These changes produced an increasing rate of amino acid deamination, thus supplying alternative substrates for gluconeogenesis. Moreover, the accumulation of urea accelerated the urea cycle; thus, more arginine was available for parasite development [ ]. Interestingly, the nitrogen degradation products could produce noxious effects on the host neuroendocrine system and even kill the infected snails, thus creating a comfortable environment for nematodes to accomplish larval-stage development.
The reduction in the population of intermediate hosts carrying pathogens has a positive impact on inhibiting the transmission of infectious diseases, especially in natural epidemic foci e. Current research has demonstrated that nematodes weaken the reproductive capacity of snails mainly by direct impairment of the reproductive tissues and organs or by indirect harm through the withdrawal of nutrients [ 12 , 13 ]. The former mechanism suggested that nematodes induced egg granuloma formation and fibrosis, rendering the snail reproductive organs vulnerable.
Over time, the inflammatory infiltration and fibrosis within cephalopods hindered motor function, thus affecting the feeding and fertilization abilities of snails. The latter mechanism speculated that nematodes competed with the host to obtain essential nutrients for proliferation, the outcome of which was the suppression of the reproductive capacity of the snails. The galactogen synthesized by the albumen gland, for instance, served as the primary energy source for snail embryos and newly hatched offspring.
A galactogen deficiency in the albumen gland would decelerate the hatching rate of infected snails, thus characterizing parasitic castration as a nutritional process [ 12 ]. Wolbachia is a renowned intracellular endosymbiont of invertebrates that is capable of protecting insects from pathogens and limiting their ability to transmit mosquito-borne pathogens by the reproductive manipulation of their hosts by means such as sperm-egg cytoplasmic incompatibility CI , which results in the production of unviable progeny when a male mosquito carrying Wolbachia mates with a wild female mosquito [ , ].
The above interaction was reported to occur during the successful introduction of Wolbachia into the mosquito species e. Specialists were inspired to apply this mechanism of antagonism in the venues for malaria control.
The development of various pathogens in mosquitoes was confirmed to be inhibited by immune preactivation, thus suggesting that constitutive immunoregulation could influence the transmission of infectious pathogens to humans [ ]. A more in-depth study conducted recently showed the capability of Wolbachia to induce immune system upregulation.
Wolbachia stimulated mosquitoes to produce reactive oxygen species ROS in testes and ovaries; this ROS production later activated the Toll pathway and resulted in the synthesis of a variety of antibacterial peptides, such as defensins and cecropins, thus suppressing other coinfected pathogens [ 9 , ].
Another striking example of this surprising ability of Wolbachia is that the over-replicating wMelPop strain of Wolbachia could induce the constitutive expression of innate immune genes in mosquitoes [ 9 ], thus implying a potential explanation for the interspecific competitive relationships between different parasites as a contributory factor to the life-shortening parasitic phenotypes [ , ].
Previous studies have illuminated the antagonism between parasites and parasites, parasites and viruses, and parasites and bacteria Table 1.
Further research has described four possible mechanisms underlying this phenomenon. In particular, the immunomodulation theory, which indicates that coinfection was able to reduce the immunopathological alterations caused by the Th1-type immune response, has been widely accepted [ 4 , 91 ].
A low intensity of Schistosoma infection could improve the protective antimalarial immune response associated with the expression of related cytokines [ 18 , 91 , 94 , ], the permeability of the BBB [ 94 ], the DC response [ 94 ], and the differentiation and activation of Tregs [ 94 ], thereby potentially being protective against cerebral malaria.
Vector modulation is another universally acknowledged hypothesis to explain antagonistic coinfection; quintessential examples of vector modulation include the effects of EPNs and Wolbachia [ 12 , 13 , , , , , , ]. Other mechanisms underlying antagonism include interference competition and exploitation competition [ 61 , , ]. In summary, antagonistic phenomena between coinfecting pathogens are common, but persistent efforts are required to elucidate the underlying mechanisms and identify more effective strategies for combating pathogenic infection [ 77 , ].
One of the most promising examples is that the Wolbachia strains that had been successfully established in wild Ae. Aegypti to control dengue virus are now undergoing field trials in dengue endemic areas of Australia, Brazil, Indonesia and Vietnam [ ].
The World Health Organization. Accessed 24 May Accessed 15 Feb Age-stratified profiles of serum IL-6, IL, and TNF-alpha cytokines among Kenyan children with Schistosoma haematobium , Plasmodium falciparum , and other chronic parasitic co-infections. Am J Trop Med Hyg. Analysis of a summary network of co-infection in humans reveals that parasites interact most via shared resources. Proc Biol Sci. Harnessing mosquito- Wolbachia symbiosis for vector and disease control.
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Wolbachia stimulates immune gene expression and inhibits Plasmodium development in Anopheles gambiae. Plos Pathog. Molluscicidal potential of Heterorhabditis baujardi Rhabditida: Heterorhabditidae , strain LPP7, on Lymnaea columella Gastropoda: Pulmonata : An alternative for biological control of fasciolosis.
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Schistosoma mansoni infection suppresses the growth of Plasmodium yoelii parasites in the liver and reduces gametocyte infectivity to mosquitoes. Filarial infection induces protection against P. Microbes Infect. Predicting the effects of parasite co-infection across species boundaries. Suppression of Plasmodium cynomolgi in rhesus macaques by coinfection with Babesia microti.
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Int J Parasitol. The zygotes in turn become motile and elongated ookinetes which invade the midgut wall of the mosquito where they develop into oocysts. Inoculation of the sporozoites into a new human host perpetuates the malaria life cycle. 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, m. However, this present distribution could be affected by climatic changes and population movements. Plasmodium falciparum is the predominant species in the world.
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.
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.
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. Other species can also have severe manifestations. Complications of P.
Parasites may be visualized on both thick and thin blood smears stained with Giemsa, Wright, or Wright-Giemsa stains. Giemsa is the preferred stain, as it allows for detection of certain morphologic features e. Ideally, the thick smears are used to detect the presence of parasites while the thin smears are used for species-level identification. Quantification may be done on both thick and thin smears.
Morphologic characteristics of malaria parasites can determine a parasite species, however, microscopists may occasionally fail to differentiate between species in cases where morphologic characteristics overlap especially Plasmodium vivax and P. In such cases, the Plasmodium species can be determined by using confirmatory molecular diagnostic tests. In addition, molecular tests such as PCR can detect parasites in specimens where the parasitemia may be below the detectable level of blood film examination.
The methods currently used at CDC are described below. Detection and identification of Plasmodium to the species level is done with a real-time PCR assay as described by Rougemont et al This is a dual duplex assay that detects P. In cases where infection by more than one Plasmodium species is suspected, there is an option to use a conventional nested PCR assay Snounou el al, that has an improved resolution of mixed infection compared to the real-time PCR assay.
PCR was performed using nested primers of Snounou et al. High sensitivity detection of human malaria parasites by the use of nested polymerase chain reaction. Mol Biochem Parasitol ; Positive IFA result with P. Malaria antibody detection for clinical diagnosis is performed using the indirect fluorescent antibody IFA test.
The IFA procedure can be used as a diagnostic tool to determine if a patient has been infected with Plasmodium. Because of the time required for development of antibody and also the persistence of antibodies, serologic testing is not practical for routine diagnosis of acute malaria.
However, antibody detection may be useful for:. Species-specific testing is available for the four human species: P. Cross reactions often occur between Plasmodium species and Babesia species.
Blood stage Plasmodium species schizonts meronts are used as antigen. When examined with a fluorescence microscope, a positive reaction is when the parasites fluoresce an apple green color. Sulzer AJ, and Wilson M. The fluorescent antibody test for malaria. Crit Rev Clin Lab Sci ; In addition to microscopy and molecular methods, there are methods for detecting malaria parasites on the basis of antigens or enzymatic activities associated with the parasites.
These methods are often packaged as individual test kits called rapid diagnostic tests or RDTs. DPDx is an educational resource designed for health professionals and laboratory scientists. For an overview including prevention, control, and treatment visit www. Skip directly to site content Skip directly to page options Skip directly to A-Z link. Section Navigation. Facebook Twitter LinkedIn Syndicate. Minus Related Pages. Life Cycle The malaria parasite life cycle involves two hosts.
Geographic Distribution Malaria generally occurs in areas where environmental conditions allow parasite multiplication in the vector. Plasmodium falciparum Ring-form trophozoites of P. Rings may possess one or two chromatin dots. Ring forms may become compact or pleomorphic depending on the quality of the blood or if there is a delay in making smears. There is usually no enlargement of infected RBCs. Figure A: Rings of P. View Larger. Figure D: Rings of P.
Figure G: Rings of P. Figure J: Rings of P. Figure B: Rings of P. Figure E: Rings of P. Figure H: Rings of P. Figure K: Rings of P. Figure C: Rings of P. Figure F: Rings of P. Figure I: Rings of P. Figure L: Rings of P.
Ring-form trophozoites of P. Visualization of these structures is dependent on the quality of the smear preparation and the pH of the Giemsa stain. Figure A: Ring-form trophozoites of P.
Figure E: Ring-form trophozoites of P. Figure B: Ring-form trophozoites of P. Figure F: Ring-form trophozoites of P. Figure C: Ring-form trophozoites of P.
Figure D: Ring-form trophozoites of P. Developing and older trophozoites of P. Developing trophozoites of P. The amount of pigment and chromatin may also increase. Compact or amoeboid forms may be seen in smears where there was a delay in processing the blood. Figure A: Trophozoites of P. Figure E: Trophozoites of P. Figure B: Trophozoite of P. Figure F: Trophozoites of P. Figure C: Trophozoite of P.
Figure D: Trophozoite of P. In this figure, a gametocyte can also be seen in the upper half of the image. Gametocytes of P. Another interesting drug mainly used for the treatment of helminth infections but also active on Plasmodium spp.
The antiparasitic mechanism of ivermectin on helminths including nematodes and insects is binding to glutamate-gated chloride channels in invertebrate muscles and nerves, which leaves the channels open leading to a flow increase of the chloride ions and subsequent hyperpolarization of the cell membranes and paralyzes and kills the parasites Shiomi, Studies demonstrated the activity of ivermectin against hepatic stages, erythrocytic stages, sexual stages, and oocyst and sporozoite stages of Plasmodium spp Kobylinski et al.
Studies reported the antiviral activity of ivermectin against HIV Wagstaff et al. Though most of the studies of antiviral activities of ivermectin were based on assessments with in vitro assays, some studies on its effect on SARS-CoV-2 patient treatment were performed based on a small-scale clinical trial Pott-Junior et al. The antiparasitic mechanism of artemisinin is not well understood despite some are proposed as above, in contrast to its well-understood mechanism for the parasites, which is one of the hurdles of the drug for its practical use for patients with viral pathogens Dinesh Kumar et al.
One such drug is antiretroviral protease inhibitors ARPIs , which are known to inhibit the growth of malaria parasites Parikh et al. ARPIs are transition state analogs that inhibit viral aspartic protease essential for viral maturation. HIV expresses Gag-Pol polyprotein whose cleavage is essential for the virus replication Konvalinka et al.
Studies reported some ARPIs with the ability to enhance the antimalarial activity of artemisinin and chloroquine Mishra et al. In in vivo assay with P. While the antimalarial mechanism of ARPIs has not been understood yet, some studies suggest plasmepsins and its homologous proteases as important targets of ARPIs for P. The results of in silico docking analysis supported the bindings of ARPIs saquinavir, ritonavir, and lopinavir with the active sites of P.
In support of this finding, gene-disrupted mutants for each of the four food-vacuole-localizing plasmepsins were produced, and two of them, gene-knockout mutants for PfPM1 or PfPM4, displayed substantially slower growth, indicating the important roles of plasmepsins for the growth of intraerythrocytic stages of P.
Since detoxication of heme in the parasites is essential for the survival of Plasmodium spp. Amantadine is a drug used for the treatment of influenza A virus infection. With a large number of deaths with infected patients every year, the influenza A virus is an enveloped virus with the segments of single-stranded, negative-sense RNA genome, which causes the most severe diseases among the four influenza virus types and infects a variety of animals such as humans, pigs, horses, and bird species, and therefore, becomes sources of serious zoonotic infections Kumar et al.
Amantadine blocks the M2 protein, a transmembrane proton channel on the virus particle, to inhibit proton flow into the virus which is required for the uncoating of the virus Kausar et al. Amantadine exhibited inhibition of P. These differences may be explained with the characteristics of amantadine as a channel blocker Johnson et al. CQ-resistant P. In addition, single amino acid mutation of serine to arginine at position on PfCRT was found in amantadine-resistant P.
The mechanism of amantadine, the inhibition of the proton channels of influenza A virus and P. On the other hand, its effect on P. Antibacterial drugs have been widely used for the treatment of infectious diseases caused by bacterial infections.
Among the antibacterial drugs, a number of antibacterial drugs target the bacterial cell wall e. Due to the similarities in the protein structures and requirements of some metabolic pathways between bacteria and Plasmodium spp. Here, we describe some of such examples and the potential antimalarial mechanisms of the drugs. Inhibitors of folate synthesis pathway FSP , such as sulfonamides, are widely used antibacterial agents and inhibit the synthesis of folate, a major precursor of nucleic acids of bacteria.
Though it was once recommended by the WHO for malaria treatment, it is currently not used regularly due to the emergence of drug resistance but still used for pregnant women and infants [intermittent preventive treatment for malaria in pregnancy IPTp ] World Malaria Report, Antimalarial activity was reported for another combination of FPS inhibitors, co-trimoxazole, a mixture of trimethoprim and sulfamethoxazole, through clinical studies of HIV patients Mermin et al.
Daily administrations of co-trimoxazole to HIV-infected patients for prophylaxis against opportunistic infections resulted in lower rates of Plasmodium spp. Tetracycline antibiotics tetracyclines are a group of antibiotics effective against a wide range of bacteria, including Gram-positive and Gram-negative bacteria, which have been used for the treatment and prophylaxis of P.
Tigecycline is a member of the third-generation TC derivatives and in a class of tetracyclines, glycylcycline, which was developed to overcome multidrug-resistant bacteria Yaghoubi et al. Based on in vitro assay with a clinical isolate of P. The target of tetracyclines in Plasmodium spp. The antibacterial action of tetracyclines is translation inhibition of the chromosomal genes by the drug binding to several proteins in the 30S ribosomal small subunit and to some different ribonucleic acids in the 16S rRNA Gaillard et al.
Multiple studies reported that the component of expression machinery for the genes contained in the genome of apicoplast, a unique plastid organelle of apicomplexan parasites, was the target of tetracyclines, and doxycycline directly inhibited the expression of genes in the apicoplast genome of P.
Loss of apicoplast functions in the doxycycline-treated parasite led to delayed death in the second cycle Dahl et al. Although slow actions of many tetracyclines can be problematic for malaria treatments, the potentiation of tigecycline of CQ for CQ-resistant P. Fosmidomycin is an antibiotic derived from Streptomyces lavendulae Iguchi et al.
Fosmidomycin inhibits 1-deoxy-D-xylulose 5-phosphate DOXP reductoisomerase, which is associated with non-mevalonate pathway MEP in isoprenoid biosynthesis Kuzuyama et al. MEP is utilized by Gram-negative bacteria, some Gram-positive bacteria, plastid-containing eukaryotes, and plants, while mammals use the mevalonate pathway Rohmer et al. Apicomplexa parasites including Plasmodium spp. The discovery of MEP in malaria parasites provided the potential target of new antimalarial compounds Wiesner et al.
The effectiveness of fosmidomycin against malaria was examined with in vitro and in vivo assays as well as clinical trial. In addition, fosmidomycin—piperaquine combination therapy for uncomplicated malaria was on phase 2 clinical trial performed in Gabon between and and demonstrated high efficacy Mombo-Ngoma et al. Using fosmidomycin for malaria treatments can be an attractive drug choice since it targets an enzymatic pathway in a unique organelle of the apicoplast, though similar to other apicoplast-target antimalarial drugs such as tetracycline, a slower action compared with other antimalarials can be a consideration for its practical use.
Macrolides are a class of natural products used to treat bacterial, viral, and parasitic infections Lee et al. In bacteria, macrolides bind to the neighbor of the entrance of polypeptide tunnel in 50S ribosomal subunit. This binding prevents transpeptidation of polypeptides, leading to immature peptide chain production and cell death Retsema and Fu, ; Hansen et al. The efficacy of azithromycin against malaria parasites has been confirmed in in vitro and in vivo experiments and clinical trials Andersen et al.
The target of azithromycin in P. The delayed effect of azithromycin was documented in this study with IC 50 values of 3, nm for 48 h of incubation and nm for 96 h of incubation, more than 30 times difference at the delayed time point Sidhu et al. The delayed effect of azithromycin was explained by the effect of specific toxicity of the drug on apicoplast and death of the parasite in the second cycle due to lack of the apicoplast genome replication in the first cycle Dahl and Rosenthal, b.
In addition to this delayed action, azithromycin demonstrated fast-killing activity which was independent of apicoplast-mediating delayed killing and augmented in azithromycin analogs with side-chain modifications, although the mechanism of this fast-killing mode of the drug was not understood Burns et al.
Similar to other drugs like tetracycline and fosmidomycin, azithromycin targets an enzymatic pathway in apicoplast, which makes the drug selective to Plasmodium parasites Sidhu et al. Manzamine A has been isolated from several sponge species such as Haliclona , Pellina , Pachypellina , Xestospongia , Ircinia , and Amphimedon Ang et al.
Manzamine A and 8-hydroxymanzamine A were reported to have in vivo antimalarial effect on Plasmodium berghei -infected mice Ang et al. Manzamines are inhibitors of glycogen synthase kinase-3 GSK-3 , which is also thought to be the target for their antimalarial activities Skropeta et al. The target of manzamines for its antimalarial activity is unique compared with other major antimalarials, while toxicity due to the similarity between enzymes of the malaria parasites and human can be a major disadvantage of the drug.
The first marine isonitrile was found from the sponge Axinella cannabina Emsermann et al. The antimalarial activity of several isonitriles was reported Emsermann et al. A docking study of some isonitriles with human hemoglobin suggested their bindings with heme, formations of a complex with heme iron, and subsequent inhibition of heme detoxication process as their antimalarial mechanism Wright et al.
Fungal pathogens are involved in various types of diseases, such as skin diseases and diseases on mucus membranes like the throat and female genitalia, and can be fatal when the infections spread to the whole body through the blood system Crowley and Gallagher, The treatment can be problematic since fungal pathogens are eukaryotic organisms like human hosts, and many drugs that kill fungus are also toxic to humans, and antifungal drugs have to have drug mechanisms selective to the fungal pathogens despite the similarities as eukaryotes between fungi and humans.
On the other hand, some antifungal drugs also kill malaria parasites due to their similarities to the fungi as they are both eukaryotic organisms Crowley and Gallagher, Clotrimazole is an antimycotic drug used for the treatment of skin infections, such as Candida albicans and other fungal infections, by inhibition of the biosynthesis of ergosterol, a sterol found in fungi and protozoa Crowley and Gallagher, Clotrimazole also inhibits P.
Inhibition of hemoperoxidase by clotrimazole leading to the subsequent induction of oxidative stress in P. Clotrimazole scaffold and its analogs were designed and synthesized as potent antimalarial agents Gemma et al. Clotrimazole nanoemulsion was formulated to improve its solubility Borhade et al.
Selectivity is one of the advantages of clotrimazole for its antimalarial activity due to its effect on the synthesis of ergosterols, which can be found mainly in fungi and protozoa Crowley and Gallagher, Drug delivery to the place of pathogen multiplication can be an issue for its practical use. Griseofulvin is used to treat dermatophyte fungal infections, which binds to intracellular microtubules inhibiting mitosis of fungi Lambert et al.
Griseofulvin inhibited intraerythrocytic growth of P. The antimalarial mechanism of action of griseofulvin was reported to be its cytochrome Pmediated production of N -methyl protoporphyrin IX N -MPP and its inhibition of the heme-synthesizing ability of ferrochelatase, and despite its failure in clinical trial, this unique mode of action of griseofulvin demonstrated a new potential lead chemical to develop new antimalarial drugs Smith et al.
Ketoconazole interferes with ergosterol synthesis by inhibition of cytochrome P CYP 3A4 and is used to treat a number of fungal infections Deutsch and Quintiliani, The action of slowing down the speed of metabolism of artemisinin is an attractive feature of ketoconazole, since short half-life is one of the weaknesses of these drugs, but ketoconazole cannot be used by itself also for this very reason Tripathi et al.
Due to the impact of COVID, significant effort has been taken for the discovery of antiviral drugs since the need for serious countermeasures was recognized when the virus was spreading throughout the world.
At the same time, antibacterial, antifungal, or antiparasitic drugs with promising antiviral activities were sought more than ever.
The drugs described in this article are summarized in Table 1 and Figure 1. The use of some major antimalarial and antiparasitic drugs such as dihydrochloroquine, artemisinin, and ivermectin has been considered for COVID treatment, although none of these were proven for their effectiveness or officially approved for clinical use against the disease. On the other hand, antimalarial activities of some known antimicrobials were examined, although none of them were considered for clinical use except some antibiotics, such as sulfadoxine—pyrimethamine prophylactic treatment for pregnant women and infants.
Although further studies are necessary for the drugs described in this article to find the precise potentials of these drugs, a substantial number of drugs have demonstrated significantly different mechanisms of action from the ones that existed before. Studies of repurposing drugs for different pathogens are worth investing in this sense, in addition to the financial benefit for drug-developing companies.
The targets of the drugs for Plasmodium parasites and viruses described in this article. TF: manuscript writing, editing, and figure and table production. All authors contributed to the article and approved the submitted version. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. National Center for Biotechnology Information , U.
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