Answer 5

peaks during or just after rainy season based on increased mosquito replication in standing water

Question 6

malaria in the US statistics

Answer 6

600K cases in the US in 1914 primarily in louisiana and florida

CDC says there are 1700 imported cases annually

Question 7

malaria mosquito vector control

Answer 7

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

Question 8

malaria eradication in the US (1947-1951)

Answer 8

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

Question 9

global malaria eradication campaign (1947-1955)

Answer 9

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

Question 10

why did the first global malaria eradication campaign end?

Answer 10

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

Question 11

global malaria control strategy in the 1990s

Answer 11

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

Question 12

malaria as an intracellular protozoan parasite

Answer 12

caused by 4 species
- focus on plasmodium falciparum, which causes the most disease and deaths

other species-specific plasmodium

Question 13

what does the malaria parasite do?

Answer 13

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

Question 14

malaria parasite in the body

Answer 14

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

Question 15

merozoite form of malaria

Answer 15

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

Question 16

where does malaria disease come from?

Answer 16

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

Question 17

clinical diagnosis of malaria

Answer 17

similar to other infections

plasmodium falciparum typically associated with higher levels of infected RBCs and have a different periodicity of fever than other species

Question 18

malaria statistics

Answer 18

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

Question 19

immune response to malaria

Answer 19

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

Question 20

why is malaria such a successful antigen?

Answer 20

well-adapted for humans with no animal reservoir

evolved for transmission only in Anopheles mosquitos

plasmodium parasites are god at evading adaptive immune response

Question 21

what is partial immunity with regards to malaria?

Answer 21

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

Question 22

how does malaria evade antibodies?

Answer 22

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

Question 23

malaria immune evasion - changes in surface antigens and knobs

Answer 23

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

Question 24

protective vs. sterilising immunity

Answer 24

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

Question 25

anti-malarial drugs

Answer 25

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

Question 26

non-medical prevention of malaria

Answer 26

mosquito control

insecticide-treated bednets that is affordable and effective

Question 27

natural resistance to malaria

Answer 27

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

Question 28

issues with malaria vaccine design

Answer 28

no way to know what would provide full immunity since humans mostly don’t have full immunity

most vaccines target sporozoites (95%)

Question 29

new recombinant vaccine against pre-liver stage

Answer 29

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