Welcome
Hello readers,
sometime ago (end of 2006) i wanted to know about malaria,
so i took some time (4 weeks at 70 hours/week) to find information about it,
and another 3 weeks to organize that into a document.
My original goal was to get a solid basis to find numerical values of anti-malaria measures,
and i have succeeded in compiling a basis of knowledge,
but not in finding the numerical data.
The result would take you a day to read, and represents more than a month of literature-study,
so it might be profitable for you to read,
and that is why i have put it on the web.
Warning to the reader
I am not a medical doctor, and my knowledge about malaria is far from complete.
Therefore, for those of you who read this because
they will be going to a country where malaria is endemic,
please be aware that you NEED to get medical advice from a real doctor ;
Do not let your life depend on what you read here !
Version
This is version 1 , of 2008 march 25
Feedback, author and copyright
If you happen to know about anything that is marked 'unknown' here,
or that is omitted, or described incorrectly,
please let me know by sending an email to siward@wanadoo.nl .
This text was written in october/november 2006 and march 2008 by Siward de Groot.
This is a copyrighted text that you can use, modify, and distribute as you see fit,
provided that
* you do not change the authorname, and
* if you distribute a modified version, you clearly mark it as modified.
|
2 - Mosquitos
Mosquitos are flying insects,
that usually breed in stagnant water (eg swamps),
bite humans or animals to feed on their blood,
and in doing that can transmit diseases.
There are islands in pacific ocean that do not have any mosquitos,
so it looks like there is nothing against eradicating all mosquitos from whole world
(except that it would not be worth it's huge cost).
2.1 - Mosquito species
Malaria is mainly transmitted by mosquitos,
and, conversely, mosquitos are mainly important because they transmit diseases.
There are about 3500 species of mosquitos, grouped into 41 genera.
Malaria is transmitted only by mosquitos of genus 'anopheles'.
Of this genus, there are 460 species described
(meaning that more species could still be discovered).
Not all of these are 'vectors' of malaria
('vector' means that they are capable of transmitting a disease).
Currently only 68 species of anopheles are known vectors of human malaria, because
some anopheles do not feed on humans,
some are not susceptible to human malaria parasites,
some have a life-span too short to allow the parasite to mature inside it.
2.2 - Anopheles
Anopheles mosquitos are 8 -13 mm long (looked smaller in a picture i saw),
with a body circa 1 millimeter thick,
and mostly whitish-translucent
(when they have sucked blood, they are red).
Like all mosquitos, adult anophelines have slender bodies
with 3 sections: head, thorax and abdomen.
Head contains
two eyes,
one proboscis (snout) : elongate, forward-projecting, used for feeding,
two many-segmented antennae, for smelling ;
these antennae are important for detecting host odors
as well as odors of breeding sites where females lay eggs.
('Malaria' is derived from 'mala aria' which means 'bad air').
two sensory palps.
Thorax has usual internal organs,
and serves as attachment for three pairs of legs and one pair of wings.
Abdomen is for food digestion and egg development ;
it expands considerably during a blood meal, and shrinks during egg-laying.
Anopheles mosquitos can be distinguished from other mosquitos
by the palps, which are as long as the proboscis, and
by the presence of discrete blocks of black and white scales on the wings.
Adult Anopheles can also be identified by their typical resting position :
males and females rest with their abdomens sticking up in the air
rather than parallel to the surface on which they are resting.
Anopheles species differ in
* whether they prefer blood from humans or from animals
* whether they prefer to live near human settlements (anthropophilic) or not
* whether they prefer to bite indoors or outdoors
* whether they prefer to rest inside house after having bitten, or prefer resting outside
* how long they live
* what climate they are best adapted to
* their feeding and mating patterns
* their sensitivity to insecticides
Table (very incomplete) :
| Species | Location | Anthropophilic | Bite | Rest | Bitetime | Remarks |
|---|
| A.gambiae | Africa | yes | indoor | indoor | latenight | prefers biting ankles and feet (related to feet smell?) |
| A.arabiensis | Africa | no | outdoor | ? | ? | seems to like rivers. |
| A.funestus | Africa | ? | outdoor | ? | ? | can survive dry spells. |
| A.Quadrimaculatus | SouthUSA | ? | ? | ? | ? |
| A.freeborni | SouthUSA | ? | ? | ? | ? |
| ??? | Mexico | ? | ? | ? | ? |
A.albimanus | Central+SouthAmerica | ? | outdoor | ? | ? |
| ??? | Papua New-Guinea | ? | ? | ? | ? |
Anopheles species in asia are zoophilic
ie they primarily prey on some species of animal, cows being well known,
and humans are second choice.
Anopheles species in africa primarily prey on humans.
When a disease is spread by an animal that is itself not cause of that disease,
that animal is referred to as 'vector' of that disease.
The best vectors
are abundant and long-lived,
prefer to feed on humans, and
usually prefer to live in close proximity to human habitation.
Anopheles gambiae has all these characteristics and is, consequently, the best vector.
This is an important factor of high malaria prevalence in Africa.
Mosquitos do not specialize in type of plasmodium they transmit.
Mosquitos generally don't seem to become ill from plasmodia in their bodies
as plasmodia can develop inside mosquito, but can not repeatedly multiply there.
They are adversely affected by plasmodium, however,
because an infectious mosquito usually needs multiple bites to get a full blood meal,
while a non-infectious one can ingest a full meal with one bite ;
This might be caused by human immune-system detecting injected plasmodia,
and human body reacting to it.
'Species' are usually understood to be
groups of similar animals that can reproduce among themselves,
and if two individuals can reproduce together, then they are from same species.
For A.gambiae this is not quite so.
Literature has it that it forms a 'species-complex',
of which A.arabiensis and A.funestus are also part.
What exactly this means in practice, i don't know.
2.3 - Mosquito lifecycle
Like all mosquitos, anopheles have four stages of life : egg, larva, pupa, and adult.
2.3.1 - Adult
Adult anopheles are flying insects.
They are crepuscular (active at dawn or dusk) or nocturnal (active at night).
FOOD
Anopheles feed on nectar,
from flowers, extra-floral nectaries, leave-edges (of cassava plant for example),
and other sources of sugar (eg maize pollen, honeydew produced by mealybug),
from which they derive their energy,
but females also need blood, as source of proteins for development of eggs ;
As human blood is unusual in composition by having very few of one type of amino-acid,
a blood-meal can not be completely converted to offspring of mosquito,
and fraction of blood that can not be used for synthesis is available as source of energy.
Females can do completely without sugar (although they feed on nectar if given chance),
provided that they can eat blood at least every 3 days,
but males, being physically incapable of biting animals, absolutely need a sugar-food.
MALES
Males live for circa 1 week (circa half as long as a female), and die,
and consequently mosquito populations consist of twice as many females as males.
Males spend their whole life on feeding from sugar-food sources and on swarming.
MATING
In most Anopheles species, mating is usually done at dusk ;
males form swarms then, into which a female flies to get fertilized.
These swarms often occur at places where a female can lay eggs or feed on sugar.
These swarms occur mainly at dusk, and last for 1-2 hours ;
at dawn there is similar (but much less pronounced) swarming behaviour.
This might be caused by need for some light,
for female to find swarm, or when inside swarm, to interact with a male.
One female gets fertilized by multiple males, and stores their sperm in her body ;
it is used later, after she has fed on blood, and eggs are being developed.
This way survival of small number of mosquitos still represents a relatively large genepool,
and female does not have to do a mating flight with weight of eggs in her body.
It is likely that females are attracted to swarms of males,
and, when in a swarm, by individual males,
which might be by some smelly substance males secrete
(It was found that when males can not feed on sugar,
their chances of successfull mating are much smaller,
unless they are in a very small cage (where male would be hard to miss)).
It is not impossible that males convert part of sugars they eat,
and transfer this to female when they mate.
BITING
After female is fertilized (typically at dusk), she starts seeking a human to bite.
For A.gambiae it has been found that peak biting time is
from a few hours after swarming time, to end of night
(but biting is not unusual from right after fertilization to early morning).
This would increase chance that victim is asleep, and thus chance for mosquito to survive biting.
So other species likely behave similarly.
During time between getting fertilized and peak biting time,
they probably sit down somewhere.
Those species that like to be indoors, can settle down on a wall in a house,
waiting untill late at night before they bite ;
Female is guided to victims by scents in air,
for which she needs to discern direction scent comes from,
which is probably why antennae are placed as far apart as possible.
A house that has little human smell would give a smaller chance of getting bitten.
A house that is upwind from a mating/sugarfeeding location
would give a larger chance of getting bitten.
When female finds a victim, and it looks safe and acceptable enough, she bites it.
First thing a mosquito does when it bites, is inject some saliva into victim ;
this 'saliva' contains pain-killers, so victim won't notice being bitten,
and anti-coagulants, for easy sucking,
and, if mosquito is infected, also contains malaria parasites.
An uninterrupted blood-meal usually takes 2-3 minutes.
Quantity of blood ingested at a single feed can be up to 25 mm3 ;
this amount exceeds normal body weight and size of mosquito.
RESTING
After having sucked blood,
they find a place to rest, to digest food and let eggs develop ;
This process depends on temperature : it usually takes 2-3 days in tropical conditions.
Some species prefer to rest inside house, while others prefer outdoors.
During that time, place previously taken by blood (being digested)
is becoming used by eggs (that are developing) ;
total size of eggs is however smaller than that of blood ingested
(to extent that a female that failed to find a place to lay eggs
can bite a second time, and develop a second batch of eggs, before laying them ;
second batch is circa half size of a normal batch in that case).
EGG LAYING
When eggs are ripe, mossie starts seeking for stagnant water, to use as a breeding place,
for which she prefers clean water over polluted water as found in gutters.
It is likely that she flies downwind, to find same breeding area she herself emerged from,
which would be near local swarm and sugar-feeding locations.
After mossie has laid eggs,
she goes looking for males for mating or sugar for eating,
whichever she encounters first.
Females are known to be attracted to smells like sweet flowers
and at this stage in their life are often attracted more to sweet smells than to host-smells
(which are smells that guide them to a human victim).
2.3.2 - Gonadotrophic Cycle
Female anopheles repeat this mating/biting/resting/egglaying cycle for rest of their lives.
This cycle is called 'gonadotrophic cycle'.
It's duration varies with temperature and per species.
In A.gambiae, cycle takes 48 hours when average day-night temperature is 23 oC .
In malaria models, gonadotrophic cycle is measured in degree-days,
and i did not find a definition of that in what i read.
In A.gambiae living at a temperature near 25 oC,
speed of it's metabolism is roughly proportional to ambient temperature minus 14 oC.
So if i define 'degree-days' like that, then A.gambiae needs 18 degree-days for egg-maturation.
(and thus if temperature is 20 oC they would need 3 days for it).
Female anopheles feed on blood every 2 - 3 days,
starting 2 - 3 days after they emerge from pupa
(in which time they feed on blood 2 or 3 times, to fully mature).
Adult female mosquitos live for upto 4 weeks on average in a laboratory,
1-2 weeks on average in nature.
They can withstand temperatures up to 40 oC ; 42 oC kills them fast.
Models of mosquito population size often assume a constant chance of surviving to next day,
which is often in order of magnitude of 75 % .
Their chances of survival are said to be mainly determined by
temperature, humidity, rainfall, and getting killed when feeding on blood.
2.3.3 - Egg
Egglaying is called 'oviposition' in Latin.
Adult female mosquitos lay 50-200 eggs per oviposition ; 100 is a typical value.
Eggs are laid on surface of water, as individual eggs (not as a group),
where they float, because they have floaters on either side
(which is unique ; other insect's eggs have only one floater).
Eggs, when fully developed, are circa 0.6 mm long and 0.2 mm in diameter ;
they are dark brown to black when they are near hatching.
Eggs are not resistant to drying.
Eggs hatch within 2-3 days,
although hatching may take up to 2-3 weeks in "colder climates".
Out of these eggs, larvae emerge.
2.3.4 - Larvae
Larvae are oxygen-breathing filter-feeders.
They live on surface of water,
feeding on algae, bacteria, and other micro-organisms that live in surface-layer.
They are motile,
swimming
either by jerky movements of entire body, moving with an S-shaped motion,
or through propulsion with the mouth brushes.
They dive underwater when disturbed, but need to surface frequently to breathe.
Larvae have
a well-developed head, with mouth brushes (primarily used for feeding, but also for propulsion),
a large thorax, and
a segmented abdomen, with spiracles on 8th abdominal segment, through which they breathe.
They have no legs.
In contrast to other mosquitos, Anopheles larvae lack a respiratory siphon
and for this reason position themselves so that their body is parallel to surface of water.
Could this be why they need stagnant water ?
Could this be why they need two floaters, to not drown as soon as they emerge from egg ?
Larvae have a natural enemy in 'mosquito fish' (Gambusia affinis),
but this only applies to those that live in larger bodies of water that have that fish.
Larvae develop through 4 stages (called 'instars') ;
At the end of each instar, larvae molt, shedding their exoskeleton, or skin,
to allow for further growth.
After this sequnece of instars, they metamorphose into pupae.
Amount of food available to larvae is important,
as it determines energy-reserves of mosquito they will develop into,
which determines it's reproductive success,
and it's survival chances immediately after birth.
2.3.5 - Pupa
Anopheles pupa does not have separate head and thorax,
but it has a combination, called cephalothorax,
which floats on top.
Abdomen has a curved shape and floats underneath cephalothorax.
Thus pupa is comma shaped when viewed from side.
Pupae are oxygen-breathing, and must come to surface frequently to breathe.
They breathe through a pair of respiratory trumpets on the cephalothorax.
After a few days as a pupa,
dorsal surface of cephalothorax splits, and young adult mosquito emerges.
2.3.6 - From Egg to Adult
Time from laying egg to mosquito emerging from pupa depends on species and ambient temperature.
It is usually 10-14 days in tropical conditions, but some mosquitos do it in 5 days.
When water in which eggs were laid dries up before fly emerges from pupa, they die ;
nor eggs nor larvae nor pupa can stand drought
In some species of anopheles, adult can survive dry spells, by sleeping through it ;
this is called 'aestivation' ;
I read about one example of this, which concerned A.arabiensis
living in roof of a cow-shed, from where it emerged periodically to feed on blood.
Rainfall is also dangerous for eggs (and larvae and pupae),
as they might get washed away to a place that would dry up.
2.3.7 - Adult
Adult mosquitos start mating circa 2- 3 days after having emerged from pupa.
Females start seeking a human to bite after being fertilized.
First batch of eggs may require 2 to 3 bloodmeals to mature,
because fly itself still has to mature.
After first egg-laying, they start mating/blood-sucking/egg-laying cycle,
in which they mate once and suck blood once and lay eggs once per cycle,
as described above.
Adults have natural enemies in spiders.
When they fly, they can get caught in a web.
This may be one factor that makes males live shorter than females, as males fly every day.
2.4 - Mosquito behaviour
2.4.1 - Activity Time
Most adult Anopheles are crepuscular or nocturnal in their activities.
Thus, blood-feeding and oviposition (laying eggs) normally occur
in the evening, at night or in the early morning, before sunrise.
Anopheles mosquitos prefer to bite when it is dark,
probably mainly because they would have better chance of surviving blood-sucking time,
but maybe also because they have infra-red sight,
which would be more usefull for finding exposed skin in absence of places heated by sunlight.
2.4.2 - Attraction Factors
Anopheles are attracted by human temperature, CO2, odour, and others (research is ongoing).
Mosquitos mainly find their way around by smell ;
they are attracted by smells emitted by a bacterium (brevibacterium epidermis)
that normally exists on human skin, especially skin of foot
(and especially when it has not been washed),
which has been proven to be similar to smell of limburger cheese.
Chemicals that constitute that smell include
short-chain fatty acids and
methane-thiol, responsible for the "cheesy odour".
Mosquitos can be trapped by 'light-traps' (which is usefull for research) :
A lightbulb (switched on ofcourse)
was placed near an insecticide-treated bednet under which a human was sleeping ;
Under lightbulb was an old tin can,
and in top of can there was a piece of paper folded into shape of a cone,
with narrow end of cone down, and having an opening just big enough to let a mosquito pass ;
Mosquitos would be attracted by lightbulb
(probably by it's heat ; it also works if you use blacklight tubes ; these also become warm.
attempts to kill mosquitos with ultraviolet radiation were not successfull.)
they then bump into lightbulb, fall down into cone, and slide into can,
from which it would be hard for them to escape.
It was found that putting crumbled-up inch-wide strips of paper in can
reduced likeliness that they escaped, as they tended to hide among them ;
(Other investigations found that they are hard to kill by insecticidal gases
because they hide in narrow spaces where gas would mostly blow past.)
It was found that
more mosquitos were collected when light-trap was placed at highest point of net
than when it was placed at floor,
suggesting that mosquitos go more by smell than by light.
It was also found that more mosquitos were caught if trap was near feat
than when it was near head,
suggesting that feet-smell is main attractive smell for mosquitos ;
In other experiments, where mosquitos could freely choose where on a human they would land,
it was found that more of them landed on ankles and feet than on other parts of body.
2.4.3 - Victim-Seeking
When mosquitos are looking for a human to bite, they follow smells,
and if there were a crack in wall of a house, smell would emerge there,
and mosquitos would enter house there.
It is likely that when looking for a human to prey on,
they fly relatively low, probably mostly not higher than most houses,
as that would give them best chance to detect smells of their preys ;
There are indigenous people in southern Egypt that
protect themselves by sleeping in towers that they build for that purpose.
Mosquitos do not usually fly long distances, apparently.
From a study undertaken in a valley in east-africa,
where A.arabiensis had it's habitat near river in centre of valley,
"occasionally" A.arabiensis were found in villages bordering valley,
which were probably circa 7 km distant from river.
This still leaves open possibilities that they
migrate over long distances over time, transferring from one habitat to next,
or are blown by strong winds to far-away places.
One report says that 10 km is unusual, and 100 km has been observed but is extremely rare.
How fast moquitoes fly was not mentioned in what i read.
It does seem to be important, however, since, as mosquitos are guided by smell,
they fly against wind,
and must fly faster than wind, or they would never reach origin of smell.
Which would lead to conclusion that there is some maximum windspeed
above which mosquitos do not like to fly.
As a rough guess, from mosquitos i saw in Netherlands, i think 10 km/hour is not unusual,
which equals 2.7 m/s,
and a wind with that speed is said to have a force of 2 to 3 beaufort,
which are described as "light breeze" and "gentle breeze" respectively.
This would fit well with observations that mosquitos swarm for circa 1 hour,
and are unusual to be found 10 km from their base.
One person claimed that mosquitos do not like air-currents caused by ceiling-fans.
Mosquitos do not like smoke.
It was found that women sitting unhealthily near inefficient indigenous cooking fires
were less likely to get bitten by mosquitos.
2.5 - Mosquito population
There is some evidence that mosquitos occur in groups.
Especially for A.gambiae, which likes to stay near human settlements,
it is probably true that most mosquitos stay near same settlement they were born near to.
For other anopheles species this may be less true.
Mosquitos usually fly less than 10 kilometers, 100 km being extremely unusual ;
It may be that a strong wind could sweep mosquitos away over long distances.
It was found that in two villages (more than 10 miles apart)
that each had malaria,
strains of plasmodium in each village were genetically different,
which means that mosquitos from one village did not reach other village.
So a mosquito population is not a continent-wide thing,
but local to a village or town,
especially for most effective vector A.gambiae.
I assume that female mosquitos, after being fertilized, and being guided by smell,
fly against wind.
When they are ready to lay eggs,
they could reach their old breeding ground by simply flying with wind,
which would also be most efficient, as they are much heavier when filled with eggs.
As they are said to prefer clean water for breeding,
it is probably not true that they are guided to their breeding grounds by smell,
as is sometimes claimed.
2.5.1 - Population Size
When looking for info about malaria,
i found no info about which factor constrains size of mosquito population,
so what follows is just a guess.
A female anopheles lays circa 100 eggs,
each egg has some chance to survive and develop into a mosquito,
half of these mosquitos are female,
these have some chance to become fertilized and feed on blood and live long enough to lay eggs.
If product of these factors is bigger than 1, then mosquito population size will increase.
If it is smaller, then population will decrease.
Increase or decrease is then exponentially,
with a timeconstant of probably circa 15 days :
12 days for eggs to develop,
3 days for emerging mosquitos to die from exhausted energy reserves,
or 3-4 days to feed, mate, bite and lay eggs.
Survival chances depend on
environment, climate, and availability of food, blood and breeding sites.
Reproduction chances depend on survival and chance for a female to find a swarm,
and for males in a swarm to have eaten enough sugar to successfully mate.
Environment and climate do not depend on mosquito population size,
so if chances are good enough for one mosquito, they could multiply to infinite numbers.
In most parts of africa, climate is conducive for mosquitos all year round.
Chance to find a swarm would probably increase as swarms are larger, not decrease,
so does not form an upper limit for population size.
As there are more mosquitos, they compete for victims to bite ;
it was found in endemic areas that number of bites per person per night varies widely,
so it is likely that this is not limiting factor,
except possibly for those areas that showed highest biting rate.
Availability of breeding sites is a more uncertain factor.
Pupas are roughly as big as a mosquito,
so 100,000 of them would fit on a square meter of water,
but they also need food : micro-organismas from surface layer of water,
and i have no idea how abundant these are.
It is said that mosquitos can breed in cups filled by rainwater,
(in tropical conditions, where pollen could be blown into cup)
so 20 cm2 would suffice for at least one pupa ;
this provides a lower limit of 500 pupas per square meter.
This lower limit is probably nearer to truth than upper limit of 100,000 per m2 .
Studies in a highly endemic area in Kenya showed that
rate of infectious bites was a bit less than one per person per night,
and only a few percent of bites were infectious.
Total number of bites would thus be smaller than 50 per person per night,
and thus for a village of 100 persons, there would be less than 5000 bites per night,
which would be equivalent to a population of 12,500 adult female mosquitos.
Female mosquitos live circa 2 weeks on average,
and it takes a similar amount of time for an egg to develop into a mosquito,
so number of female eggs at any time roughly equals number of female mosquitos.
This mosquito population would need not more than 20 cm2 per mosquito for breeding,
and half of eggs are female, so total number of eggs is circa 25000,
so total needed size of breeding water is not more than 50 square meters
(and might well be ten times less).
Mosquitos fly not more than a few miles per night,
so these breeding grounds would need to occur in an area of a few square miles.
Thus if 1/100,000th of area was suitable as breeding ground, it would suffice,
so i think in practice breeding grounds in rural settings can be considered to be abundant,
and do not limit mosquito population size in most natural rural environments.
Thus i conclude that probably
availability of sugar foods is limiting factor of population size in rural areas.
From this it follows that
an average square meter of nature provides some sugar-food and breeding area,
and number of mosquitos that that can support is limited by availability of sugar-food.
In a rural setting, like Accra, which has a surface area of a few square miles,
and a human population of a few million people,
there is a lot of roads and buildings and things like that,
which do not support mosquito life,
and there are also some nature-like patches that do support mosquito life.
There are additional non-nature-like breeding sites, like gutters.
There are probably hardly any non-nature-like sources of sugar available to mosquitos.
Thus in rural settings too,
availability of sugar-food would be limiting factor of mosquito population size.
Dr. Gary found that (in semi-natural conditions with little risks and exertions)
chance of successfull fertilization of a female
in a swarm of sugar-deprived males was circa 1 % ,
while in a swarm of sugar-fed males, it was 88 % .
The above line of reasoning does not prove that
sugar-food-availability is the limiting factor on mosquito population size.
In a sufficiently sparsely inhabited part of countryside,
the availability of humans for biting would be limiting factor.
How much would be considered "sufficiently sparse" i do not know ;
it might be determined by
comparing malaria prevalence among similar villages of different sizes in same area
(about which i did not happen to find data).
2.5.2 - Consequences of Sugar-food as limiting factor
As number of mosquitos increases,
they have to share food (eg nectar from flowers) with more mosquitos,
so chance to get enough sugars to survive decreases,
until product of all survival factors becomes 1 ;
then mosquito population has reached it's final size.
If this conclusion is correct, then it would also seem likely that
even for large cities like Accra,
mosquitos would have their main feeding grounds outside city.
Consequently mosquito biting rate could be expected to be lower on side of city
that is up-wind for usual direction of wind ;
in case of Accra it would mean that you would get bitten less frequently on sea-side of city,
because mosquitos, coming from down-wind,
would find other victims to bite before reaching up-wind part of city.
From this it follows that average biting rate for a large city
would be lower than average biting rate in rural areas.
Another consequence would be that
malaria transmission would show increases in seasons when many flowers bloom
(which would probably be in or after rainy season).
Sugar-food as limiting factor might also explain name 'malaria'.
It is well known that 'malaria' is derived from 'mala aria', which is italian for 'bad air'.
People infected with malaria do not give off any unusual smell.
Mosquitos prefer clean water over polluted water.
They do prefer stagnant water, which in swamps might be associated with smell of decay,
so this is one possibility for origin of name.
Mosquitos are attracted by stinky-cheese-like smells
given of by bacteria commonly found on human skin, especially on feet,
but highest infection rates, and thus highest malaria risk,
is not associated with concentrations of human population,
where such smells would be most intense,
but rather occur in rural settings.
If sugar-food is limiting factor of population size,
then a fully developed mosquito population will use up all available sugar-food,
and thus there will no longer be much sweet smell of flowers.
This is a possible reason for name 'malaria'.
Regulation of population size by available sugar-food is a saturated regulation.
Adults live much shorter in nature than in laboratory,
because they produce so much offspring that their survival chances decrease.
Thus if survival chances decreased, due to some other cause,
by same factor as average lifespan in lab divided by average lifespan due to competition,
then mosquito population size would remain same.
This is important for estimating effects of anti-mosquito measures,
as it means that these measures must reduce survival chances by circa 4/1.5 = 2.7
before they would make any difference at all.
2.5.3 - Age distribution of Mosquitos
If there are 1 million mosquitos in an area (as limited by availability of sugar-food),
it could mean that
females live for 2 weeks on average,
during which time they lay circa 450 eggs,
and chance for an egg to develop into a mosquito is 1/225 .
It could also mean that
females live for 1 week on average,
during which time they lay circa 200 eggs,
and chance for an egg to develop into a mosquito is 1/100 .
As will be mentioned in chapter about plasmodium,
plasmodia need nearly two weeks to develop inside mosquito, before they can infect humans.
Consequently, in former case malaria would be transmitted,
while in latter case nearly none of mosquitos live long enough to become infectious,
so malaria would be much less of a burden, and much easier to combat.
If total amount of mosquitos is limited by availability of sugar-foods,
and assuming this is distributed on a first-come first-serve basis,
young and old mosquitos would have equal chances to it.
If that is correct, then
increasing chance for eggs to develop into mosquitos
would decrease average lifetime of mosquitos.
Conversely, if adult mosquito had a lower chance of survival,
then there would be less competition for sugar-food,
so that newborn mosquitos would have an increased chance to live to egg-laying age,
which would increase overall chance for an egg to make it to that age.
It is generally assumed that this is not only factor that influences average mosquito lifetime.
Literature has it that their chances of survival depend on
temperature, humidity, rainfall, and their ability to successfully obtain a blood meal.
It is also well-known that mosquitos have an irritating tendency to
splat themselves on windscreen of your car,
so their lifetime also depends on environment.
In areas where malaria is combatted, another factor is mosquito resistance to insecticides.
Temperature and rainfall also influence amount of flowers from which nectar can be gotten,
and rainfall would influence distance to which pollen would be spread by wind,
so these factors are interrelated.
Chance for a mosquito to survive to next day
is usually considered to be independent of mosquito age.
And is usually found (actually inferred from other results)
to be circa 70 - 85 % survival chance per day.
In one study in Tanzania it was found (indirectly) that
estimates of daily survivorship of A.gambiae ranged from 0.77 to 0.84 .
However, if an area has daily survivorship 60 % or lower,
then mosquitos don't live long enough to let plasmodium develop inside them,
and consequently malaria is not transmitted,
and consequently such areas are not studied,
so it is entirely possible that values lower than 60 % do occur in nature.
|
5 - Plasmodium
Infectious parasites that cause malaria are protozoans of genus 'plasmodium'.
5.1 - Classification
Protozoans are small unicellular organisms that
have circa 6 times as much genetic information as a bacterium,
which makes them more versatile.
Protozoans are eukaryotes,
which means that they have nucleus and organelles inside internal cell walls.
Among protozoans are many subgroups, called 'phyla',
and these phyla are again divided into yet smaller groups called 'genera'.
Plasmodium is a genus of phylum 'apicomplexa'.
Apicomplexa are characterized by having
a ring-shaped skeleton-like structure at one end
(probably for providing support for proteins that bind to cell being attacked),
and sacs full of chemicals with tubes leading through ring to cell-wall.
All species in phylum apicomplexa are parasites.
Plasmodia, when bumping into a red blood cell,
quickly move ring-part of their body toward RBC,
take a firm hold of it,
and empty contents of their sacks of chemicals outside cell-wall,
so that these contents, due to pressure, end up inside cell being attacked.
5.2 - Infective species
Plasmodium genus consists of more than 125 species,
that produce malaria in mammals, birds, and reptiles.
Five of these affect humans:
* plasmodium falciparum
is main cause of malaria in africa.
nearly all deaths due to malaria are caused by P.falciparum.
* plasmodium vivax
is main cause of malaria outside of africa.
can remain dormant upto 2 years after infection (but this is rare).
* plasmodium ovale
not very common.
can remain dormant upto 4 years after infection (but this is rare).
* plasmodium malariae
occurs in southeast asia.
* plasmodium knowlesi
occurs in south-east Asia.
is mainly a disease of monkeys, but can infect humans.
it's reproductive cycle takes only 24 hours.
'Dormant' here means that they remain inactive in liver for up to a couple of years,
and thus can cause malaria long after a traveller has returned from an infected area.
Species that cause malaria in animals are not dangerous to humans,
with exception of a subspecies of plasmodium ovale
that can infect monkeys and apes.
This subspecies is much less dangerous to humans than other plasmodia.
According to CDC's website,
extent to which monkeys and apes constitute a reservoir for malaria is also negligible.
P.malariae is unusual in that it's reproductive cycle takes 72 hours
(as opposed to 48 hours for most other plasmodia).
Malaria caused by P.malariae is relatively benign (often chronic but seldom lethal).
P.knowlesi is unusual in that it's reproductive cycle only takes 24 hours
Red blood cells infected with P.knowlesi look a lot like those infected with P.malariae,
so it is advised that in areas where P.knowlesi occurs (southeast asia),
patients who are diagnosed as being infected with P.malariae
should be treated as if they are infected with P.knowlesi,
which means they get the same intensive medication as is used for P.falciparum.
Rest of this text deals nearly exclusively with P.falciparum and P.vivax,
because these cause nearly whole disease burden,
and nearly all research data is about these too.
5.3 - Live stages of plasmodium
There are 3 main live-stages of plasmodium :
5.3.1 - Sporozoites
These are present in mosquito saliva,
from which they enter human bloodstream when mosquito bites,
are then carried through body by blood,
and when they reach liver, they enter hepatocyte cells there ('hepato cyte' = 'liver cell').
In liver cells they multiply a-sexually, and their offspring are merozoites.
In some species, sporozoites can remain dormant in livercells.
These are called 'hypnozoites', and are usually not considered to be a separate life-stage.
5.3.2 - Merozoites
These are form that infects red blood cells.
They are result of
either a-sexual reproduction of sporozoites in liver cells
or a-sexual reproduction of merozoites in red blood cells .
When a merozoite has entered an RBC, it multiplies there,
and when multiplication is complete, it destroys remains of RBC,
and then young merozoites are in bloodstream ;
Each of them bumps into an RBC, clings to it like an octopus,
and injects chemicals into it, that cause RBC to go soft,
after which merozoite pulls RBC around itself.
Merozoite is then inside RBC, yet it is not in RBC's endoplasma (cell fluid),
rather it is inside a vacuole (hollow space) inside RBC,
and wall of vacuole was previously part of outside-wall of RBC.
This protects plasmodium from immune system.
Once inside RBC, plasmodium eats amino-acids that form protein-part of hemoglobin.
It uses these amino-acids to duplicate itself, repeatedly,
after which RBC bursts and young merozoites find themselves in bloodstream.
This cycle repeats itself until human host dies
(or receives medicinal treatment, or has a very effective immune system).
Some of merozoites do not duplicate themselves ;
Instead, they discard half their genetic material, and develop into gametocytes.
(thus there is never more than one gametocyte in an invaded RBC).
It is not yet known what determines whether a merozoite will become a gametocyte.
5.3.3 - Gametocytes
These are either male or female.
They can not infect RBCs.
Their purpose is to remain in bloodstream until some mosquito sucks them up.
Once inside mosquito's gut, RBC they live in is discarded,
and they develop flagella, so they can move around ;
When they encounter a gamete of opposite sex, they merge,
small gametes ('males') being absorbed into large gametes ('females') ;
result of merger is called 'ookinete' (latin for 'dynamic egg').
These move to skin of mosquito's gut, and invade a cell there,
thus forming an 'oocyst' (latin for 'egg container').
Inside this oocyst, they multiply sexually, and their offspring are sporozoites.
5.3.4 - Sporozoites
When sporozoites are ripe, they break out of mosquito-gut-skin-cell
on side of mosquito's bloodstream.
They are then carried through mosquito's body by bloodstream,
which they leave when they reach mosquito's salivary glands.
They stay there, waiting to be injected into next human victim.
5.4 - Strains
A Plasmodium inside human body multiplies there, but does not reproduce sexually,
so it's offspring all have same genetic composistion.
Thus, unlike in humans,
a different genetic composition is not same as a different individual.
A genetic composition of plasmodium is called a plasmodium 'strain'.
5.5 - Origin of mating partner ; Can plasmodia reproduce sexually inside humans ?
An interesting question is : "Where does that opposite sex gamete come from ?".
For sexual reproduction to have desired effect of increasing genetic variation,
there should be, inside mosquito gut,
an opposite-sex gamete from another plasmodium strain.
But if that other strain had to come from another bite into another infected human,
it would mean that gamete from first bite would have to wait inside mosquito gut
until mosquito had digested all it's food and became hungry again.
However, from what i read, it seems that,
while gametes are optimized for surviving mosquito's gut,
their chances of survival are not really all that good.
And also, in many areas mosquitos barely live long enough to allow oocysts time to develop,
so waiting for a few extra days would be a bad idea in itself.
So most likely answer seems to be that
infected humans are generally infected with multiple plasmodia strains,
so that these can combine sexually in mosquito, forming many new strains,
and an infection by a mosquito would then also transmit multiple strains to victim.
I have (after some more reading) found that,
in an area of low infection-rate in french guyana,
plasmodium population was said to be 'clonal'
from which it follows that male and female gametocytes of same strain can mate,
yielding a near-identical copy of their parents.
In areas of high transmission,
humans are usually infected by more than one strain simultaneously ;
A study in Papua New Guinea reported 6.6 different strains on average per infectious bite.
An other study in PapuaNG found people infected with
all 4 species of plasmodia that are infectious to humans :
P.falciparum, P.vivax, P.ovale, and P.malariae.
So it seems that mosquitos are only needed for transmitting disease,
and would not be necessary for sexual reproduction,
as it would suffice for gametocytes to mate inside infected human.
For now, all that can be said about it is that
sexual reproduction of plasmodia inside humans has never been observed.
Perhaps once an RBC is infected (ie merozoite has pulled it around itself),
it can not subsequently be also infected by an other merozoite.
5.6 - Times and numbers (of mosquito life stages)
5.6.1 - Sporozoites
Saliva injected by mosquito when it bites can contain plasmodium sporozoites.
Salivary glands of infected mosquitos can contain 10,000 to 200,000 sporozoites,
but only few sporozoites are actually found in each drop of saliva injected.
Typically, an infective bite contains between 5-200 sporozoites.
They are injected into blood, traveling from place of infection to liver.
They probably infect liver as soon as they reach it with blood flow,
which would be in less than 1 minute.
Each sporozoite penetrates cell-walls of liver cells, settling down in one them.
Infecting liver cells is done in an unusual fashion (unusual for sporozoites) :
Normal sporozoites trick a cell to encapsulate it in a vacuole,
plasmodium sporozoites, however,
traverses multiple cells rapidly, like a bullet, rupturing cell-walls,
before settling down in one of them.
One it setteles down in is thus in a deeper layer,
so that substance on outside of it's cell-wall is same as it has on inside,
and therefore cell-wall is easily repaired.
Once settled, nucleus of sporozoite divides many times
and cytoplasmic mass grows substantially (probably feeding on contents of liver cell).
Number of nuclear divisions, and duration of this 'schizogony'
varies between plasmodium species ;
in P. falciparum it reaches a diameter of 60 µm
and contains 20,000 - 40,000 nuclei .
After nuclear divisions are completed,
cytoplasm segments are formed, resulting in individual merozoites.
This process takes a few days ; how many days depends on species :
P.falciparum is fastest with a minimum of 5.5 days.
When merozoites are thus completely formed, they break out of liver cell, into bloodstream.
One falciparum sporozoite thus produces circa 30.000 merozoites.
One infectious bite (with 100 sporozoites) would thus produce 3 million merozoites.
5.6.2 - Merozoites
From a (not very detailed) picture, i estimate diameter of merozoites to be circa 1 um .
In bloodstream, they attach to an RBC relatively fast,
but it takes them about 30 minutes before they are completely enveloped by it.
Human body has circa 2E13 red blood cells,
so at this stage, infection does not yet cause clinical symptoms.
Once inside red blood cells, merozoites eat protein-part of haemoglobin,
break them down into amino-acids, and use these to multiply themselves.
Where they derive their energy from during that time was not mentioned in anything i read.
maybe from proteins ?
Inside RBCs they multiply by a factor 8 - 20, depending on species,
P.falciparum multiplies 16- to 18-fold.
P.vivax multiplies 6- to 8-fold.
This repeated division process takes a few days :
2 days for most Plasmodium species,
3 days for P.malariae.
After division is complete, young merozoites are ready for entering blood.
At this time a group of merozoites is
inside a sac inside vacuole wall formed from host RBC's cellwall.
They release enzymes that rupture host RBC.
Remaining contents and fragments of cell wall of host RBC are thus dumped in blood,
which is not healthy, as large fragments of cell wall may clog narrow blood vessels,
and heme groups (iron in porphyrin, remnants of hemoglobin)
are allegedly "poisonous" to human body.
Fragments of cell-walls are a major cause of fever,
because inside of cell-wall is not meant to be exposed to blood,
and human immune-system treats it as wall of some unknown kind of infectious cell.
After a short while, probably when remnants of destroyed RBC have become dilute enough,
protective sac is also discarded, and individual merozoites are in blood,
attaching to first RBC they bump into.
This makes me wonder how they avoid all attaching to same RBC.
As merozoites are circa 1/8th of diameter of RBCs,
this means that at this stage, RBCs infected by P.falciparum can not be flat,
but must be globe-shaped to contain this many plasmodia.
With P.vivax, which multiplies by a smaller factor,
loss of shape would not be as necessary.
From a picture (of P.falciparum) :
before an RBC ruptures, it seems completely filled with plasmodia.
Merozoites produced in RBCs are same as merozoites produced in liver cells,
so these young merozoites invade new RBCs, and multiply there,
and this cycle continues, leading to an exponentially growing number of infected RBCs.
About 30 minutes later, each surviving merozoite has infected another red blood cell,
where it again multiplies, etcetera. ad infinitum.
Time between infecting a red blood cell and breaking out of it is
48 hours for vivax and ovale,
72 hours for malariae, and
fluctuates around 48 hours for falciparum.
5.6.3 - Gametocytes
Some of merozoites' offspring formed in red blood cells, are gametocytes.
A Gametocyte is circa as big as an RBC, and banana-shaped.
I know very little about them.
How many of them there are, and what their chances are to be ingested by a mosquito
are discussed in paragraphs furtheron.
Some merozoites, after infecting an RBC, develop into gametocytes.
Some gametocytes are taken up by mosquitos feeding on blood of human host.
5.6.4 - Development inside Mosquito
When mosquito ingests blood from an infected human,
it ingests infected RBCs, merozoites and gametocytes with it.
I presume merozoites or unripe gametocytes (in an infected RBC)
find themselves in an environment that they can not handle, and die.
Gametocytes, however, are made for this environment, and survive it.
Gametocytes mate in mosquito gut.
Each male/female mating result bores through wall of gut,
and become encapsulated in a cyst called 'oocyst'.
Inside that cyst, cell divides repeatedly
(i don't know whether this is done by repeated division into independent cells,
or by multiple division of nucleus followed by formation of cellwalls,
like sporozoites do),
ultimately forming circa 1000 sporozoites, which are then released from sporocyst.
This takes 5 - 7 days for plasmodium falciparum (depends on temperature ?).
Sporozoites then travel to salivary glands (via mosquito's blood stream ?).
How long they can remain alive there is not known,
but is probably not very important,
as new gametocytes would be taken up at every bloodmeal,
so if they survived 3 days it would already be enough for continuous infectivity.
Time from ingestion of gametocytes to sporozoites present in saliva depends on temperature ;
one source says 10 - 18 days,
CDC's site says 9 - 21 days @ 25 oC, (for P.falciparum)
Models of transmission rate use 'degree-days'
and assuming plasmodium's metabolims is speeded up by temperature
just like anopheles's metabolism is,
ie assuming 14 oC as temperature of no activity,
development would take 100 - 232 degreedays.
Furthermore, it is reported that
development of gametocytes into sporozoites needs a minimum temperature,
which depends on plasmodium species :
15 oC for P.vivax, and
20 oC for P.falciparum.
This helps explain that falciparum, while being much more active and versatile,
is not dominant plasmodium species in many areas.
5.6.5 - Maturation time inside mosquito Restrains Survivability of plasmodia
Gametocytes need days to develop into infectious sporozoites,
and Anopheles do not live very long ;
As a result, only part of Anopheles are infectious,
even if they already have oocysts in their stomach-wall.
For a numeric example, see section 'Epidemic'.
5.7 - Effect of plasmodium on mosquito
Apparently a mosquito does not get ill from plasmodia it carries.
This is probably because Plasmodia do not keep multiplying inside mosquito.
Having plasmodia in it's salivary glands causes blood-meals to be taken in multiple bites,
presumably because human detects plasmodia being injected.
Mosquito does reduce number of plasmodia that enter with bite ;
there are several 10,000 in salivary glands, but only circa 100 are injected with saliva.
Infected mosquitos' immune system responds to presence of plasmodia in mosquito blood
by producing nitrogen-monoxide, which is poisonous to many micro-organisms.
None of investigations i read about found that
presence of plasmodia significantly shortened mosquito lifetime.
5.8 - Response of human immune system to plasmodia
When a human is bitten, sporozoites are injected, and travel to liver, where they settle.
Time to mature in liver cells usually lies between 7 and 30 days, depending on species,
shorter periods being more usual with P.falciparum,
and longer ones with P.malariae.
Other reports say incubation period for falciparum is 5.5 or 6 days.
For vivax and ovale it is probably 10-14 days.
During this time, in an individual without immunity,
immune-system is not aware that anything is wrong.
In immune people in endemic areas, detection of sporozoites may have led to some preparations,
but i know practically nothing about this.
When merozoites break out of liver cells, and invade RBCs,
and destroy them, and dump remnants in blood, their effect becomes noticed by immune-system.
As number of RBCs that burst increases, immune system starts reacting.
Number of plasmodium sporozoites per infectious bite is reported to be
by one source : between 1 and 100 ,
by another : between 5 and 200 .
If a human is infected by 1 falciparum sporozoite :
| day | event | number of merozoites |
|---|
| 0 | infection by 1 sporozoite | 0 |
| 6 | break out of liver cell | 3.0E4 |
| 8 | has multiplied in RBCs | 5.4E5 |
| 10 | has multiplied in RBCs | 1.0E7 |
| 12 | has multiplied in RBCs | 1.8E8 |
| 14 | has multiplied in RBCs | 3.2E9 |
| 16 | has multiplied in RBCs | 5.7E10 |
| 18 | has multiplied in RBCs | 1.0E12 |
| 20 | has multiplied in RBCs | 1.8E13 |
A human only has 2E13 RBCs, so by this time (s)he would be dead.
Some people do die from their first infection.
If they were infected by 1 sporozoite , this would happen 20 days after getting infected.
If they were infected by 10 sporozoites, this would happen 18 days after getting infected.
If they were infected by 180 sporozoites, this would happen 16 days after getting infected.
In most cases, human immune system prevents this.
5.8.1 - Incubation Time
First reaction of immune system is fever.
Cells of immune system (free floating in blood)
detect fragments of RBC cell-walls and heme-groups in blood,
which they consider to be material foreign to human body,
so they release chemicals (called cytokines) that produce fever.
Amount of fever produced depends on amount of cytokines released,
which depends on amount of destructed RBCs ;
Fever starts having an effect when
it produces a significant increase in temperature and heartbeat.
When this happens, it is apparent from outside of human, as a clinical symptom.
It is reported that time between infection and first clinical symptoms (called incubation time)
is between 10 and 14 days for P.falciparum.
As shown above, this would depend on number of sporozoites in infectious bite.
There may however be more than one infectious bite
in first night that human is exposed to mosquitos ;
In an area where malaria-transmission is extremely intense,
it was reported that natives get up to 60 bites per night
(usually only a fraction of these are infectious),
so it is quite possible to get more than 180 sporozoites in one night.
Entire range of incubation times can be explained by number of sporozoites.
Thus maximum incubation time (14 days)
would apply for infection with few sporozoites (between 1 and 15),
which means that fever becomes apparent when there are circa 1E10 merozoites,
ie 0.1 % of RBCs is infected, and 0.01 % of RBCs have recently burst.
It has been found in practice that generally at first fever
fraction of infected RBCs is circa 1 % .
It could be that figures given above only apply to
people that have absolutely no immunity against malaria.
If numbers given above are usable,
then incubation time for other plasmodium species would be considerably longer,
as their multiplication factor in RBCs is lower (typically 12 for P.vivax).
5.8.2 - A note about fever
Fever means that temperature set-point of body is raised.
This first causes a feeling of chillyness,
as body registers that it's temperature is lower than setpoint.
In response to that, body heats up, until it's temperature reaches new setpoint.
As temperature rises, heart-rate rises with it,
at a rate of 10 extra beats per minute for every degree centigrade rise in temperature.
Presumably intended effects of this are that
increased heat makes life difficult for cells of human body
(infecting organisms are not bound to human temperatures), and
increased heartbeat makes blood flow through spleen more often,
where there are a lot of immune-system cells.
Raised temperatures will hasten destruction of all red blood cells
but old or diseased ones, who are less strong, would die first.
Amount of fever produced depends on amount of cytokines released,
and so is proportional to amount of infected RBCs in blood.
I read that, with malaria, first noticeable fever occurs when
circa 1 % of RBCs has been infected.
Malaria tends to produce repetitive fevers, every 2 or 3 days.
Thus it is practically certain that in falciparum malaria,
fever after first noticable one will be at least 18 times as severe as first one.
Many deaths occur at time of second fever.
Fever is effective in killing infected RBCs,
as is demonstrated by ability of young malaria-infected children to survive.
Young children between 2-months-old and 2-years-old do not have immunity against malaria,
and falciparum can avoid most of body's other defenses,
so fever is only mechanism that reduces number of infected RBCs.
This means that a malaria fever 'attack' kills at least 17/18th of all infected RBCs,
thus limiting ultimate fraction of RBCs that is infected.
As number of infected RBCs gets lower,
fever subsides, and a smaller fraction of infected RBCs get killed,
so effect of fever is to limit infection, but not to eradicate it.
5.8.3 - Activation of Spleen
RBCs are normally destroyed in spleen (when they have become old),
and spleen is organ that takes care of recycling their components.
I did not come across any data about this in my 2-week search of malaria data,
but i assume that
increased occurence of RBC cell-wall fragments in blood (flowing through spleen)
increases spleen's activity, to clear these from blood.
Also, it may be that cytokines increase spleen activity,
as fever is reaction to infection of blood,
and spleen is important for clearing blood of infected RBCs.
More directly, when merozoites in RBC are nearly ripe,
their combined volume is so large that it makes RBC swell up to a globe shape,
which causes it to no longer be able to
pass through physical filter constituded by spleen blood-vessels,
so spleen starts destroying that RBC,
which would obviously increase activity of spleen if it happened a lot.
As fever comes with increased heart rate, blood flow through spleen increases with it,
which would make it catch more diseased RBCs.
It is known that in acute malaria, spleen is often enlarged,
to a volume that is up to 4 times it's normal volume.
Spleen is located in lower portion of rib cage,
and an enlarged spleen can easily be felt.
This causes an increased risk of rupture of spleen,
so if malaria has been cured by medicines but spleen is still enlarged,
additional bedrest is advisable.
One report had it that it took 4 days for spleen to return to a normal volume again.
In animals (eg dogs and horses) spleen acts as a reservoir of red blood cells,
which are dumped into bloodstream at times of stress,
yielding a higher oxygen transport capacity.
In humans this is much less pronounced.
5.8.4 - Role of Liver
Heme groups (iron in porphyrin rings) that form centre of hemoglobin
are not recycled when an RBC is destroyed.
(Therefore humans need small amounts of iron in their diet).
Instead they are somehow collected by liver,
which excretes them (as 'bilirubin') in bile into stomach.
Further than that, liver does not seem to do anything.
Liver can be severely affected by malaria, but it may be that
this is just caused by sporozoite infection and clogging of blood vessels.
5.8.5 - Production of Antibodies
Cells of immune system that release cytokines when they encounter foreign cells
also do something else :
they remember (part of) chemical composition of infecting cell's cell wall.
Animal cells are all roughly built same way,
but which exact proteins they have in their cell-walls differs per species and per body-tissue.
A common type of proteins of cell-wall are glyco-proteins ;
These consist of a protein stem with sugar molecule(s) at end of it ;
Probable reason for having them is that sugar group relatively strongly attracts water,
so a cell with a lot of glyco-proteins gets a slimy layer of weakly-bound water around it.
Which exact protein part and which exact sugar part are used for this
does not make much of a difference, and varies per type of cell.
Immune-system cells, when encountering an other cell,
check composition of it's glyco-proteins
by matching it against shapes and electric charges of proteins on their own cell wall ;
If they match like normal human glyco-proteins, immune-sysem cell does nothing.
If they match some other pattern, they are recognized as foreign,
upon which immune-cell releases cytokines, and remembers patterns it detected ;
It then no longer checks any further cells,
but stays like this until it reaches an area where macrophages are produced
(macrophages are big cells that can eat other cells by completely ingesting them),
such as spleen.
There it causes production of a new generation of macrophages
that only eat cells whose glyco-proteins match like those of detected foreign cell.
Result is that body can selectively attack these cells,
so that this attack does not attack cells of body,
and therefore this attack can be much more intense and effective.
Disadvantage is that it takes time to form new generation of macrophages ;
3 days is apparently a typical time for that.
For most infections, usually caused by bacteria,
this suffices to completely eradicate them from body,
so that you would experience a bit of fever, and a few days later you would be better again.
Plasmodium, a protozoan that is 6 times more complex than a bacterium,
has found a way around this immune mechanism,
so that you would experience a bit of fever, and a few days later you could be dead.
This is reason that first symptoms of malaria look a lot like common flu.
When infection has been eradicated, these macrophage antibodies would no longer be needed.
Body keeps them around for a while (i don't know exactly how long)
because it is more likely that next infection would be by same species of infecting cell
than with a random other one.
As long as antibodies specific against this infector keep being usefull,
they keep being produced.
A while after they are no longer active because there is nothing for them to do,
they are no longer produced.
At that time, body does not completely forget about infectors they were targeted at,
as it retains capability to start producing such macrophages rapidly,
ie: it would take a lot less than 3 days (i don't know how long)
to have production up to maximum level.
Over longer periods of time (can be many years),
when this rapid-production capability has not been used,
then body no longer uses resources for it, and forgets it.
Thus immunity against an infecting species is high after an infection,
and gradually becomes less over time.
5.9 - Plasmodium's countermeasures against human immune system
Each of body's defenses mentioned above
would cause RBC to be disassembled, which merozoites would not survive.
What Falciparum, does to avoid this has already largely been found out ;
there is less knowledge about what other plasmodium species do against it.
Known avoidance mechansims are :
1) Enveloping itself (against anti-bodies) :
As long as a merozoite is enveloped by an RBC,
merozoite cell-wall is not exposed to blood, so antibodies can not harm it.
When merozoites have eaten all of hemoglobin of RBC they have infected,
they have no other choice than leaving it and entering bloodstream to find an other one ;
during that time they are vulnerable.
This causes a factor (48hours/30minutes =) 96 reduction in effectiveness of immune response.
2) Synchronization (against fever) :
A merozoite that is attached to a healthy RBC, is relatively safe from fever,
as that RBC has a good chance of surviving fever.
Likewise, a merozoite that has just enveloped itself in an RBC is relatively safe from fever,
as it has not yet damaged that RBC very much, so that RBC is nearly as good as a healthy one.
Main fever triggers when merozoites leave an RBC, dumping toxic waste into bloodstream.
If merozoites left RBCs randomly, there would continually be a fever,
causing many merozoites that were nearly ready to leave their used-up RBCs to die.
Instead, and maybe even caused by fever itself,
all merozoites tend to leave their RBCs at same time,
and thus infect next RBC at same time,
so they all have same time between infecting and RBC and leaving it again.
There is ofcourse some spread-out in this time between individual infected RBCs ;
To which extent this manifests itself would depend on
amount of stress that fever posed to merozoite population,
as merozoites that are more out of sync are more affected by fever.
P.falciparum shows least synchronicity, as it has more avoidance mechanisms than other species,
and rest of plasmodia show very clear 2-day or 3-day (for P.malariae)
periods between fevers.
So at time merozoites emerge, and attach to next RBC, fever has not started yet,
and by the time they emerge from these RBCs again, fever has subsided.
3) Synchronization with mosquitos (against all human defenses) :
Fact that these periods are whole numbers of days is not a coincidence.
It has been found that plasmodia has some (yet unknown) way of
synchronizing itself with it's human host,
such that emerging from RBCs occurs much more frequently at night than in daytime.
This activity was measured in a patient that was
awake at night in a room with lights on, and sleeping in daytime in a darkened room,
which revealed that plasmodia became active when that person experienced 'evening',
ie when it was really mid-morning.
This is thought to serve purpose of
maximizing chance for gametocytes to be sucked up by mosquitos,
as mosquitos are mainly active when it is dark.
4) Stickyness (against destruction in spleen) :
This is a mechanism that only P.falciparum has.
It's merozoites inject proteins into host RBC, which then become part of host RBC's cell wall.
These proteins make RBC stick to other RBCs and to walls of blood vessels.
Then this RBC no longer flows with blood, so does not pass through spleen.
(It makes me wonder whether P.falciparum injects duffy-like proteins into RBC
to subsequently use them to enter cell.)
These sticky RBCs can form clumps that block small blood vessels,
which is main cause of death of falciparum infections,
because result is that many small vessels of brain, lungs, kidney, and heart become blocked,
leading to loss of function of these organs, which often causes death.
Infected RBCs in blocked blood vessels are relatively isolated from immune-system,
but their neighbourhood doesn't receive oxygen anymore ;
resulting chances of merozoites to survive i don't know.
Majority of infected RBCs, these that are not part of a clump that completely blocks bloodflow,
are still exposed to cells of immune-system in blood flowing past them.
Due to these infected RBCs now having sticky substances on their outside,
immune system can recognize that they are different.
Recent research in india found that stickiness only results if there is fever
They also identified surface-protein that causes it. (called PfEMP-1).
This may explain why malaria patients often deteriorate significantly at fever stage.
This discovery has also caused interest in
use of anti-fever medicines against acute falciparum malaria.
5) Release of immuno-suppressants (against immune-system) :
Falciparum releases chemicals into blood that are
same as human body uses to down-regulate activity of it's immune system.
This reduces acitvity of immune-system, but does not stop it.
I have no info about details of this, so i will mention some general features.
Usually, when body regulates some function,
it does this by changing production levels of two hormones,
one that inhibits that function, and one that activates that function.
Resulting level of that function is then determined by ratio of these hormones.
Such regulations are usually adaptive, meaning that
body monitors effect of regulation,
and adjusts production of hormones until desired effect is reached.
Body's adaptive regulations are usually of proportional type,
without integrating or differentiating component,
and loop-gain is usually at least a few dozen,
so that in final situation deviation from intended is a few percent at most.
All adaptive regulations have some slowness,
caused by need to first measure and then adjust, both of which take time.
Thus release of immuno-suppressants by plasmodia
would cause an initial reduction in immune-system activity,
that would be detected by body,
which would change it's own hormone-output to compensate for it.
That compensation would be effective,
but would take some time to be established,
during which time attack on plasmodium is less intense.
Advantage for plasmodium is apparently big enough to make releasing suppressant worthwhile.
I guess it also has another important consequence.
It was observed that a large part of mortality of falciparum malaria occurs
at time of peak fever (ie most active immune-response).
This is no doubt connected to fever causing stickyness.
However, this mortality occurs much less often in cases where a victim is infected with
both P.falciparum and P.vivax (as found in Vanuatu), or
both P.falciparum and P.malariae.
So it might be that mortality is partly caused by an overshoot in immune-system regulation :
when body succeeds in ridding itself of falciparum,
this causes a drastic reduction in release of immuno-suppressants by falciparum,
which would cause a drastic increase in activity of immune-system
beyond level that body's regulation deems optimal for acute infection.
If there is also a vivax infection, then vivax would continue to emit immuno-suppressants,
and overshoot would not happen.
But this is just a guess.
6) Clonal variation (against immune-system macrophages) :
Sooner or later an infected RBC bumps into a cell of immune system known as 'T' cell ;
'T' cells recognise that RBC as diseased,
and remember which glycoproteins they have on outside,
and pass this on, to cause creation of macrophages that eat cells that have this glycoprotein.
It takes a while (a couple of days) for those macrophages to mature,
and in meantime RBC whose glycoproteins were detected has already been used up,
and merozoites have infected next RBC.
Result of a-sexual multiplication of a merozoite inside RBCs are young merozoites,
but they are not quite clones of their parent (at least not in P.falciparum),
because falciparum has a variable portion in it's genes,
so that offspring has same genes, but which portion of it will be used is somewhat random.
This variable gene determines which glycoprotein will be put on outside of cell.
One study found that 2% of merozoites had different glycoproteins than their parent.
Importance of this is that
when human immune system has made antibodies to glycoproteins of infecting plasmodium,
which are therefore also effective against their cloned offspring,
2% of young merozoites would survive
(unless body would also have antibodies against that other glycoprotein ofcourse).
This explains why in endemic areas
children are subjected to repe |