Malaria

Who was Elijah Boardman?

- a soldier that got vivax malaria and relapsed a few times -he returned to connecticut, married, and built a mension -2 dams near his house (1796)-10 inches, 50 acres behind his house -a. quadramculatus moves in -wife and son die -1799-boardman led a mop to dam and tore it down

how many diploid sporozoites are injected by the mosquito?

-15-200, which is the amount it takes to cause disease

Galen of Pergamon

-150 CE four humor theory-need a balance of blood, black bile, yellow bile, and phlegm in order to prevent disease -bleeding and purging to create balance -lived with 1500 years of this

Who was John Snow?

-1850s -an epidemiologist that made up map of cholera in community water (pump near cesspit where diaper fell) -ended london cholera epidemic -didnt believe in miasmatic theory

What was the germ theory of diseases?

-1850s -new microscopy -italian science focused on malaria -1870-corrado tommasi-crudeli and edwin kleps identify rods in campagna, which causes fever when injected into rabbits -bacillus malariae claimed as causative agent

Who was Alphonse Laveran?

-1880 -awarded nobel prize in 1907 in recognition for discovering malaria parasite and overall work on protozoa -because slides in chemicals obscures malaria, he looked at fresh blood -one day he stepped away for 15 minutes, saw live exflagellation stage -cooling of blood tricked plasmodium into thinking it was in a mosquito and tried to reproduce sexually -convinced pasteur when invited to his laboratory

Who was George Miller Sternberg?

-1881 -army surgeon in mississippi -father of american bacteriology -survived yellow fever and typhoid -fails to duplicate klebs & tommas b malariae results -fevers he tested in rabits didnt look like malaria -injected his spit in malaria and got fevers -either spit or b malariae causes malaria, or malaria germ doesn't exist

Who was Patric Manson?

-1894-identifies vector for filarial worm infection (not by biting) -filarial patients were not contagious... so worms had another mode for transmission -virgin mosquitos feeding on filarial patients=filaria found in mosquito -was half correct because had poor knowledge of mosquito ecology (thought took 1 blood meal then laid eggs in water and died; if only 1 blood meal, can't be transmitted by biting'; dead mosquitos contaminate water) -came up with mosquito water, which was understandable bc of other water diseases like cholera and typhoid -problem with theory is that plasmodium are too fragile to live outside a body and multiple studies feeding on swamp water failed to produce malaria -pointed out that transmission does not require eradication

Who was Sir Ronald Ross?

-1898 -manson's protege; asked him to prove mosquito water -can't find people to drink water and give blood -ignores mosquito ecology, can't get mosquito to bite and uses wrong species -called indian malaria victims people love filth and more near a monkey -finally discovered anopheles mosquito and tested on virgin birds and mosquitos (Saw transmission) -grassi and bignami get first credit (indian medical service totally ignore's ross's findings) -campaigns with ross to get 1902 nobel prize, but turned out ugly

What did American Leo Howard note?

-1920s-many more species than supposed and with infinite variations

When was P. Knowlesi Discovered?

-1965 -causes endemic -transmission from monkeys to humans -hard to distinguish from malarie but causes severe malaria -

What progress has been made in reducing malaria burden in 2010-2015?

-21% decrease in global incidence -29% decrease in global mortality but still, a lot of cases and deaths

Why did Scotland lose their independence?

-2500 chip in to darien scheme and sail to panama-inspired by a pirate's journal-panama colony and road across isthmus -were wracked by malaria by caribbean route to colony -few hundred survive, but became bankrupted and england paid their depts

How did plasmodium revive in africa?

-2500 years ago, formation of sahara desert and bantu migration -bantu cut jungle for farming -forest floor replaced with pools -no domestic animals to tempt mosquitos away -deforestation led to increase of chimps and birds (malaria preys) -mosquito colonize sunny, fish larvae free puddles, giving rise to anopheles gambiae

Bantu Take Over

-2500 yrs ago-sahara starts drying up and bantu farmers move south and reach south africa by 300 CE -cut down jungles, creating more mosquito habitats (A. gambiae arises) -bantu villages get constant exposure --> sickle cell trait develops against falciparum--> innate immunity high population density-->stable transmission-->continuous exposure-->acquired falciparum immunity

who was the first malariologist?

-400 BCE-hippocrates -describes fever patterns (quartan, tertian, quotidian) -notes swollen spleens -relates infection to season and swamps

sickle-cell mutation

-4000 years ago -homozygous-death -heterozygous-rbc destruction=increased o2=sickling; reduced cell invasion -found in 40% of africa, south asia and middle east

Fall of Rome

-5th century falciparum endemic -lugnano graves (buried with dogs?) -mal aria -rome became known as a dark area (florence nightengale)-valley of the shadow of death-1847 -1740-horace walpole-horrid thing called malaria that comes to rome every summer and kills one -dante allegheri died

What was the italian job?

-Amico Bignami considers Malaria victims informed about malaria than medical men -visits victims and talks to people about things they do to prevent malaria (close windows, don't go out at night, protective clothing) -giovanni grassi joins bignami and describes distribution of mosquitos, describes different malaria in owls and sparrows, and was thus convinced of a mosquito vector

Who was Domenico Falleroni?

-Collects mosquito eggs for a hobby -noted two different eggs

What is the dominant vector in colonial new england?

-a. punctipennis -likes shaded runing waters -prefers animals over humans -bad falciparum vector -when people started to realize they can build dams for power, it changed shaded brooks to sunny marches; a. quadramaculatus was the new dominant form (moved from southern colonies where it was prime to north)

What is hyperreactive malarial splenomegaly?

-also called tropical splenomegaly syndrome -doesn't occur frequently -abnormal immune response to repeated malarial infections -enlarged spleen and liver, abnormal immunologic findings, anemia, and a susceptibility to other infections (such as skin or resp)

Malaria's arrival in the new world

-americas malaria free before europeans -nathaniel powell-contracted in west indies and arrived to jamestown colony in chesapeake bay in 1607-a mosquito area -vulnerable native american population; habitat in millions of acres of swamp, bog and marsh that were malaria free -rapid endemic -north and south america connected=unbroken transmission zone

Before Bantu dominate africa..

-before, sub-saharan africa was colder and dominated by hunter-gatherers -nomadic lifestyle across dry grasslands; irregular exposure, no innate immunity -low population = less chance for malaria to jump = no acquired immunity -cold temp hinders malarial life cycle (<68=2-4 weeks for replication) -forests have less mosquito habitat

fever patterns and malaria

-benign tertian (vivax, ovale) -malignant tertian (falciparum) -quartan (evours)-malariery 3 days/72 hae -quotidian-every 24 hrs-knowlesi

plasmodium knowleski

-causes malaria in long tailed macaques (macaca fasicularis)-zoonosis that can jump to humans -mainly in south east asia (70% of cases) -transmitted by several anopheles -used as pyretic treatment for neurosyphillis (1930-1955) -cycles in 24hrs in blood -forest workers are at greatest risk

what was the miasmatic theory?

-china, india, europe-unhealthy fog from decaying vegetation, animal remains and stagnant water -more dangerous in hot climates (which fits some observations of malaria); also worse near swamps so draining swams helps -led to sanitary forms which protected against many diseases, but not because of miasmass

what were the early theories for malaria?

-china-3 demons-water, hammer and stove -babylon-nergal-god of pestilence and destruction -800 BCE-indian-mosquito bites cause disease

What are Malarial fever paroxysm?

-classic presentation of fever paroxysm is rare early on -due to multiple broods erupting RBC at different times -more likely to occur in synchronous infections -shivering-->fever-->sweating -tertian (mild or severe) or quartan (mild) -associated with synchrony of merozoite release -falciparum may not exhibit classic paroxysms

New England

-cold weather, less marshy, poor farmland, poor vectors, land travel, better relationship with natives = 60 year life expectancy

what has been the legacy of malaria research so far?

-ego driven, non-collaborative -single bullet (hackett) solution still sought despite its futility -funded centers are far from endemic areas -key research and observational evidence ignored

what is the definition of fever?

-elevated body temp (>37.8 orally or >38.2 rectally) -or above known normal value -body's thermostat/set-point reset at a higher temperature -

plasmodium falciparum

-emerged 4,000 year ago -50% of malaria today -variable expression of surface antigens -infects 80x more than vivax -rapid blood cycle (24hrs) -sequester RBC (infected rbc stick to vessel wall and avoid slaughter in spleen; causes small vessel occlusion and end organ damage) -heterozygous for sickle cell = 90% reduction in death; constant exposure-partial immunity (<6 months)

What are the three parts of malaria life cycle?

-exo-erythyroyctic cycle (human) -erythrocytic (human) -sporogenic (mosquito)

How was Africa protected by malaria?

-falciparum repels european invaders (no immunity in europeans) -50% mortality after first year arriving; choose to settle in australia

How did the building of dams affect people?

-favored a new vector for falciparum (quadramaculatus) -50% of power was water power by 1800 -mass complaint because association with malaria; mill acts protect mill owners and liability -not until after civil war when coal replace water did dams wane; 1919-6% power was water -maps showing decrease of water power (1882-->1912-->1932-->1934(slight increase?))

Exo-Erthyrocytic Schizogony Cycle

-feeding mosquito injects sporozoites -sporozoites are teh infective, motile form that are in salivary glands of a mosquito -if body finds them, will attack -if they make it to liver, can undergo asexual reproduction (schizogony) in liver cells (hepatocyte invasion) and form merozoites (1000-10,000) -liver cells rupture, and merozoites enter blood stream to attack RBC -in vivax and ovale, hypnozoites are formed and can remain dormant for weeks to years

anopheles gambiae **

-feeds almost exclusively on humans -adapted for human habitations -became most reliable vector

malaria antiquity/first definitions

-fevers -india western medicine-hippocrates, varo medieval-mal air

Who first described fever as the disease?

-galen-1st century -caused by yellow fever, blackwater fever, fever of unknown origin

erythrocytic cycle schizogony

-haploid merozoites invade RBC (60 sec) via surface proteins and merozoite ligands (vivax only recognize duffy antigens, while falciparum recognizes many; more surface proteins make it harder to develop immuntiy) -RBC membrane used to create a parasitophorous vacuole -eat hemoglobin, while iron sequestered as pigment (hemozoin) -old rbc membrane becomes permeable for nutrient absorption and waste excretion -8-32 fresh merozoites made, which infect more RBC -some are not made into fresh merozoites, but made into haploid male and female gametocytes

plasmodium ovale

-has 2 identical subspecies (wallikeri and curtesi) -similar (almost indistinguishable) to vivax, but can infect duffy-less cells -replicated in 49 hours in blood -treatment is same for vivax

what does it mean when Malaria survive in two hosts?

-in salivary glands of mosquitos and inside human bloodstream/liver -known and unknown proteins for this

What are symptoms of uncomplicated malaria?

-initially flu like symptoms (non specific) -headache, lassitude, fatigue, fevere, shivering, arthralgia (joint stiffness), vomiting, malaise -abdominal pain, muscle, joint discomfort signs: anemia perspiration, mild jaundice, splenomegaly, hepatomegaly, increased respirations, diarrhea/vomiting

Who discovered different mosquitos?

-italian scientisits and rockefeller-identical looking mosquito is actually 5 different ones

evolution of malaria **need to know ancestry?

-malaria are successful across a wide range of habitats and solutions -found in all continents but antarctica -probably jumped from great apes to humans -most genus of mosquitos transfers it

What are the 5 species of malaria that infect humans?

-malariae (ancestral, mild), vivax (rarely fatal), ovale (rarely fatal), falciparum (most maligant), knowlesi(primate species infecting humans; severe illness; looks like malariae).

Slavery and Malaria

-malarial death in new world creates labor shortage (80% of carolinians die before 20) -african slaves had duffy antigen, sickle cell..seasoned -rationalized a racist outlook-1937 lewis hackett-lower animals who can withstand malaria

sporogenic cycle

-male and female gametocytes picked up by mosquito in a blood meal -mature in mosquito gut; fuse to form ookinetes (fertilized motile zygote) -ookinetes form new sporozoites, and migrate to salivary gland to enter new host

Erythrocytic Cycle

-merozoites attach to and invated RBS -undergo asexual rep inside RBC (blood schizogony); 8-24 new infective merozoites formed, RBC rupture, and new infective cycle begins -some merozoites form immature gametocytes and wait for feeding mosquito to pick them up

southern colonies

-more marsh, warm weathers, more farmland, good vectors, water travel, worse relationship with natives=choosing malarious places to live = 40 year life expectancy

What are some malaria initiatives today?

-most research in non malaria areas -london school of medicine (founded by Manson) -rockefeller foundation funds harvard (HMI) and John Hopkins -little will to set up a mulit-disciplinary driven investigations

How were the spanish in Panama affected by malaria?

-native slaves died from smallpox and other diseases, so important african slaves w falciparum -by 1500s, malaria became an endemic -escaped slaves lived in kuna -1596-sir francis drake dies of fever in portobelo

Sporozoite migration and mobility in exo-erythrocytic cycle

-need to get through skin then liver 1) glide-have external adhesins used for traction on surfaces 2) active transocytosis (penetrate cell membrane through chemical disruption; heals afterwards) 3) form a parasitophorous vacuole and glide and develop within it -migrate through several liver cells before setting into one -host factors from breached cells finalize invasion -passes through about once cell/minute -finally form parasitophorous vacuole in hepatocyte

Nomad immunity**

-non immune nomads encountering bantu village -few survivals pushed to edges of continent, where land is undesirable for farming today: khoisan, pygmy, cushite, mande

what is hyperthermia?

-not a fever; not a set point change -elevated temperature-ex-heatstroke

What is the classical definition of malaria?

-periodic bouts of fever, chills, muscle pain, chronic debilitation -paroxysm of fever occurs every 2-3 days, with feeling well in between episodes -associated with enlarged spleen, pallor and jaundice

ancient rome

-pontine marshes and campagna -unused farmland -regular exposed marshes-->partial immunity, so invaders died -a. atroparvus-attack mosquitos (good vivax vector, bad falciparum) -bad air theory incorrect -house structure -abracadabra -forests cut down, marshes formed and anopheles labranchia from north africa colonizes (good falciparum vector) -stable transmission interrupted-->loss of immunity and massive falciparum endemic

plasmodium malariae

-precedes crowd diseases (measles, smallpox, and cholera) by hundred thousands of years -has the longest incubation period -no hypnozoite stage -preys on old, aging rbcs -can have a prolonged asymptomatic erythrocytic stage (up to 70 years)-->symptomatic years later -mates and develops slowly in mosquitos: >68-2 weeks; <68-4+weeks -uncertain transmission cycle (risk of extinction)

What are symptoms of severe malaria?

-severe anemia and malaise -acute kidney failure -acute respiratory distress syndrome -pulmonary edema -hypoglycemia -metabolic acidoses/acidemia -hyperparasitemia -extreme weakness -circulatory collapse -cerebral malaria (impaired consciousness/coma, seizures, neurologic manifestations), enlarged spleen and liver, miscarriage, low birth weights, death.

What are the classifications of fever patterns?

-sustained-higher than normal and stays around that temperature -intermittent-fever and back to normal patterns throughout a week -remittent-fever-normal-than fever higher than before, than normal (continues to rise and drop) -relapsing-on and off fever pattern, then no fever for a few days then a spike

What in our bodies specifically cause fever?

-temp determined by balance between heat production by tissues (liver and muscles) and heat loss (from the periphery) -regulatory center in hypothalamus-maintains set point is between 37-38 degrees or increases it ex: vasoconstrict-reduce heat loss -shunt peripheral blood to core (Reduce heat loss) -shiver (produce heat)

Remittent Fever

-temp is greater than normal for 24 hours -fluctuates more than 2 degrees every 24 hours, but still stays above normal -ex of diseases with this pattern: typhoid and endocarditis

sustained/continuous fever

-temp is greater than normal for more than 24 hours -doesn't fluctuate more than 1 degree for 24 hours -ex of diseases with this fever pattern: lobar pneumonia, typhoid, UTI, endocarditis, brucellosis, and typhus

Recurrent/relapsing fever

-temp is greater than normal more than 3 times in 6 months, at least 3 weeks a part, lasting few hours to few weeks -fevers separated by symptom free intervals -not from known one off cause -can also be at regular intervals -ex-periodic fever, aphthous ulcers, pharyngitis, adenopathy, borelia, epstein-barr, dental abcess, malaria

Intermittent Fever

-temp is normal except for a few hours/day or period of days -paroxysmal if rapid onset of symptoms -diseases with this fever pattern include malaria, pyemia, and septicaemia

Genome Sequencing

-to develop new anti-malarial meds -greatly speeds up resistance -may only affect one phase of lifecycle -compare to more general anti -malarial activity (quinine, artemesinin); plant-derived, diffuse acting, provoke less resistance

How many days after infection does malaria present itself?

-typically 8-40 days -depends on top of malaria or any innate or acquired immunity -may also present later if taking prophylaxis

Plasmodium Vivax

-use surface proteins (duffy antigens) to adhere to RBC and speed invasion (leading to less time exposed in blood stream) -3 days in human host -preys on young immature RBC -low mortality, but chronic infections puts communities at risk and can kill unborn -but human communities small and mobile (hunters)=no acquired immunity=ferocious epidemics -ice age=mosquitos hibernate during winter-evolved a hypnozoite stage to hide in liver to wait during winter, and reactivate during spring and fall (mech uncleaR) -5,000 years ago-african americans duffy free -but vivax escaped + other RBC disorders??

Malaria in London

-warmer temperatures after ice age -malaria emerges to mediterranean and warm southern regions of eurasia -follows land clearing for agriculture -at firt, england protected by roman technology? breeze?** -malaria takes alexander, byron, charles v, oliver cromwell, popes, and others

Review of malaria life cycle

1)transmission to human (injects sporozoites in blood meal) 2) sporozoites enter liver and infect hepatocytes; undergo mitotic replication 3) liver cells rupture and release merozoites 4) intraerythrocytic cycle-asexual and symptomatic cycle 5) sexual cycle (merozoites produces gametocytes) 6) transmission to mosquito (ingests gametocytes via bite) 7) gametocytes mate and undergo meiosis 8) migrate through gut wall and form oocytes 9) oocyte develop to sporozoites

When did measurement of body temperature begin?

1868 -carl wunderlich-introduced temperature charts in hospitals -claimed fever is a symptom

What did rockefeller scientist lewis hackett note?

1930-malaria was molded and altered by local conditions that it becomes disease and epidemiological puzzles -best method in one place might be the worst 40 miles away -local, ecologically driven malaria research is the solution..

how long do mosquitos live?

2-4 weeks

Robert Koch

??

skepticism of mosquito theory?

???

What can be damaged from a fever?

Cellular function-membrane, mitochondrial DNA, stimulation of excitotoxic mechanisms, protein denaturation, cell death -local effects-cytokine stimulation, inflammatory response, vascular stasis, oedema -systemic-gut bacterial translocation

true and false: anopheles atroparvus is a good falciparum vector.

False; good vivax vector; anopheles labranchia is a good falciparum vector.

Malaria as a tweet

Infection by protozoan parasites (plasmodium) transmitted by mosquitoes. Cause fever, anemia, and death, and primarily affects the poor.

True or false: there are 100+ species of malaria (plasmodium), but there are 5 (6?) species that infect humans.

True. Some ex of species that don't infect humans are sceloporus occidentalis. Malaria can also hide in sparrows, that is why it is important to eradicate malaria in everything.

what is the timeline in the exo-erythrocytic cycle for different species?

avg 5-16 days falciparum: 5-6 vivax:8 ovale:9 malariae:13 knowlesi: 8-9

how does body set point chemically change?

by pyrogens-heat -producing substances ex: exogenous-staph aureus toxin -endogenous (IL-1, TNF-alpha, IL-6, & other cytokines): stimulate OVLT in anterior hypo (highly vascular-lacks-easily stimulated by pyrogens) --> >synthesis of prostanoids (PG)E2 --> <neuronal firing in hypo --> > body temp

Schizogony cycle in different species

knowlesi: every 24 hours falciparum, vivax and ovale: every 48 hours malariae: every 72 hours

When was fever first described?

medical literature in 6th century bC -debate on if it is a disease or symptom, or adaptive response

What is the definitive host for malaria? what is the secondary (intermediate) host for malaria?

mosquitos-definitive humans-secondary/intermediate

what is an example of innate immunity against malaria?

sickle cell disease

what are damages from malarial fever?**

uncomplicated: limited end organ damage, splenomegaly and anemia in endemic areas severe malaria: severe anemia, rupture of RBCs/sickling adhesion-->small vessel occlusion-->disseminated intravascular coagulation-->ischemic end organ damage: resp distress-pulmonary edema; still birth, low birth weight, abortion; kidney (acute chronic) liver-jaundice, hepatomegaly; splenomegaly; brain-coma, cognitive impairment, neurologic

What is a definitive host?

where parasite reaches maturity and reproduces sexually

what is a secondary host?

where parasite resides for a short period of time, in an immature form