BLOOD
READ!
Circulatory system
Anatomy and physiology
animation [hhmi]
physiology
physiology2
electrical
Definitions:
- bacteremia – brief transit
- septicemia – proliferation in the blood [=sepis]
- non-cellular component = plasma, leaks into most organs
- white blood cells [wbc] can exit blood via the lymphatics.
- fluid and wbc – in lymph, go through lymph nodes
- spleen – abdominal lymphoid organ
Heart
Endocarditis – bacterial, occurs in the lining
- subacute endocarditis – commonly caused by Staphlococci, also Strep. pneumonia, Strep. viridans, and Mycobacterium. If milder than acute form called subacute. The bacteria stay in small blood clot around a defective heart valvue, this protects them from phagocytosis. “Vegetations” in clot can break off and cause distant blood vessel blockage.
- acute endocarditis – Pseudomonas, Coxiella burnetti, Strep viridans
Myocarditis – Acute Rheumatic Fever;
- Follows severe throat infections by Streptococcus, which are of specific serotypes M1,M3, and M5.
- This is of autoimmune origin. After infection approx. 3 weeks later heart prblems begin. Strep. M proteins have antibodies made to them by the immune system, this cross-reacts with the heart and damage occurs. The bacteria does not cause this part of the disease. The damage is actually caused by the immune system.
Septicemia
- Enterobacteria: G neg sepsis; includes Salmonella, E. coli, Camphylobacter. They make endotoxins, when in bloodstream induce widespread blood clotting via the systemic release of TNF-alpha .
Lymph Node Infections
spread by node travel
- caused by Francisella tularencis. Lives on rabbits, and is spread by the bite of the arthropod. This is an intracellular parasite, G negative, aerobic, rod. Can survive within the macrophage. An anti-phagocitic capsule is used for pathogenicity. It also has endotoxin activity. At the first site and ulcer can be seen. Mostly seen in OZARKS=Arkansas, Oklahoma, and Missouri.
Brucella abortus –
- in cattle, within the utters and uterus cause spontaneous abortion. G- rod. In man transit and invasion is through the skin. They are capable of surviving within the macrophage. Can cause abscesses locally or in lymph nodes.
- causes bubonic plague. Requires presence of amino acids.
- Virulence factors include:
- 1) adaptation to intracellular survival
- 2) presence of protein polysaccharide capsule.
- 3) plasmid dependent cytotoxic factors
- more specifically the virulence factors are diagrammed in this table
- Cause widespread hemorrhages. Transmitted by fleas.
- NOTE: Common route of infection by direct flea bite. Alternative route: lung via breathing feces. Hemorrhages occur within the lung this is pneumonic plague. Mortality here is high. Widespread cell death due to cytotoxic factors made by Yersinia which is dependant on the plasmid.
VIRAL INFECTIONS OF THE LYMPHATIC SYSTEM
Epstein Barr Virus
- causative agent of infectious mononucleosis
- and Burkitt’s lymphomas.
- which disease is dependant on nutritional state and the environment.
- a Herpes virus
- uses receptors to bind which has 3 names: complement C3d, CR2, CD21.
- The receptor is found on epithelial cells and B lymphocytes.
- In latent infection, the cells contain a small number of circular plasmid-like EBV genomes that replicate only during cell division. Here it makes EBNA, and shows LYDMA. The infected cell begins B cell proliferation, turns off programmed cell death pathway (apoptosis). These cells start making IL5, IL6, and IL10. EBV can make a viral mimic of IL10.
- T cells kill infected B cells.
- Cancer potential includes the epithelial cells in the pharynx–nasopharengeal carcinoma.
- If the B cells are affected it will lead to Burkitt’s lymphomas.
CYTOMEGALOVIRUS [CMV], a herpes virus
50% of adults
0.5-2.5% of newborns
causes hearing loss, mental retardation, most common cause of congenital effects,
disease prominent in immunocompromised, if cell mediated immunity is suppressed: blindness, pneumonia, meningitis, mono-like disease, hepatitis
only a human pathogen, grows in fibroblasts, lymphocytes, some bone marrow cells, latent in T cells, macrophages
transferred via blood or secretions
Virulence factors:
Avoids immunity by 2 strategies
1. stealth –infected cells lose MHC class I expression–so T cell cannot recognize them
2. decoy — infected cells put up a decoy of MHC class I-like molecules [no filled groove, no TCR recognition] BUT this molecule is sufficient to turn OFF killing by NK cells.
Malaria
Plasmodium protozoa
5 = vivax, malaria, ovale, falciparum, knowlesi
bite of mosquito–injects sporozoite
bind to liver cells, first replication in liver
merozoites burst out of cell –into blood
if stay in liver without replicating called hypnozoites [sleeping bugs]
now infect rbc, P. falciparum can infect any rbc which is why it causes the most severe infection, degrades and uses hemoglobin as its iron source, make knob protein which appear on surface of rbc, anchor deep in capillaries and prevent premature lysis of rbc
divides–ring forms–makes a cluster of “grapes” which is called a schizont
synchronous maturation of schizonts–cause burst of rbc–out into circulation, large number of cells dies and toxic metabolite cause recurring chills and fever [103-6°F]–exhaustion
merozoites reinfect rbc–cycles
merozoites of P. vivax retrun to liver cause exoerythrocytic cycle [more pathology]
causes anemia, spleen full of debris
infected rbc not as flexible, clump and sludge in small blood vessels–organ damage
sludge is most common is P. falciparum [infects more rbc], sludge in brain causes cerebral malaria, in kidney-black water fever
merozoites cannot be ingested by mosquitoes, a minority of rbc develop the sexual phases called gametocytes [male or female forms], these are picked up by mosquito [host sexual phase] and only there develop into sporozoites that can start human infection [host asexual phase] again.
Human evolution:
1. Sickle cell is only a disease in its homozygous state. Heterozygotes are more resistant to malaria
2 Some human MHC class II alleles predispose to cerebral malaria–low frequency in malaria endemic areas [Mexico, Middle East, Mediterranean, S.A, India, Africa.]
Malaria
Cases in US only 1200/yr [ but historically–Tontitown founded by folks fleeing indenture servitude in malaria prone rice fields of our delta]
World wide over
x cases [twice? US population]
with 3 million fatal cases [1.5 to 2.7 children are dying each yr]
So malaria is only a curiosity in the US but is not only one of the great killers in tropical climates but is one of the few infections that have demonstrably had effects on human evolution. Malaria is caused by plasmodium protozoa. Four distinct species: vivax, malaria, ovale, and falciparum are involved. Infection starts with the bite of an infected mosquito which injects the sporozoite stage of the organism. The sporozoites have receptors for liver cells and enter and begin their first replication inside liver cells and come up now with a different stage of their life cycle called the merozoite. In occasional cases they apparently sit inside liver cells without replicating and are graphically called hypnozoites–meaning sleeping bugs.
Once mature merozoites are formed in the liver cell, the cell bursts and merozoites come into the blood stream. These merozoites now infect P. Falciparum can infect any red blood cell and is probably why it is a more severe infection. The parasite now degrades and uses hemoglobin as an iron source. It makes and puts out so-called knob proteins in little clusters on the surface of the RBC. These help it to anchor the rbc in deep capillaries possible to avoid premature lysis of the rbc. It begins to divide through forms descriptively called the ring form until it makes a little cluster of grapes of progeny merozoites. The whole cluster is called a schizont.
More or less synchronously the mature schizonts burst infected rbc s and come out into the circulation. This means the sudden release of large quantities of cell damage and toxic parasite metabolites and these cause the regularly recurring chills and fever and inflammation of malaria. The chills are in part due to loss of rbc–our circulation keeps us warm. The merozoites reinfect rbcs and the cycle goes on. The merozoites of P vivax can actually go back to the liver and set up the so called exo-erythrocytic cycle and this is a separate headache during treatment.
Regular destruction of rbc finally causes anemia, the spleen becomes very large because it is the sink for dealing with circulating cell debris. The spleen collects this debris and gets big and is now susceptible to rupturing. In other words, the patient is one chronically sick creature.
Infected rbcs are not as flexible as they should be so they tend to clump together and sludge in small blood vessels this can cause severe damage to the organs in which they sludge. Such sludging is commoner in falciparum malaria because falciparum infects all rbcs. When it happens in the brain it causes cerebral malaria and when it happens in the kidney it is called black water fever.
Merozoites however cannot be picked up by mosquitoes and transmitted. A small minority of infect rbcs develop male or female sexual phases instead of merozoites. These are called gametocytes. If gametocytes are picked up by a biting mosquito, they will conjugate in the mosquito and only in the mosquito and develop into sporozoites that can be injected by the mosquito back into people and start infection again. Thus, the mosquito is the host for the sexual stage while man is the host for the asexual stage of the parasite.
Virulence factors
1. There is the ability of the merozoites to use the iron in the rbc
2. Knob protein: These molecules come to the surface of the rbc to anchor the rbc in the capillaries and prevent the lysis of the rbc prematurely–that is, before the merozoites are ready for release.
3. Uses PfEMP1 for two functions: to bind to endothelium of blood vessels [again preventing trauma from rupturing the rbc] and to bind host cells types called dendritic cells and their precursors [pre-DC]. DC are the best and most essential APC the body has. This binding inhibits the DC from maturing. [first shown 1999 Nature] Thus this centrally important APC is stopped from functioning and the infection is much less likely to be cleared by the immune system. It inhibits the development of other sorts of immune responses too.
There are 50+ different PfEMP var genes and they splice themselves together in different combinations–which makes immunity hard to achieve naturally or with a vaccine
Finally an explanation of how malaria has been seen to affect human evolution. Although sickle cell anemia is rated as a disease, that is true only of the homozygous state. Heterozygousity or half inheritance of the sickle cell gene appears to make people a little more resistant to malaria. This is possibly the reason why the sickle cell gene is prevalent in Africa and the Mediterranean. Similarly there is evidence that certain human MHC class II alleles predispose to cerebral malaria and these are found at extremely low frequency in the adult population of malaria endemic areas.
Influenced human evolution:
1. The cerebral form of malaria is fatal. MHC class II there is an allele amongst the Dutch that predisposes to the cerebral from. If now compare the current Dutch relatives in the Netherlands vs their Dutch descendants in Africa : find a loss of alleles that allow cerebral malaria to be a common result of infection. Missing–has reduced the frequency of this allele in the human population. Selected against.
2. HbS sickle cell
In heterozygous form 10x more resistant to the fatal forms of malaria
HbS is found worldwide in populations exposed to malaria
HbS is a val instead of glutamic acid at the 6th position of the b-globulin chain.
In homozygous form sickle cells is a disease resulting in [see flow sheet]
…..but still has benefits in terms of survival of malaria [check this!]
In two copies the sickle cell gene causes rbc to lose oxygen more readily and to warp into a sickle cell shape during periods of high activity
The sickled cells become stuck in the small blood vessels. This can present as sickle cell crisis which is pain, fever, welling and tissue damage that can cause death.
In some regions of Africa as many as 40% of the populations carries at least 1 HbS allele.
We know that in the heterozygous state that their cells sickle when infected by the malaria parasite. When the cells are sickled they are removed at a greater rate, they are culled by the spleen because of their shape. This keeps the merozoite load down.
In heterozygous form–vastly increases chances of survival A CROSS:
+/- x +/- = +/- 50% R to malaria [10x lower change of getting lethal form]
Hb/Hb -25% Sensitive to malaria
25% HbS–will get sickle cell anemia
This is a stark example of a genetic compromise, an evolutionary trade off. There is evidence that the sickle cells gene has appeared and disappeared in the populations several times but became fixed [permanently established[ when a particular lethal form of malaria jumped from animals to humans in Asia, the Middle East and Africa.
The explanation of how this all works may be more complex in HbS/HbA there are distinct age effects on protection. See protective effects in somewhat immunocompromised people –that is children and preg women–milder malaria–so other effects [influences of immune system] may further explain the reasons the Hb alleles make a difference.
recent sources see
globalhealth reporting.org
rxpgnews.com/research/infectiousdiseases/malaria
ALSO HbC –another Hb variant that helps protect against malaria but less severe consequences than HbS
3. Thalassemias cause the disordered regulation of Hb production. This lessens the number of rbc that the parasites can mature inside and lessens the severity of the disease.
4. variations in glucose6phosphate dehydrogenase: G6PD deficiency is found in 400 million people. They have ½ the risk of getting severe anemia due to malaria
There are multiple forms and “A” variant found in Africa and a “Med” variant found in the Mediterranean, Middle East and India
12,000 yrs ago there was a climatic change in the Sahara from arid wasteland to green savanna with lakes and ponds. This resulted in agriculture with much cutting of forests, communities settling by mosquito breeding grounds. Time wise also see mutations coinciding with the explorations of Greeks and Macedonians [yes, Alexander the Great]. Putting the genetics, history and archeology together–this variant allowed survival under these new conditions. So historically seems a great time for selection of this variant and its becoming fixed in the population.
5. ovalocytosis [this results in a structural protein defect that formally maintained a rbc’s shape [again better clearance of infected rbc’s–due to overall increased clearance.
6. Duffy antigen is present on the rbc surface. If one has a variant of Duffy then it protects from getting infected with P. vivax since Duffy IS the receptor for vivax.
7. HLBB allele is present in a lo freq in West Africans. As a class I molecules this is present on liver cells and not on rbc. Here there are immune mechanisms that protect against the severe anemia that are dependent on keeping the liver infection under control.
8. If have a NOS2 enzyme variant that makes 2x NO this protect carrier from extensive tissue and brain damage caused by malaria and from the severe anemia. Kenyans 75% less likely and Tanzanians 88% less likely of becoming severely ill.
NO suppresses the proliferation of parasites in liver and rbc, stops adhesion of these rbc to blood lining vessels and decrease production of cytokines that exacerbate disease. While we have emphasized that TNFa and NO can be harmful n excess, the NO is useful in malaria.
Other knowledge of interest to MechPATH
quinine is a substance from the bark of a South American rain forest tree [so early on needed world travelers to export it!] It kills malarial parasites in rbc[s] so it does alleviate the fever but it doesn’t completely destroy the parasite. This means that if quinine halted then there is relapse. The Dutch had a monopoly on the quinine trade.
DDT banned in many places. Many even environmentalists are no saying that using DDT at about 0.1% of the concentration that it was used at in the 1960s would be effective in preventing most malaria deaths and disease. Undoubtedly we will hear more!