What is malaria? a disease that causes acute fever, chills, and headaches in infected humans
Transmission Vector: Anopheles mosquito bites a human. The mosquito is infected by an Apicomplexa protozoans (parasites), specifically Plasmodium (P. falciparum, P. malariae, P. vivax & P. ovale) .Infected pregnant or breastfeeding mom can pass to baby). Less commonly spread via parenteral route (infected needles etc).
Location: Tropical and subtropical areas
Patient population: Anyone, but especially young or old, and immunocompromised populations.
How to prevent it: Take prophylactic drugs if you are traveling to a high-risk areas (parts of Africa, Asia, Latin America). Use your usual "keep the bugs away from me" methods- long shirts, bug spray, hats etc. Individuals that lack the "Duffy" antigen/ may have a polymorphism that protects their RBCs from getting infected.
Common Terminology
The life cycle includes both sexual & asexual reproduction stages via three distinct processes- sporogony, merogony & gametogeny.
Sporogony = Asexual reproduction; produces sporozoites (“spore-like cells”). This is the invasive form; invade host cells and then go through merogony
Mergonony = Asexual reproduction that produces merozoites (which have different names in different species!).There can be multiple rounds of merogony, as merozoites re invade cells and go through additional rounds of merogony. Some merozoites can go through gametogony (aka, gametogenesis, aka, gamogony).
Gametogony is a sexually reproductive stage that produces male and female gametes.This process includes formation of gamonts, then gamontocysts, which divide to form male and female gametes which then fuse to form a zygote. Genetic recombination can occur here. Zygotes then complete the cycle and go back through sporogony, (asexual process) to produce more sporozoites and thus, the cycle continues...
NOTE: Some use "merogony" and "schizogony" interchangeably, whereas others use "schizogony" to include all three processes (merogony, sporogony, and gametogony).
An extremely simplified overview of the life cycle:
The Anopheles mosquito bites a human and injects sporozoite forms.
These move to the liver and invade hepatocytes, in which they develop to produce exo-erythrocytic merozoite forms that are released into the blood stream.
Merozoites invade erythrocytes and grow into trophozoites and mature schizonts. The newly formed merozoites are released to re invade new RBCs (and this merogony cycle repeats again and again...)
Gametocytes, formed from the asexual blood stage, are taken up by a feeding mosquito into the gut where they mature to form male and female gametes. The fertilized zygote develops to an ookinete and an oocyst and finally sporozoites that migrate to the salivary glands.
Mosquito then bites and infects another human (repeating this cycle)
Now for a more detailed look into the life cycle...
WHAT HAPPENS IN THE MOSQUITO...
Note that the mosquito is not harmed by the parasite, as the human host is.
Mosquito ingests gametocytes from an infected human during a blood meal.
Gametocytes go through sporogonic cycle, give rise to gametes (gametogenesis), which fuse to produce zygotes.
Zygotes become motile and elongate, are now called ookinetes.
Ookinetes invade the mosquito midgut wall, develop into oocytes on its external surface.
Oocytes go through sporogony (asexual reproduction) to produce thousands of haploid sporozoites.
The oocytes rupture and release the sporozoites, which migrate to the mosquito's salivary glands.
The sporozoites are transferred to human host during a blood meal
WHAT HAPPENS IN THE HUMAN...
Asexual Reproduction
Remember that an infected female Anopheles mosquito bit a human host and transmitted sporozoites in its saliva (see above).
Exo-erythrocytic Phase (Liver)
Sporozoites travel to & infect liver cells within a few hours of the mosquito bite. Invasion is aided by apical complex. NOTE: P. vivax and P. ovale sporozoites can stay dormant in liver as hypozoites, but may continue the replication process (below) later.
Think HYPNOzoites = ASLEEP in the liver (P. vivax & P. ovale)
Sporozoites develop into hepatic schizonts, which contain tens of thousands of merozoites (this processes is often called "exo-erythrocytic shizogony," which is a type of merogony).
The infected hepatocytes rupture,resulting in the schizonts releasing tons of merozoites into the bloodstream (the merozoites are packaged in to help protect the parasite from the host immune system. These vesicles later release the merozoites in the pulmonary capillaries).
Erythrocytic Phase (RBC "Ring phase")
Merozoites go & infect RBCs. Be aware that different species of Plasmodia target RBC of different developmental stages.
Infect ANY/all RBCs = P. falciparum
Infect only Young RBCs = P. vivax & P. ovale (these also are the ones that can remain dormant in the liver (Hypozoites)
Infect only senescent RBCs= P. malariae
Merozoites become trophozoites which break down hemoglobin to access amino acid nutrients; the process produces malaria pigment hemozoin. Thus, the yellow/brown and black granules are indicative of blood-stage parasite form.
Some trophozoites become erythrocytic schizonts (via multiple rounds of nuclear division w/out cytokineses).
Schizonts give rise to new generations of merozoites (erythrocytic schizogony, a form of merogony). In late stage schizonts, aka, segmenters, you can see the individual merozoites. RBCs rupture and release the merozoites, which infect other RBCs.
Some parasites bypass additional rounds of merogony and enter the sexual reproduction pathway to produce gametocytes,which circulate in the blood extracellularly (and are non-pathogenic).
Clinical Correlation:
Every time the parasites break free and invade new RBCs (referred to as parasitemia), the release of antigens & waste products from the ruptured RBC causes clinical symptoms (fever) . The timing of this erythrocytic cycle varies by species of Plasmodium. This explains the cyclical timing of symptoms (i.e. the patient gets a fever every ___ hours).
Fever every 24 hours = P. knowlesi
Fever every 48 hours= P. falciparum, P. vivax, and P. ovale
Fever every 72 hours = P. malariae
Peripheral Blood Findings:
TIPS & TRICKS
P. falciparum (Malignant tertian malaria- 48 hrs):
heavy parasitemia, Infects RBCs of all ages, No RBC distortion. Ring forms (usually at edge/periphery of RBC ("applique" pattern)), Multiple ring forms per RBC , no/rare shizonts, no Schuffner's dots, May see Maurer's clefts, banana/crescent shaped gametocytes present; 48 hr fever cycle - most severe clinically. Africa.
NOTE: RBCs infected by P. falciparum trophozoites and schizonts stick to capillary endothelial cells, so they aren’t found in peripheral circulation like other Plasmodium spp are.
P. knowlesii (Quotidian malaria- 24 hrs):
normal size RBCs, band forms, no Schuffner dots; 24 hour fever cycle, severe, potentially fatal clinically (same morphology as P. malariae)
P. malariae (Quartan malaria- 72 hrs):
Infected senescent (old) RBCs are normal size/shape, Schizonts can have rosette pattern. Trophozoites appear as "bands" across RBC forms, no Schuffner's dots; 72 hour fever cycle; moderate severity (Looks exactly like P. knowlesii)
P. ovale (Benign tertian malaria- 48 hrs):
Infected immature RBCs are enlarged, distorted, oval RBCs with cytoplasmic extensions and Schuffner's dots, Multiple ring forms within a single RBC. <12 nuclei in schizonts; 48 hr fever cycle. Trophozoites are compact & may cause the RBC to have fimbrae & stippling. Dormant hypozoite form in liver (reactivation). Mild clinically
P. vivax (Benign tertian malaria- 48 hrs):
All stages seen in peripheral blood. Infected immature RBCs are large, distorted round RBCs with cytoplasmic extensions. Mature trophozoite has "amoeboid shape" & may contain Schuffer's dots on Giemsa stain. >12 nuclei in schizonts; 48 hr fever cycle; Dormant hypozoite form in liver (reactivation) . Moderate-severe clinically
References:
"The cellular and molecular basis for malaria parasite invasion of the human red blood cell".
Alan F. Cowman, Drew Berry, Jake Baum. J Cell Biol Sep 2012, 198 (6) 961-971; DOI: 10.1083/jcb.201206112
"The Next Vaccine Generation Against Malaria: Structurally Modulated Plasmodium Antigens". José Manuel Lozano Moreno. http://dx.doi.org/10.5772/65251 InTech 2016. Creative Commons Attribution License.
"Plasmodia (Malaria)"
Online lecture/tutorial. Drawittoknowit.com Accessed 3.22.19.
"Image analysis and machine learning for detecting malaria".
Poostchi, Mahdieh & Silamut, Kamolrat & Maude, Richard & Jaeger, Stefan & Thoma, George. (2018). Translational Research. 194. 10.1016/j.trsl.2017.12.004.
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