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Does malaria have a reservoir host?

Does malaria have a reservoir host?


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Can warm blooded vertebrates other than humans act as reservoir hosts for malaria parasites? I'm mainly interested in Plasmodium vivax and possible reservoir hosts in the wider area of Europe/ Eurasia.


There are 5 species of Malaria the can infect humans, and Chimpanzees and gorillas have also been found with 5 species, including vivax and falciparum. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089193/

The parasite can go dormant in the liver for days to years, causing no symptoms and remaining undetectable in blood tests. They form what are called hypnozoites (the name derives from "sleeping organisms"), a small form that nestles inside an individual liver cell. The hypnozoites allow the parasite to survive in more temperate zones, where mosquitoes bite only part of the year.

Cows are known to carry falciparum protozoa, which has at least four reservoir species. (cows, chimps, gorillas, humans) Human with sickle cells also act as a reservoir in a different way, perhaps more or less invisible or innocuous, i haven't studied recent research, and sickle cell may also have some effect in cows and chimps and gorillas.


From Wikipedia Plasmodium spp. have a huge range of hosts, including: human, primates, mammals, reptiles and birds.

Four important points to note:

  1. The Plasmodium genus contains about 200 species.
  2. Further important to note is that P. falciparum, P. vivax, P. ovale, and P. malariae are responsible for almost all of human malaria infections, and the distribution of Plasmodium species varies between different animals.
  3. Humans are not in fact the definitive host of Plasmodium species. Vertebrate hosts simply serve as a site for the parasite to replicate asexually, and the sexual replication occurs in the mosquitoes.
  4. To act as a reservoir, the host needs to suffer a long term infection. P. vivax is one species noted for its ability to form a dormant stage in the liver, and cause relapses.

So I think it would certainly be possible for there to be other vertebrate hosts (warm blooded or not) aiding in the spread of malaria to humans, but I think it's unlikely to be occurring at an epidemiologically significant rate. I think if that did happen, we would already know about it, given the considerable study that has been done on malaria.


Biology of malaria parasites

There are several hundred species of malaria parasite (Plasmodium spp) that infect mammals, birds and a wide variety of reptiles.

We mostly use 4 species of rodent malaria parasite to test whether evolutionary and ecological theories can explain the extensive variation in the traits underlying the virulence and infectiousness of parasites.

Specifically, we study how parasites adjust traits during infections in response to changes to the in-host environment (e.g. development of anaemia, immune responses, infection genetic diversity, drugs) to maximise fitness.


Host Energy Source Is Important for Disease Tolerance to Malaria

Pathologic infections are accompanied by a collection of short-term behavioral perturbations collectively termed sickness behaviors [1, 2]. These include changes in body temperature, reduced eating and drinking, and lethargy and mimic behaviors of animals in torpor and hibernation [1, 3-6]. Sickness behaviors are important, pathogen-specific components of the host response to infection [1, 3, 7-9]. In particular, host anorexia has been shown to be beneficial or detrimental depending on the infection [7, 8]. While these studies have illuminated the effects of anorexia on infection, they consider this behavior in isolation from other behaviors and from its effects on host metabolism and energy. Here, we explored the temporal dynamics of multiple sickness behaviors and their effect on host energy and metabolism throughout infection. We used the Plasmodium chabaudi AJ murine model of malaria as it causes severe pathology from which most animals recover. We found that infected animals did become anorexic, skewing their metabolism toward fatty acid oxidation and ketosis. Metabolism of fats requires oxygen for the production of ATP. In this model, animals also suffer severe anemia, limiting their ability to carry oxygen concurrent with their switch toward fatty acid metabolism. We reasoned that the combination of anorexia and anemia would increase pressure on glycolysis as a critical energy pathway because it does not require oxygen. Treating infected mice when anorexic with the glycolytic inhibitor 2-deoxyglucose (2DG) reduced survival treating animals with glucose improved survival. Peak parasite loads were unchanged, demonstrating changes in disease tolerance. Parasite clearance was reduced with 2DG treatment, suggesting altered resistance.

Keywords: Malaria Plasmodium chabaudi anorexia disease tolerance glucose ketosis resilience.


Lesson 1: Introduction to Epidemiology

As described above, the traditional epidemiologic triad model holds that infectious diseases result from the interaction of agent, host, and environment. More specifically, transmission occurs when the agent leaves its reservoir or host through a portal of exit, is conveyed by some mode of transmission, and enters through an appropriate portal of entry to infect a susceptible host. This sequence is sometimes called the chain of infection.

Figure 1.19 Chain of Infection

Source: Centers for Disease Control and Prevention. Principles of epidemiology, 2nd ed. Atlanta: U.S. Department of Health and Human Services1992.

Reservoir

The reservoir of an infectious agent is the habitat in which the agent normally lives, grows, and multiplies. Reservoirs include humans, animals, and the environment. The reservoir may or may not be the source from which an agent is transferred to a host. For example, the reservoir of Clostridium botulinum is soil, but the source of most botulism infections is improperly canned food containing C. botulinum spores.

Human reservoirs. Many common infectious diseases have human reservoirs. Diseases that are transmitted from person to person without intermediaries include the sexually transmitted diseases, measles, mumps, streptococcal infection, and many respiratory pathogens. Because humans were the only reservoir for the smallpox virus, naturally occurring smallpox was eradicated after the last human case was identified and isolated.8

Human reservoirs may or may not show the effects of illness. As noted earlier, a carrier is a person with inapparent infection who is capable of transmitting the pathogen to others. Asymptomatic or passive or healthy carriers are those who never experience symptoms despite being infected. Incubatory carriers are those who can transmit the agent during the incubation period before clinical illness begins. Convalescent carriers are those who have recovered from their illness but remain capable of transmitting to others. Chronic carriers are those who continue to harbor a pathogen such as hepatitis B virus or Salmonella Typhi, the causative agent of typhoid fever, for months or even years after their initial infection. One notorious carrier is Mary Mallon, or Typhoid Mary, who was an asymptomatic chronic carrier of Salmonella Typhi. As a cook in New York City and New Jersey in the early 1900s, she unintentionally infected dozens of people until she was placed in isolation on an island in the East River, where she died 23 years later.(45)

Carriers commonly transmit disease because they do not realize they are infected, and consequently take no special precautions to prevent transmission. Symptomatic persons who are aware of their illness, on the other hand, may be less likely to transmit infection because they are either too sick to be out and about, take precautions to reduce transmission, or receive treatment that limits the disease.

Animal reservoirs. Humans are also subject to diseases that have animal reservoirs. Many of these diseases are transmitted from animal to animal, with humans as incidental hosts. The term zoonosis refers to an infectious disease that is transmissible under natural conditions from vertebrate animals to humans. Long recognized zoonotic diseases include brucellosis (cows and pigs), anthrax (sheep), plague (rodents), trichinellosis/trichinosis (swine), tularemia (rabbits), and rabies (bats, raccoons, dogs, and other mammals). Zoonoses newly emergent in North America include West Nile encephalitis (birds), and monkeypox (prairie dogs). Many newly recognized infectious diseases in humans, including HIV/AIDS, Ebola infection and SARS, are thought to have emerged from animal hosts, although those hosts have not yet been identified.

Environmental reservoirs. Plants, soil, and water in the environment are also reservoirs for some infectious agents. Many fungal agents, such as those that cause histoplasmosis, live and multiply in the soil. Outbreaks of Legionnaires disease are often traced to water supplies in cooling towers and evaporative condensers, reservoirs for the causative organism Legionella pneumophila.

Portal of exit

Portal of exit is the path by which a pathogen leaves its host. The portal of exit usually corresponds to the site where the pathogen is localized. For example, influenza viruses and Mycobacterium tuberculosis exit the respiratory tract, schistosomes through urine, cholera vibrios in feces, Sarcoptes scabiei in scabies skin lesions, and enterovirus 70, a cause of hemorrhagic conjunctivitis, in conjunctival secretions. Some bloodborne agents can exit by crossing the placenta from mother to fetus (rubella, syphilis, toxoplasmosis), while others exit through cuts or needles in the skin (hepatitis B) or blood-sucking arthropods (malaria).

Modes of transmission

An infectious agent may be transmitted from its natural reservoir to a susceptible host in different ways. There are different classifications for modes of transmission. Here is one classification:

  • Direct
    • Direct contact
    • Droplet spread
    • Airborne
    • Vehicleborne
    • Vectorborne (mechanical or biologic)

    In direct transmission, an infectious agent is transferred from a reservoir to a susceptible host by direct contact or droplet spread.

    Direct contact occurs through skin-to-skin contact, kissing, and sexual intercourse. Direct contact also refers to contact with soil or vegetation harboring infectious organisms. Thus, infectious mononucleosis (&ldquokissing disease&rdquo) and gonorrhea are spread from person to person by direct contact. Hookworm is spread by direct contact with contaminated soil.

    Droplet spread refers to spray with relatively large, short-range aerosols produced by sneezing, coughing, or even talking. Droplet spread is classified as direct because transmission is by direct spray over a few feet, before the droplets fall to the ground. Pertussis and meningococcal infection are examples of diseases transmitted from an infectious patient to a susceptible host by droplet spread.

    Indirect transmission refers to the transfer of an infectious agent from a reservoir to a host by suspended air particles, inanimate objects (vehicles), or animate intermediaries (vectors).

    Airborne transmission occurs when infectious agents are carried by dust or droplet nuclei suspended in air. Airborne dust includes material that has settled on surfaces and become resuspended by air currents as well as infectious particles blown from the soil by the wind. Droplet nuclei are dried residue of less than 5 microns in size. In contrast to droplets that fall to the ground within a few feet, droplet nuclei may remain suspended in the air for long periods of time and may be blown over great distances. Measles, for example, has occurred in children who came into a physician&rsquos office after a child with measles had left, because the measles virus remained suspended in the air.(46)

    Vehicles that may indirectly transmit an infectious agent include food, water, biologic products (blood), and fomites (inanimate objects such as handkerchiefs, bedding, or surgical scalpels). A vehicle may passively carry a pathogen &mdash as food or water may carry hepatitis A virus. Alternatively, the vehicle may provide an environment in which the agent grows, multiplies, or produces toxin &mdash as improperly canned foods provide an environment that supports production of botulinum toxin by Clostridium botulinum.

    Vectors such as mosquitoes, fleas, and ticks may carry an infectious agent through purely mechanical means or may support growth or changes in the agent. Examples of mechanical transmission are flies carrying Shigella on their appendages and fleas carrying Yersinia pestis, the causative agent of plague, in their gut. In contrast, in biologic transmission, the causative agent of malaria or guinea worm disease undergoes maturation in an intermediate host before it can be transmitted to humans (Figure 1.20).

    Portal of entry

    The portal of entry refers to the manner in which a pathogen enters a susceptible host. The portal of entry must provide access to tissues in which the pathogen can multiply or a toxin can act. Often, infectious agents use the same portal to enter a new host that they used to exit the source host. For example, influenza virus exits the respiratory tract of the source host and enters the respiratory tract of the new host. In contrast, many pathogens that cause gastroenteritis follow a so-called &ldquofecal-oral&rdquo route because they exit the source host in feces, are carried on inadequately washed hands to a vehicle such as food, water, or utensil, and enter a new host through the mouth. Other portals of entry include the skin (hookworm), mucous membranes (syphilis), and blood (hepatitis B, human immunodeficiency virus).

    Figure 1.20 Complex Life Cycle of Dracunculus medinensis (Guinea worm)

    Source: Centers for Disease Control and Prevention. Principles of epidemiology, 2nd ed. Atlanta: U.S. Department of Health and Human Services1992.

    The final link in the chain of infection is a susceptible host. Susceptibility of a host depends on genetic or constitutional factors, specific immunity, and nonspecific factors that affect an individual&rsquos ability to resist infection or to limit pathogenicity. An individual&rsquos genetic makeup may either increase or decrease susceptibility. For example, persons with sickle cell trait seem to be at least partially protected from a particular type of malaria. Specific immunity refers to protective antibodies that are directed against a specific agent. Such antibodies may develop in response to infection, vaccine, or toxoid (toxin that has been deactivated but retains its capacity to stimulate production of toxin antibodies) or may be acquired by transplacental transfer from mother to fetus or by injection of antitoxin or immune globulin. Nonspecific factors that defend against infection include the skin, mucous membranes, gastric acidity, cilia in the respiratory tract, the cough reflex, and nonspecific immune response. Factors that may increase susceptibility to infection by disrupting host defenses include malnutrition, alcoholism, and disease or therapy that impairs the nonspecific immune response.

    Implications for public health

    Knowledge of the portals of exit and entry and modes of transmission provides a basis for determining appropriate control measures. In general, control measures are usually directed against the segment in the infection chain that is most susceptible to intervention, unless practical issues dictate otherwise.

    Interventions are directed at:

    • Controlling or eliminating agent at source of transmission
    • Protecting portals of entry
    • Increasing host&rsquos defenses

    For some diseases, the most appropriate intervention may be directed at controlling or eliminating the agent at its source. A patient sick with a communicable disease may be treated with antibiotics to eliminate the infection. An asymptomatic but infected person may be treated both to clear the infection and to reduce the risk of transmission to others. In the community, soil may be decontaminated or covered to prevent escape of the agent.

    Some interventions are directed at the mode of transmission. Interruption of direct transmission may be accomplished by isolation of someone with infection, or counseling persons to avoid the specific type of contact associated with transmission. Vehicleborne transmission may be interrupted by elimination or decontamination of the vehicle. To prevent fecal-oral transmission, efforts often focus on rearranging the environment to reduce the risk of contamination in the future and on changing behaviors, such as promoting handwashing. For airborne diseases, strategies may be directed at modifying ventilation or air pressure, and filtering or treating the air. To interrupt vectorborne transmission, measures may be directed toward controlling the vector population, such as spraying to reduce the mosquito population.

    Some strategies that protect portals of entry are simple and effective. For example, bed nets are used to protect sleeping persons from being bitten by mosquitoes that may transmit malaria. A dentist&rsquos mask and gloves are intended to protect the dentist from a patient&rsquos blood, secretions, and droplets, as well to protect the patient from the dentist. Wearing of long pants and sleeves and use of insect repellent are recommended to reduce the risk of Lyme disease and West Nile virus infection, which are transmitted by the bite of ticks and mosquitoes, respectively.

    Some interventions aim to increase a host&rsquos defenses. Vaccinations promote development of specific antibodies that protect against infection. On the other hand, prophylactic use of antimalarial drugs, recommended for visitors to malaria-endemic areas, does not prevent exposure through mosquito bites, but does prevent infection from taking root.

    Finally, some interventions attempt to prevent a pathogen from encountering a susceptible host. The concept of herd immunity suggests that if a high enough proportion of individuals in a population are resistant to an agent, then those few who are susceptible will be protected by the resistant majority, since the pathogen will be unlikely to &ldquofind&rdquo those few susceptible individuals. The degree of herd immunity necessary to prevent or interrupt an outbreak varies by disease. In theory, herd immunity means that not everyone in a community needs to be resistant (immune) to prevent disease spread and occurrence of an outbreak. In practice, herd immunity has not prevented outbreaks of measles and rubella in populations with immunization levels as high as 85% to 90%. One problem is that, in highly immunized populations, the relatively few susceptible persons are often clustered in subgroups defined by socioeconomic or cultural factors. If the pathogen is introduced into one of these subgroups, an outbreak may occur.

    Exercise 1.9

    Information about dengue fever is provided on the following pages. After studying this information, outline the chain of infection by identifying the reservoir(s), portal(s) of exit, mode(s) of transmission, portal(s) of entry, and factors in host susceptibility.

    1. Reservoirs:
    2. Portals of exit:
    3. Modes of transmission:
    4. Portals of entry:
    5. Factors in host susceptibility:

    Dengue Fact Sheet

    Dengue is an acute infectious disease that comes in two forms: dengue and dengue hemorrhagic fever. The principal symptoms of dengue are high fever, severe headache, backache, joint pains, nausea and vomiting, eye pain, and rash. Generally, younger children have a milder illness than older children and adults.

    Dengue hemorrhagic fever is a more severe form of dengue. It is characterized by a fever that lasts from 2 to 7 days, with general signs and symptoms that could occur with many other illnesses (e.g., nausea, vomiting, abdominal pain, and headache). This stage is followed by hemorrhagic manifestations, tendency to bruise easily or other types of skin hemorrhages, bleeding nose or gums, and possibly internal bleeding. The smallest blood vessels (capillaries) become excessively permeable (&ldquoleaky&rdquo), allowing the fluid component to escape from the blood vessels. This may lead to failure of the circulatory system and shock, followed by death, if circulatory failure is not corrected. Although the average case-fatality rate is about 5%, with good medical management, mortality can be less than 1%.

    Dengue and dengue hemorrhagic fever are caused by any one of four closely related flaviviruses, designated DEN-1, DEN&ndash2, DEN-3, or DEN-4.

    Diagnosis of dengue infection requires laboratory confirmation, either by isolating the virus from serum within 5 days after onset of symptoms, or by detecting convalescent-phase specific antibodies obtained at least 6 days after onset of symptoms.

    What is the treatment for dengue or dengue hemorrhagic fever?

    There is no specific medication for treatment of a dengue infection. Persons who think they have dengue should use analgesics (pain relievers) with acetaminophen and avoid those containing aspirin. They should also rest, drink plenty of fluids, and consult a physician. Persons with dengue hemorrhagic fever can be effectively treated by fluid replacement therapy if an early clinical diagnosis is made, but hospitalization is often required.

    How common is dengue and where is it found?

    Dengue is endemic in many tropical countries in Asia and Latin America, most countries in Africa, and much of the Caribbean, including Puerto Rico. Cases have occurred sporadically in Texas. Epidemics occur periodically. Globally, an estimated 50 to 100 million cases of dengue and several hundred thousand cases of dengue hemorrhagic fever occur each year, depending on epidemic activity. Between 100 and 200 suspected cases are introduced into the United States each year by travelers.

    How is dengue transmitted?

    Dengue is transmitted to people by the bite of an Aedes mosquito that is infected with a dengue virus. The mosquito becomes infected with dengue virus when it bites a person who has dengue or DHF and after about a week can transmit the virus while biting a healthy person. Monkeys may serve as a reservoir in some parts of Asia and Africa. Dengue cannot be spread directly from person to person.

    Who has an increased risk of being exposed to dengue?

    Susceptibility to dengue is universal. Residents of or visitors to tropical urban areas and other areas where dengue is endemic are at highest risk of becoming infected. While a person who survives a bout of dengue caused by one serotype develops lifelong immunity to that serotype, there is no cross-protection against the three other serotypes.

    What can be done to reduce the risk of acquiring dengue?

    There is no vaccine for preventing dengue. The best preventive measure for residents living in areas infested with Aedes aegypti is to eliminate the places where the mosquito lays her eggs, primarily artificial containers that hold water.

    Items that collect rainwater or are used to store water (for example, plastic containers, 55-gallon drums, buckets, or used automobile tires) should be covered or properly discarded. Pet and animal watering containers and vases with fresh flowers should be emptied and scoured at least once a week. This will eliminate the mosquito eggs and larvae and reduce the number of mosquitoes present in these areas.

    For travelers to areas with dengue, as well as people living in areas with dengue, the risk of being bitten by mosquitoes indoors is reduced by utilization of air conditioning or windows and doors that are screened. Proper application of mosquito repellents containing 20% to 30% DEET as the active ingredient on exposed skin and clothing decreases the risk of being bitten by mosquitoes. The risk of dengue infection for international travelers appears to be small, unless an epidemic is in progress.

    Can epidemics of dengue hemorrhagic fever be prevented?

    The emphasis for dengue prevention is on sustainable, community-based, integrated mosquito control, with limited reliance on insecticides (chemical larvicides and adulticides). Preventing epidemic disease requires a coordinated community effort to increase awareness about dengue/DHF, how to recognize it, and how to control the mosquito that transmits it. Residents are responsible for keeping their yards and patios free of sites where mosquitoes can be produced.


    Results

    Nested PCR examination of blood samples from 108 wild macaques (82 long-tailed, 26 pig-tailed), sampled from 17 different locations in the Kapit Division of Sarawak, showed that 101 (94%) of the macaques were infected with malaria parasites. Long-tailed macaques had a higher prevalence of infection (98%) than pig-tailed macaques (81%) (Fisher's Exact P = 0.009) (Table 1). By nested PCR assays, we detected 5 species of Plasmodium, with P. inui being the most common (prevalence of 82%), followed by P. knowlesi (78%), P. coatneyi (66%), P. cynomolgi (56%), and P. fieldi (4%). Multiple species infections were very common, with 91 of the 108 (84%) macaques being infected by two or more species of Plasmodium each. There was a higher prevalence of P. knowlesi among long-tailed macaques (87%) than pig-tailed macaques (50%) (P = 0.006).

    To compare the molecular identity of the parasites in macaques and humans, we first sequenced the P. knowlesi csp gene in blood samples from 31 patients admitted to Kapit Hospital and 16 wild macaques. Most macaques (10 of 16), but only a minority of humans (3 of 31) contained 2 or more csp alleles (Fig. 1A). Overall, we derived 48 csp allele sequences of P. knowlesi from the macaques and 34 from the human samples, with 61 different alleles observed in total. Three of these csp alleles were shared between human and macaques, three were shared by macaques, and the remaining alleles were detected in only macaques or humans (Fig. S1 and Fig. 1B). We found that the central region of the P. knowlesi csp was composed of highly polymorphic repeat sequences (Table S1). Analysis of the aligned non-repeat regions of csp showed 19 polymorphic sites, of which 14 were shared polymorphisms in samples from both host populations (Fig. S2). The nucleotide diversity of csp was similar in both hosts (π = 2.2×10 −2 in humans and 2.4×10 −2 in macaques), although the haplotype diversity was marginally higher in macaques (H = 0.82, SD = 0.03) than in humans (H = 0.73, SD = 0.06). There was no clustering of csp allele sequence type associated with either host (Fig. 1B).

    (A) Histogram showing proportion of human and macaque individuals with different numbers of full length csp alleles detected per infection. (B) Diversity of csp alleles in the P. knowlesi clade of the phylogenetic tree of Plasmodium spp. (Fig. S1), based on the non-repeat region of the gene. These intraspecific relationships clustered by the neighbor-joining method on a Kimura 2-parameter distance matrix represent observed pairwise sequence similarity (phylogeny cannot be determined within the species for a nuclear gene due to recombination). Figures on the branches are bootstrap percentages based on 1,000 replicates and only those above 70% are shown. The horizontal branch lengths indicate nucleotide differences per site compared with the scale bar. Parasite clones in the boxes represent sequences that are completely identical for the whole csp gene (including repeat sequences not analysed by alignment but given separately in Supplementary Table S1).

    We also sequenced the ∼6-kilobase mtDNA genome of P. knowlesi parasites isolated from 25 malaria patients and 11 macaques. Each human sample had a single mtDNA haplotype, while all except one macaque sample contained multiple (2 to 6) haplotypes (Fig. 2A). In total, we generated 54 complete mtDNA genome sequences, representing 37 different mtDNA haplotypes, with a higher number of haplotypes in the macaques (23 haplotypes from 11 samples) than in the humans (17 haplotypes from 25 samples). Six of the haplotypes were found in more than 1 sample, and 3 of these were shared between the human and macaque hosts (Fig. 2B). Forty-five single nucleotide polymorphisms (SNPs) and a 4-base insertion/deletion within the P. knowlesi mtDNA genome were identified (Fig. S3), and the level of nucleotide diversity (π) of mtDNA was estimated as 7.5±0.7×10 −4 .

    (A) Histogram showing proportion of human and macaque individuals with different numbers of mtDNA haplotypes detected per infection. (B) Schematic diagram of genealogical network showing relationship among 37 mtDNA haplotypes of P. knowlesi. Numbers in larger circles represent number of haplotypes and unnumbered circles represent a single haplotype. Each line connecting the circles represents a mutational step and black dots represent hypothetical missing intermediates.

    The Bayesian coalescent approach [19] was used to estimate the time to the most recent common ancestor (TMRCA) for P. knowlesi. A nucleotide substitution rate for the mtDNA genome of 3.13×10 −9 (95% HPD, 1.94–4.45×10 −9 ) substitutions per site per year was estimated by comparing mtDNA sequences of P. knowlesi, P. fragile, P. cynomolgi, P. simiovale (parasites of Asian macaques) with P. gonderi (a parasite of African mangabeys) and Plasmodium sp. (Mandrill), assuming parasite lineages separated when Asian Old World monkeys and African Old World monkeys diverged 10 million years ago (MYA) [20]. This derived rate yielded an estimate of 257,000 (95% HPD: 98,000–478,000) years before present as the TMRCA of P. knowlesi (Fig. 3).

    Phylogenetic tree scaled to time generated using uncorrelated relaxed clock model and Bayesian skyline coalescent tree prior, with the divergence of Plasmodium spp. of Asian macaques and P. gonderi/Plasmodium sp. (Mandrill) as the calibration point (black circle). TMRCAs and HPDs for P. knowlesi and Plasmodium of Asian macaques are indicated. Numbers on branches are values of posterior probabilities. The accession numbers of sequence data of P. knowlesi were deposited in GenBank under the accession numbers EU880446–EU880499 and accession numbers of the other sequences are provided in the Methods section.

    There was no evidence of recombination in the mtDNA of P. knowlesi (Table S2), and reconstruction of the haplotype genealogical network demonstrated that no distinct lineages of mtDNA were exclusively associated with either human or macaque hosts (Fig. 2B). Our phylogeny-trait association tests based on association index (AI) [21] and parsimony score (PS) [22] of host-parasite phylogenetic substructure do not reject the null hypothesis of no association between parasite and host (Table S3). Hence, this further indicates the absence of a distinct lineage of P. knowlesi parasites associated with either human or macaque hosts.

    We observed an excess of unique mtDNA haplotypes, which appear at the edges of a star-like structure of the haplotype genealogical network (Fig. 2B), and this is indicative of an evolutionarily recent population expansion of P. knowlesi. The signature of population expansion is also evident from the unimodal shape of the pairwise mismatch distribution (Fig. 4A), and this is supported by a low Harpending's raggedness index (r = 0.009, P = 0.87) [23]. In addition we used the Tajima's D [24], Fu and Li's D and F (with out-group) [25] and Fay and Wu's H [26] statistics to detect deviation from the model of neutral evolution considering that the deviation from neutrality could be due to demographic processes such as population expansion, population bottleneck or mutation rate heterogeneity [27]. We obtained significant negative values for all these statistics (Tajima's D = −1.88, P = 0.001 Fu and Li's D = −2.60, P = 0.02 Fu and Li's F = −2.80, P = 0.009 Fay and Wu's H = −10.33, P = 0.044), thereby providing further evidence for an expansion of the P. knowlesi parasite population.

    (A) Pairwise mismatch distribution of the P. knowlesi mt genome. The bars represent observed frequency of the pairwise differences among mtDNA sequences and the line represents the expected curve for a population that has undergone a demographic expansion. (B) Bayesian skyline plot showing changes in effective population size (Ne) through time as estimated using uncorrelated log-normal relaxed molecular clock and Bayesian skyline coalescent model (10 coalescent-interval groups) with the substitution rate of 3.13×10 −9 substitutions per site per year. The y-axis representing the effective population size is given on a logarithmic scale and the x-axis represents time in thousands of years ago. The thick solid black line is the median estimate and the blue shaded area represents the 95% highest probability density (HPD) intervals for effective population size.

    To further investigate the demographic history of P. knowlesi, we estimated the changes in effective population size of the parasite through time, using a coalescent approach called the Bayesian skyline plot [19]. The plot indicates that P. knowlesi underwent a rapid population growth between approximately 30,000 and 40,000 years before present (Fig. 4B). In addition, we performed independent analyses for P. knowlesi mtDNA sequences derived from humans and macaques. Similar trends were reflected in the Bayesian skyline plots for each host (Fig. S4), showing that there are no differences between the demographic history of P. knowlesi for either host.

    We analysed mtDNA cytochrome b sequence data for long-tailed macaques in Southeast Asia using a similar approach, but did not find any evidence for changes in population size between 100,000 and 10,000 years before present (Fig. S5).


    Discussion

    Malaria occurrences are not randomly distributed across space and time [16]. This variation is likely influenced by the combined effect of factors that characterize individuals and areas [2]. Findings of the study show that factors at both the community-level and individual level are important in understanding the variation of malaria risk among individuals. In addition, temporal changes in the community factors, e.g., seasonal variation and control intervention programmes, can have a major impact on individual malaria outcome.

    The relationship of malaria incidence with monthly minimum temperature rather than rainfall may be unique to this wet, higher altitude area. While the optimal temperature for the development of both vector and parasite is between 25°C and 30°C, the lower temperature during dry season may jeopardize the transmission capability of mosquitoes [17–19]. Since P. vivax is more tolerant at a relatively low temperature condition, the effect of temperature would be expected to be less for P. vivax than P. falciparum, which is consistent with the study findings. This may provide opportunities for new strategies that target interventions to eliminate transmission during these periods when temperature favors success. It may also raise concerns about future failure of control programmes in such regions if warming climate occurs even without changes in rainfall.

    Malaria control interventions were associated with a substantial impact on the inter-annual reduction in malaria risk in this population, after adjusting for the temperature effect. Routine active surveillance allows detection of asymptomatic cases, which are the important infectious reservoirs of malaria [20–22]. In addition, symptomatic patients can be detected and treated earlier during active surveillance than when passive surveillance is operating alone [18]. The resulting of reduction in both the number of reservoir hosts and in an individual's infectious period could both decrease infection pressure in a hamlet.

    The finding of the effectiveness of artemisinin-based combination therapy (ACT) on P. falciparum occurrence is consistent with research conducted in other areas [23–25]. Artemisinin has been shown to be effective in killing both the asexual stages and the immature sexual stages of P. falciparum parasites, which consequentially prevents onward transmission [26–29]. Although ACT was used only for treatment of P. falciparum, a substantial reduction in P. vivax incidence was also observed during the ACT use period this could be possibly explained by the additional effect of artesunate in killing asexual P. vivax in patients who initially had mixed infection. Mixed infection is likely to be undetected using microscopy [30]. In Thailand, using molecular techniques, mixed P. falciparum and P. vivax infections have been reported in about 60% of clinical malaria patients, and when it presents, P. falciparum generally dominates [30]. Although ACT has no reported impact on eliminating P. vivax hypnozoites, the liver stage parasite that causes relapse, a clinical trial conducted in Thailand has shown that about 50% of P. vivax patients who received either 5- or 7-day artesunate treatment remained parasite-free at day 28 after the treatment [31]. However, the effect of ACT on reducing subsequent P.vivax reappearance among submicroscopic mixed infection patients is still unclear.

    The effect of age and gender on malaria incidence in low transmission settings varies across areas [21, 22, 32, 33]. Unlike areas with high malaria transmission, an increased risk of malaria attack among children in malaria low transmission areas could be easily attributable to their lack of development of immunity, since exposure and clinical episodes are uncommon in all age groups [1, 32]. The pattern of age-gender distribution of malaria risk may, in part, be due to behavioural exposure to vector or to other unmeasured variables, such as intrinsic differences in immune function or hormonal response among different age groups and genders [34, 35]. Future work to explore this pattern, including immunological tests, is needed in hypo-endemic areas.

    In this study, the risk of malaria attack was not significantly different for individuals living at variable locations relative to a stream. Although an association between topographical characteristics and malaria incidence has been reported in many areas, these observations are generally where there are large variations in attributes of house locations [21, 36–38]. For example, an increased risk of malaria was found to be associated with houses located farther than 500 or 1,000 meters from a river [21, 36, 37]. However, in this study area, the mean distance from an individual house to a stream was about 200 meters with a range of 200 to 500 meters. This relatively small variation may mean that vector abundance is similar among houses. The hamlet's light forest cover area had a marginal effect on the risk of P. falciparum attack but no effect on the risk of P. vivax attack. There are differences in the preferred habitats of Anopheles vector species in Thailand. An. minimus, a predominant vector in Thailand, is commonly found close to stream margins in forested and foothill areas [39–41]. However, the association between hamlets' light forest area and malaria risk was still uncertain due to limited number of landscape data for comparison at hamlet-level. Future research with wider spatial and temporal coverage is needed to understand which environments might favor transmission.

    Malaria transmission directly depends on the presence of a human reservoir as well as the level of vector-human contact [1, 42]. While the factors most commonly found to be associated with vector abundance were relatively stable across the area, changes in the number of infectious human reservoirs in the community could potentially affect transmission probabilities for individuals in the population [43, 44]. For high transmission areas, stable areas of higher and lower incidence have been associated with spatially identifiable transmission and control factors. However, in low transmission areas where the majority of cases are quickly treated, other factors, such as immigrant cases or individual risk behaviours might be more important. In this study, the addition of one human reservoir per 100 persons in a hamlet resulted in 1.14 and 1.34 times higher risk for contracting P. falciparum and P. vivax, respectively, among individuals who lived in the hamlet. Spatial variation in level of gametocyte carriage in the population may have a major role in defining risk for malaria transmission in low endemicity areas.

    Gametocyte carriers are vital for sustaining the disease in a population. However, number of humans available to infect mosquitoes may not be a limiting factor in high endemic regions. Interventions that have a strong community-level effect, particularly early detection and treatment to decrease number and duration of gametocyte carriage may have a more powerful effect on reducing malaria transmission in hypoendemic regions [18, 23]. The study findings showed that people who lived far from the malaria clinic were more likely to have P. falciparum attacks than those who lived closer. Distance to the malaria clinic may reflect how quickly people receive treatment. Those who live farther may take longer time to seek treatment, which consequently increases the infectious duration. Although the Euclidean distance used in the study was not accounted for the actual route and terrain to the clinic, the pattern of main roads and terrain features of the area suggests that the Euclidean distance and via route distance are likely to be proportionately similar.

    Results of this study may be subject to misclassification bias. The incidence of malaria in a previous month was used as a proxy for the level of infectious individuals in each hamlet. For malaria infection, especially P. falciparum, infected patients do not always represent an infectious population. While this would bias estimates of incidence for each hamlet, the OR's would be biased toward the null (underestimated) unless the rates of infectious to infected individuals varied systematically between hamlets, which could possibly occur if the pattern of treatment and clearance of parasites differed across hamlets. Misclassification of landscape features was also possible because of the limited resolution of LandSat images. Additionally, land use changes were occurring over this period in several of hamlets, which can have variable effects on vector dynamics. However, characterizing spatial attributes may be less critical for a region with widespread water and vector habitat availability.

    Although the one-month lag time used for hamlet incidence was based on the time from parasite uptake from one person until clinical symptoms appear in another individual, this lag time did not account for different durations of infectiousness and the infectivity dynamic among individuals. An individual's infectious period is usually less than one week. However, some individuals may remain infectious up to a month, even after treatment [44, 45]. In addition, recrudescence may prolong the duration of infectiousness and relapse may result in multiple episodes of infectious period. Individuals who had a long infectious period could continue to infect mosquitoes and be a source for the disease in their hamlets in the next two or three months. However, in this study area, short duration from clinical attack to treatment and the low number of asymptomatic cases found during active surveillance suggest that a prolong individual's duration of infectiousness may be less likely, with an exception in 2003 and 2004 when recrudescence was observed in about 10% to 15% of all P. falciparum malaria cases, due to mefloquine resistance. Additionally, previous higher incidence in a hamlet may simply be a proxy for a higher risk in location where malaria is generally found. Findings from the preliminary analysis showed that the locations with highest incidence moved over time in this study area. Further, the effect of hamlet incidence became non-significant in the sensitivity analysis using different lag times (zero and two months lag).

    To study the epidemiology of malaria, one must consider the relationship among factors that characterize time, person, and place. In this study, potential malaria risk factors at temporal-level, individual-level, and community-level were simultaneously examined. The 8-year longitudinal data used in the study allowed us to determine the effect of temporal and spatial changes over time. Unlike ecological studies where inferences are drawn on the basis of aggregated outcomes for a group, the individually specified, hierarchical outcomes used in this study provide more valid inferences regarding malaria. Results of this study provide new insight into the malaria epidemiology in a low malaria transmission area, where malaria elimination is feasible. Moreover, similar patterns of P. falciparum and P. vivax risk factors found in the study suggest that a uniform intervention could have an effect on both P. falciparum and P. vivax incidence. However, further research is needed to investigate the effects of ACT on P. vivax among individuals with submicroscopic mixed infection.


    Malaria

    Blood parasites of the genus Plasmodium. There are approximately 156 named species of Plasmodium which infect various species of vertebrates. Four species are considered true parasites of humans, as they utilize humans almost exclusively as a natural intermediate host: P. falciparum, P. vivax, P. ovale and P. malariae. However, there are periodic reports of simian malaria parasites being found in humans, most reports implicating P. knowlesi. At the time of this writing, it has not been determined if P. knowlesi is being naturally transmitted from human to human via the mosquito, without the natural intermediate host (macaque monkeys, genus Macaca). Therefore, P. knowlesi is still considered a zoonotic malaria.

    Life Cycle

    The malaria parasite life cycle involves two hosts. During a blood meal, a malaria-infected female Anopheles mosquito inoculates sporozoites into the human host . Sporozoites infect liver cells and mature into schizonts , which rupture and release merozoites . (Of note, in P. vivax and P. ovale a dormant stage [hypnozoites] can persist in the liver and cause relapses by invading the bloodstream weeks, or even years later.) After this initial replication in the liver (exo-erythrocytic schizogony ), the parasites undergo asexual multiplication in the erythrocytes (erythrocytic schizogony ). Merozoites infect red blood cells . The ring stage trophozoites mature into schizonts, which rupture releasing merozoites . Some parasites differentiate into sexual erythrocytic stages (gametocytes) . Blood stage parasites are responsible for the clinical manifestations of the disease.

    The gametocytes, male (microgametocytes) and female (macrogametocytes), are ingested by an Anopheles mosquito during a blood meal . The parasites&rsquo multiplication in the mosquito is known as the sporogonic cycle . While in the mosquito&rsquos stomach, the microgametes penetrate the macrogametes generating zygotes . The zygotes in turn become motile and elongated (ookinetes) which invade the midgut wall of the mosquito where they develop into oocysts . The oocysts grow, rupture, and release sporozoites , which make their way to the mosquito&rsquos salivary glands. Inoculation of the sporozoites into a new human host perpetuates the malaria life cycle .

    Geographic Distribution

    Malaria generally occurs in areas where environmental conditions allow parasite multiplication in the vector. Malaria today is usually restricted to tropical and subtropical areas and altitudes below 1,500 m., although in the past malaria was endemic in much of North America, Europe and even parts of northern Asia, and today is still present on the Korean peninsula. However, this present distribution could be affected by climatic changes and population movements. Plasmodium falciparum is the predominant species in the world. P. vivax and P. ovale are traditionally thought to occupy complementary niches, with P. ovale predominating in Sub-Saharan Africa and P. vivax in the other areas but their geographical ranges do overlap. These two species are not always distinguishable on the basis of morphologic characteristics alone, and the use of molecular tools will help clarify their diagnosis and exact distribution. P. malariae has wide global distribution, being found in South America, Asia, and Africa, but it is less frequent than P. falciparum in terms of association with cases of infection. P. knowlesi is found in southeast Asia.

    Clinical Presentation

    The symptoms of uncomplicated malaria can be rather non-specific and the diagnosis can be missed if health providers are not alert to the possibility of this disease. Since untreated malaria can progress to severe forms that may be rapidly (<24 hours) fatal, malaria should always be considered in patients who have a history of exposure (mostly: past travel or residence in disease-endemic areas). The most frequent symptoms include fever and chills, which can be accompanied by headache, myalgias, arthralgias, weakness, vomiting, and diarrhea. Other clinical features include splenomegaly, anemia, thrombocytopenia, hypoglycemia, pulmonary or renal dysfunction, and neurologic changes. The clinical presentation can vary substantially depending on the infecting species, the level of parasitemia, and the immune status of the patient. Infections caused by P. falciparum are the most likely to progress to severe, potentially fatal forms with central nervous system involvement (cerebral malaria), acute renal failure, severe anemia, or acute respiratory distress syndrome. Other species can also have severe manifestations. Complications of P. vivax malaria include splenomegaly (with, rarely, splenic rupture), and those of P. malariae include nephrotic syndrome.


    Contents

    The great diversity of infectious pathogens, their possible hosts, and the ways in which their hosts respond to infection has resulted in multiple definitions for "natural reservoir", many of which are conflicting or incomplete. In a 2002 conceptual exploration published in the CDC's Emerging Infectious Diseases, the natural reservoir of a given pathogen is defined as "one or more epidemiologically connected populations or environments in which the pathogen can be permanently maintained and from which infection is transmitted to the defined target population." [2] The target population is the population or species in which the pathogen causes disease it is the population of interest because it suffers from disease when infected by the pathogen (for example, humans are the target population in most medical epidemiological studies). [3]

    A common criterion in other definitions distinguishes reservoirs from non-reservoirs by the degree to which the infected host shows symptoms of disease. By these definitions, a reservoir is a host that does not experience the symptoms of disease when infected by the pathogen, whereas non-reservoirs show symptoms of the disease. [4] The pathogen still feeds, grows, and reproduces inside a reservoir host, but otherwise does not significantly affect its health the relationship between pathogen and reservoir is more or less commensal, whereas in susceptible hosts that do suffer disease caused by the pathogen, the pathogen is considered parasitic.

    What further defines a reservoir for a specific pathogen is where it can be maintained and from where it can be transmitted. A "multi-host" organism is capable of having more than one natural reservoir.

    Natural reservoirs can be divided into three main types: human, animal (non-human), and environmental. [1]

    Human reservoirs Edit

    Human reservoirs are human beings infected by pathogens that exist on or within the human body. [1] Poliomyelitis and smallpox exist exclusively within a human reservoir. [5] Humans can act as reservoirs for sexually transmitted diseases, measles, mumps, streptococcal infection, various respiratory pathogens, and the smallpox virus. [1]

    Animal reservoirs Edit

    Animal (non-human) reservoirs consist of domesticated and wild animals infected by pathogens. [1] [2] For example, the bacterium Vibrio cholerae, which causes cholera in humans, has natural reservoirs in copepods, zooplankton, and shellfish. Parasitic blood-flukes of the genus Schistosoma, responsible for schistosomiasis, spend part of their lives inside freshwater snails before completing their life cycles in vertebrate hosts. [7] Viruses of the taxon Ebolavirus, which causes Ebola virus disease, are thought to have a natural reservoir in bats or other animals exposed to the virus. [8] Other zoonotic diseases that have been transmitted from animals to humans include: rabies, blastomycosis, psittacosis, trichinosis, cat-scratch disease, histoplasmosis, coccidiomycosis and salmonella. [9]

    Common animal reservoirs include: bats, rodents, cows, pigs, sheep, swine, rabbits, raccoons, dogs, other mammals. [1]

    Common animal reservoirs Edit

    Bats Edit

    Numerous zoonotic diseases have been traced back to bats. [10] There are a couple theories that serve as possible explanations as to why bats carry so many viruses. One proposed theory is that there exist so many bat-borne illnesses because there exist a large amount of bat species and individuals. The second possibility is that something about bats' physiology make them especially good reservoir hosts. [10] Perhaps bats' "food choices, population structure, ability to fly, seasonal migration and daily movement patterns, torpor and hibernation, life span, and roosting behaviors" are responsible for making them especially suitable reservoir hosts. [11] Lyssaviruses (including the Rabies virus), Henipaviruses, Menangle and Tioman viruses, SARS-CoV-Like Viruses, and Ebola viruses have all been traced back to different species of bats. [11] Fruit bats in particular serve as the reservoir host for Nipah virus (NiV). [12]

    Rats Edit

    Rats are known to be the reservoir hosts for a number of zoonotic diseases. Norway rats were found to be infested with the Lyme disease spirochetes. [13] In Mexico rats are known carriers of Trypanosoma cruzi, which causes Chagas disease. [14]

    Mice Edit

    White-footed mice (Peromyscus leucopus) are one of the most important animal reservoirs for the Lyme disease spirochete (Borrelia burgdorferi). [15] Deer mice serve as reservoir hosts for Sin Nombre virus, which causes Hantavirus Pulmonary Syndrome (HPS). [16]

    Monkeys Edit

    The Zika virus originated from monkeys in Africa. In São José do Rio Preto and Belo Horizonte, Brazil the zika virus has been found in dead monkeys. Genome sequencing has revealed the virus to be very similar to the type that infects humans. [17]

    Environmental reservoirs Edit

    Environmental reservoirs include living and non-living reservoirs that harbor infectious pathogens outside the bodies of animals. These reservoirs may exist on land (plants and soil), in water, or in the air. [1] Pathogens found in these reservoirs are sometimes free-living. The bacteria Legionella pneumophila, a facultative intracellular parasite which causes Legionnaires' disease, and Vibrio cholerae, which causes cholera, can both exist as free-living parasites in certain water sources as well as in invertebrate animal hosts. [1] [18]

    A disease reservoir acts as a transmission point between a pathogen and a susceptible host. [1] Transmission can occur directly or indirectly.

    Direct transmission Edit

    Direct transmission can occur from direct contact or direct droplet spread. Direct contact transmission between two people can happen through skin contact, kissing, and sexual contact. Humans serving as disease reservoirs can be symptomatic (showing illness) or asymptomatic (not showing illness), act as disease carriers, and often spread illness unknowingly. Human carriers commonly transmit disease because they do not realize they are infected, and consequently take no special precautions to prevent transmission. Symptomatic persons who are aware of their illness are not as likely to transmit infection because they take precautions to reduce possible transmission of the disease and/or seek out treatment to prevent the spread of the disease. [1] Direct droplet spread is due to solid particles or liquid droplet suspended in air for some time. Droplet spread is considered the transmission of the pathogen to susceptible host within a meter of distance, they can spread from coughing, sneezing, and talking.

    • Neisseria gonorrhoeae (Gonorrhea) is transmitted by sexual contact involving the penis, vagina, mouth, and anus through direct contact transmission.
    • Bordetella pertussis (Pertussis) is transmitted by cough from human reservoir to susceptible host through direct droplet spread.

    Indirect transmission Edit

    Indirect transmission can occur by airborne transmission, by vehicles (including fomites), and by vectors.

    Airborne transmission is different from direct droplet spread as it is defined as disease transmission that takes place over a distance larger than a meter. Pathogens that can be transmitted through airborne sources are carried by particles such as dust or dried residue (referred to as droplet nuclei).

    Vehicles such as food, water, blood and fomites can act as passive transmission points between reservoirs and susceptible hosts. Fomites are inanimate objects (doorknobs, medical equipment, etc.) that become contaminated by a reservoir source or someone/something that is a carrier. A vehicle, like a reservoir, may also be a favorable environment for the growth of an infectious agent, as coming into contact with a vehicle leads to its transmission.

    Vector transmission occurs most often from insect bites from mosquitoes, flies, fleas, and ticks. There are two sub-categories of vectors: mechanical (an insect transmits the pathogen to a host without the insect itself being affected) and biological (reproduction of the pathogen occurs within the vector before the pathogen is transmitted to a host). To give a few examples, Morbillivirus (measles) is transmitted from an infected human host to a susceptible host as they are transmitted by respiration through airborne transmission. Campylobacter (campylobacteriosis) is a common bacterial infection that is spread from human or non-human reservoirs by vehicles such as contaminated food and water. Plasmodium falciparum (malaria) can be transmitted from an infected mosquito, an animal (non-human) reservoir, to human host by biological vector transmission.


    West African bats - no safe haven for malaria parasites

    In Europe, bats are normally discussed in the context of endangered species threatened by loss of their habitats. However, in recent years, bats have caught the eye of infection biologists. The animals are namely hosts to a surprising number of pathogens, many of which could be dangerous to humans. Scientists at the Max Planck Institute for Infection Biology, the Museum für Naturkunde in Berlin and the American Museum of Natural History have been able to identify in West African bats four genera of parasites that are closely related to the malaria pathogen. One of them is the genus Plasmodium, which also includes the species that cause malaria in humans. The Plasmodium species in bats are very similar to that found in rodents and could advance the study of malaria pathogens’ defence strategies against immune system responses.

    The bat Hipposideros cyclops hosts the parasite Plasmodium cyclopsi (upper left).

    Bats can transmit various diseases to human beings. Indeed, they serve as reservoir hosts for a long list of pathogens, including the “who’s who” of dreaded killer viruses: Ebola, Marburg, Nipah, Hendra and Lyssa. The SARS outbreak in 2002 in Asia and the transmission of a previously unidentified virus (MERS) to humans in the Middle East in 2013 can both be traced back to viruses that have switched hosts from bats to humans. Bats have an exceptional immune system that can hold all these viruses in check. However, some infections in humans often have a deadly outcome.

    Recently, the researchers have also found an astonishing variety of blood parasites in West African bats. They examined 31 bat species from the West African forest in Guinea, Liberia and the Ivory Coast with regard to parasites that attack red blood cells. 40 per cent of the approximately 270 examined animals carried parasites of the genera Plasmodium, Polychromophilus, Nycteria and Hepatocystis. According to the study, at least two species of Plasmodium can be found in bats. These bat pathogens are very similar to those found in rodents. “There are different arboreal rodents in the tropics that live in close vicinity to bats and in result might attract the same mosquitoes that transmit parasites from one group of animals to another,” says Juliane Schaer from the Max Planck Institute in Berlin.

    Plasmodium parasites cause malaria, the most important vector-borne infectious disease on the planet. These protozoan parasites reproduce in different host cells and undergo a complex life cycle in two alternating hosts. Their sexual reproduction takes place in insects usually Anopheles mosquitoes. Following a mosquito bite, they reproduce asexually in different vertebrates. By comparing DNA, the scientists were able to establish a phlyogenetic tree for haemosporidians in bats. This showed that bats were the first mammal hosts to the pathogens. “In a later evolutionary stage, they switched to rodents and primates,” Susan Perkins from the American Museum of Natural History in New York says.

    Micropteropus pusillus with a gametocyte of the parasite Hepatocystis.

    © MPI f. Infection Biology/Schaer

    It is not yet clear why bats are hosts to such a multitude of microorganisms. “One reason is probably that, in evolutionary terms, this is a very old group of animals, which moreover comprises a large number of different species. The bats’ ability to fly and their tendency to form big colonies are other factors that help the parasites spread,” explains Schaer.

    As a consequence of the pathogen threat, bats have developed a sophisticated immune system. This might explain the finding that certain bat species show infection rates of over 60 per cent by haemosporidians and still manage to keep the parasites at bay without becoming ill. “Also, the fast asexual reproduction of the genera Polychromophilus, Nycteria and Hepatocystis in bats takes place in hepatocytes, and not in erythrocytes as in humans. Such a liver stage cannot be clinically detected in humans. “It may be that the effective immune system ousted the pathogens from the blood cells, so that they were limited to multiply in the liver,” says Kai Matuschewski, Leader of the Parasitology Research Group at the Max Planck Institute for Infection Biology.

    For the scientists, the bat haemosporidians offer an opportunity for studying how the pathogens adapt to new organisms and thus also the immune responses of an organism. In addition, they hope to learn more about malaria parasites in humans. Many studies focussing on vaccines and antimalarial drugs make use of mouse models. As the parasites found in bats are so similar to those in rodents, it may be easy to transfer them to mice and study them closer.


    FUTURE PERSPECTIVES

    Almost any endeavor in the field of immunity to malaria represents a step in the journey to a practical and effective vaccine that serves to diminish the enormous losses of life, health, and prosperity imposed by these parasites. As with any journey to an unfamiliar destination, the traveler must stop, take bearings, and ask, 𠇊m I going in the right direction?” We consider the endeavor represented by this review to be such a pause. The long chronological reach of this paper was not a matter of academics. Our assessment of bearings reached the point of origin by the necessity of addressing this question: how did parasite antigenic variation come to dominate strategic thinking in vaccine development? The answer, we believe, is found primarily in three sets of observations: (i) the seemingly slow onset of acquired immunity in areas of heavy transmission, where the effects of age and cumulative exposure could not be separated (ii) the rapid onset of acquired immunity in neurosyphilis patients being reconciled to the slow onset in settings of endemicity by the invocation of strain-specific immunity and (iii) the discoveries of variant antigenic types, var genes, and PfEMP1 proteins being held as the molecular basis of the slow onset of strain-specific NAI in zones of heavy endemicity.

    Against this backdrop, the goal of vaccine development became discovery of an antigen or set of antigens that could mount a strain-transcending immune response capable of defeating the array of antigenic variation defenses mounted by the parasite. A dominant role for antigenic variation in host susceptibility to the parasite lies at the core of this strategic thinking, based largely on the three sets of observations listed above.

    In this review we have made an argument for an alternative hypothesis for the basis of host susceptibility to falciparum malaria. That hypothesis represents an almost complete departure from the conventional view, placing intrinsic differences in how acquired immunity operates in immature and mature immune systems as the basis of host susceptibility to malaria. The genesis of this hypothesis may be found in observations that challenged the earliest assumptions regarding the onset of NAI. When a population of nonimmune migrants of all ages became abruptly exposed to hyper- to holoendemic transmission of malaria, the adults developed clinical immunity after three or four infections within 12 to 24 months. Their children did not. These data upset two of the three foundations of antigenic variation as the basis of host susceptibility. Onset of immunity was not slow it only seemed that way when age and cumulative exposure could not be separated. A reexamination of the strain-specific immunity described for the neurosyphilis patients revealed substantial evidence of potent strain-transcending immunity. The focus on the often relatively slight differences between homologous and heterologous strain immunity in that body of work began to resemble a forced fit to the hypothesis of antigenic variation as basis of host susceptibility. Indeed, the onset of immunity in the Indonesian migrants very closely resembled that among the neurosyphilis patients.

    We consider the body of evidence supporting intrinsic age-related factors as the key determinants of host susceptibility to falciparum malaria to be compelling. However, it is also incomplete in terms of mechanistic detail and, therefore, conclusive proofs. The literature demonstrating age-related differences in host responses and susceptibility to infectious diseases is as vast as it is heterogeneous. None of the many systems studied, including falciparum malaria in humans, provides a testable hypothesis of cellular and molecular mechanisms that could account for the age-related phenomena observed in organisms and populations. There remains no understanding of what may be at work in establishing the often very conspicuous differences between immature and mature animals coping with challenge by infection.

    One likely starting point for more firmly establishing age-dependent, strain-transcending immunity in malaria and for beginning to sort through the myriad possible mechanisms at work may be a nonhuman primate model. In particular, the system of P. knowlesi in rhesus macaques offers important advantages. The course and consequence of P. knowlesi infection in that monkey species resemble the hyperparasitemia and death caused by P. falciparum in humans. Breeding colonies of rhesus macaques may offer a sufficient cross-section of ages, and the available immunological reagents for that animal would permit relatively inexpensive, sophisticated, and immediate work. If adult animals in that model prove to be more susceptible to acute infection than younger animals and if older animals experience more rapid and complete onset of protective acquired immunity to P. knowlesi than younger animals, the ground may be laid for penetrating analyses of similar immune processes at work in humans.

    Human populations offering the same analytical insights rarely appear. In areas of heavy exposure, separation of the cumulative effects of heavy exposure from those of intrinsic age-related factors will be difficult. Nonetheless, Kurtis et al. (178) achieved this by examining susceptibility to fever with malaria relative to physiological markers of onset of puberty demonstrating the event (signaling physiological age) rather than calendar age as the principal determinant of resistance to fever with parasitemia. It may be possible to conduct similar analyses by applying other physiological markers of age among younger people. The work of Reyburn et al. (247), conducted along a gradient of elevation and intensity of transmission pressure, also offers analytical leverage against age versus exposure. Another approach to teasing out the relative effect of age versus exposure on the development of NAI in areas of holoendemicity where both are superimposed is to design and conduct intervention studies using targeted malaria tools, such as IPT or continuous chemoprophylaxis, in defined age groups or age-stratified cohorts (8).

    Migration of nonimmune people of all ages into areas of heavy endemicity occurs under some circumstances, as in the studies from Indonesian New Guinea discussed here. The increasing demand for natural resources and people striving for improvement of their economic welfare will continue to push development into less and less hospitable surroundings. These migrations occur despite the risks to life from many causes, including malaria. What is a normal hazard in the pursuit of life hinges upon what is necessary to secure essential needs, and people in a London suburb will have different standards from those at the edge of an Amazonian forest. Provided that a research agenda did not prompt the migration, the study of the people who embark on journeys of high risk of their own free will (298) imposes no ethical obstacles beyond those of international standards for research involving human subjects. Indeed, avoiding health research in such populations may be ethically dubious without a compelling justification. A dislike of the consequences of human migrations does not adequately support assertions of ethical compromise in the conduct of medical research within such populations.


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