Year : 2016 | Volume
: 9 | Issue : 2 | Page : 65--79
Gene mutations in parasitic diseases Part I: Host gene mutations
Manar M.S El-Tonsy1, Sherif M Abaza2,
1 Parasitology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
2 Parasitology Department, Faculty of Medicine, Suez Canal University, Egypt
Manar M.S El-Tonsy
Department of Parasitology, Faculty of Medicine, Ain Shams University, Cairo
To a large extent, the development and cellular function of any organism are controlled by genes. A gene is the functional unit of inheritance controlling the transmission and expression of one or more traits. The gene is made from a DNA molecule which is copied and inherited across generations and from RNAs that code for a polypeptide or for a RNA chain that has a function in the organism. Gene mutation is a change in DNA nucleotide sequence of a short region of a genome. Alteration in DNA sequence affects all copies of the encoded protein resulting in structural and functional changes or decrease or complete expression loss of the encoded protein. Gene mutation may occur in either the parasite or the host, which may be beneficial or harmful for each. All through this review, the authors will focus on host or parasite gene mutations (causes and types) and their relation(s) to or effect(s) on parasitic diseases. The review presents examples of gene mutations in the host (part I) or parasite (part II) focusing on disease susceptibility or resistance, drug resistance encountered in several parasitic diseases, carcinogenesis, virulence, pathogenesis, and clinical outcome as well as their relations with insecticide resistance and vector control.
Abbreviations: CM: Cerebral malaria, G6PD: Glucose-6-phosphate dehydrogenase; MBL: Mannose-binding lectin; mdr: Multi-drug resistance gene; NO: Nitric oxide; SNP: Single-nucleotide polymorphism; VL: Visceral leishmaniasis.
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El-Tonsy MM, Abaza SM. Gene mutations in parasitic diseases Part I: Host gene mutations.Parasitol United J 2016;9:65-79
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El-Tonsy MM, Abaza SM. Gene mutations in parasitic diseases Part I: Host gene mutations. Parasitol United J [serial online] 2016 [cited 2018 Sep 26 ];9:65-79
Available from: http://www.new.puj.eg.net/text.asp?2016/9/2/65/205166
The word gene is derived from the Greek word genesis meaning ‘birth’, or genos meaning ‘origin’. All organisms have genes that carry the information to build their cells, maintain their functions, and pass genetic traits to offspring. Genes relate to various biological traits, some of which are instantly visible, such as eye color, and some of which are not, such as blood type, increased susceptibility or resistance for specific diseases, or the thousands of basic biochemical processes that comprise life . The genetic code is composed of nucleotides each of which contains a phosphate group, a sugar group, and one of the nitrogen bases: adenine (A), thymine (T), guanine (G), and cytosine (C). The nucleotides are attached together to form two long strands that spiral to create a double-helix structure composed of DNA.
The order of these nucleotide bases determines the DNA instructions, or genetic code; in other words, the order of nitrogen bases in a DNA sequence forms the genes, which guide the cell to produce a certain protein. Transmission of genetic information from DNA into proteins is through RNA . Accordingly, the molecular definition of a gene indicates that it is a segment of DNA with certain nucleotide sequence that is required for the synthesis of a functional protein or RNA molecule. In addition to the coding regions (exons), the gene includes all nucleotides encoding the amino acid sequence of a protein, DNA sequences required for the synthesis of a particular RNA transcript, as well as transcription-control regions. Although most genes encode proteins, some encode transfer-RNA (tRNAs), ribosomal-RNA (rRNAs), and other types of RNA. Hence, gene expression is most frequently regulated by DNA-binding proteins that control the initiation of transcription; some cells use specific rearrangements of the DNA sequence to control expression of certain genes .
Genes are generally used for genotyping, which should be differentiated from the term ‘phenotyping’. The first is a description of the entire set of genes carried by any creature, whereas the latter describes the functional and physical appearance of the creature . For example, C. hominis and C. parvum were considered as the same species because of their apparent similarity and are now known to be two distinct species. Both exhibit significant differences in host range, infectivity, and pathogenicity, although their sequenced genomes are 95–97% identical. It was concluded that the phenotypic differences between Cryptosporidium spp. are not because of obvious genomic alterations. Generally, any observed phenotypic differences are because of subtle variations in the sequences of proteins that act at the interface between the parasite and its host. In other words, Cryptosporidium spp. genotypes include mutations in a single gene or a small number of genes that distinguish between the different species, whereas phenotype denotes the functional and physical characters of that genotype .
Mutation of a gene occurs because of a change in the nucleotide sequence of a short region of a genome in the DNA or RNA sequence. However, the change in RNA is not serious as several RNA copies are synthesized for each RNA. On the contrary, alteration in DNA sequence affects all copies of the encoded protein, resulting in structural and functional changes or decrease or complete expression loss of the encoded protein. When gene mutations occur, the difference between the mutant organisms and their normal counterparts ranges from elusive change in cellular functions to significant developmental or morphological changes, and even organismal death . This gene mutation may occur in either the parasite or the host, which may turn out to be beneficial or harmful for each.
One of the most interesting applications of host gene mutation(s) is the X-linked hyper IgM syndrome, which results from cd40lg gene mutation and is inherited in an X-linked manner. It was reported that patients with this syndrome are more susceptible to opportunistic infections ,,. An example of parasite gene mutation occurs with the myotubularin genes family which is reported to be expanded in E. histolytica, with great influence on its transmission and host infection. In a phylogenetic research conducted in Canada, the investigators attributed pathogenic amoebic invasion to mutation in myotubularin gene family . Another example of useful application of determination of gene mutation(s) is the development of DBDiaSNP, which is one of the first drug resistance databases for diarrheal pathogens. It covers mutations and resistance genes related to clinical relevance from several pathogens and hosts, offers veritable potentials, and presents effective treatment against diarrhea caused by several microorganisms . On the other hand, microsporidiosis is considered a genotoxic infection with several documentations revealing increased frequency of associated host cellular mutation. Several mechanisms were postulated: 1) secretion of toxins that directly damage host DNA or indirectly interfere with host DNA repair, 2) affection of patients with high levels of reactive chemical species that cause oxidative DNA damage with elevation of host DNA mutation frequency, and 3) interference with p53-induced apoptosis by manipulation of different pathways related to DNA repair and apoptosis .
The objective of the present review is to identify causes and types of host or parasite gene mutations and their relations to overt disease. We wish to specially emphasize on susceptibility or resistance to parasites, drug resistance or toxicity, parasite virulence, changes in host clinical manifestations, as well as the role of such mutations as promoting factors for the induction and prognosis of malignancy.
1. Parasite genomics and host genealogy
In a review published in 2003, Ersfeld defined parasite genomics as the data analysis of its genomic sequence, as a first step toward understanding how it lives and grows. It could eventually lead to the development of new and specific drug targets to overcome drug resistance of some strains. Parasite genome sequencing is either comparative or functional. The former deals with high-quality reference genomes used to understand host-parasite interactions and population structure. The latter deals with dynamic biological data, such as changes in transcriptome, proteome, and epigenome that occur in the course of the parasite’s life cycle. Several genes have been found unique to parasites and require gene sequencing data to uncover their uncharacterized functions. Therefore, functional genomics is achieved by understanding when and where it is expressed in the parasite life cycle, or by identifying which genes change on interaction with the parasite’s host. In addition, the author also reviewed the current status of protozoan parasite genome projects, presented the findings observed because of the availability of genomic data, and discussed the potential effect of genome information on disease control .
An American team examined the dynamics of evolution in a generic spatial model of a pathogen infecting a population of hosts. Their results revealed that mutant strains continually arose and grew rapidly for many generations but eventually died before dominating the system. Death is due to the depletion of those that are susceptible to the local environment of these mutant strains . Another study conducted in Belgium showed that genetic information is extensively used to reconstruct the evolutionary and demographic history of organisms. It was suggested that genetic information from some parasites can complement genetic data from their hosts. This approach relies on the hypothesis that such parasites share a common history with their host. Additionally, in some cases, parasites could provide an additional source of information because parasite data can better reconstruct the common history. The authors also discussed the important characters of the parasite to determine if they are of value to analyze their host history. They matched the parasite characteristics, such as effective population size, generation time, mutation rate and level of host specificity, with the phylogenetic, phylogeographic, and demographic time scales that are relevant to the issues of concern in host history .
2. Gene mutations
Most of the gene mutations that cause disease are uncommon in the general population. However, other gene mutations cause changes that are either not related to disease (more frequent) or cause disease (less common). Genetic alterations that occur in more than 1% of the population are called polymorphisms. They are common enough to be considered a normal variation in the DNA. Polymorphisms are responsible for many of the normal differences between people such as eye color, hair color, and blood type. Although many polymorphisms have no negative effects on a person’s health, some of these variations may influence the risk of developing certain disorders . Usually, cells of a complex multicellular organism as Drosophila spp. and mice, or entity such as human, carry two copies of a chromosomal set (haploid). Meanwhile, alleles denote different forms of a gene (normal or mutant), and diploid organisms carry two copies of each gene; either identical normal or identical mutant alleles (homozygous) or different alleles (heterozygous). In a homozygous individual with both identical mutant alleles, a mutant phenotype should be consequently observed (recessive mutation). On the other hand, a heterozygous individual carrying one allele of each is characterized as having dominant mutation with phenotypic consequences. Recessive mutations may replace part of the gene or remove it from the chromosome leading to decrease or complete loss of its expression. It may also lead to structural and functional alterations of the encoded protein. In contrast, dominant mutations often lead to function’ gain, that is, it may increase its expression with increased activity of its products . However, in some cases where both gene copies are required for a normal specific function, a mutant allele leads to a mutant phenotype, and these genes are referred to as haploinsufficient. In cases of dominant negative mutations, the mutant allele affects the protein that interferes with the function of the wild-type protein encoded by the other allele. However, in few instances, some alleles can be associated with both a recessive and a dominant phenotype. The Drosophila spp. heterozygous for the mutant Stubble (Sb) allele has its hairs short and stubby, rather than long and slender, that is, the mutant allele is dominant. In contrast, flies homozygous for this allele die during development. Therefore, the same allele is associated with lethal recessive phenotype and nonlethal dominant phenotype .
Causes and types: Gene mutations arise either spontaneously or on exposure to certain environmental factors such as ultraviolet light, radiation, and chemical carcinogens as aflatoxin B1 . Most mutations are point mutations in which one nucleotide is replaced by another, whereas others involve insertion or deletion of one or few nucleotides. All cells possess DNA-repair enzymes to minimize mutation occurrence, and these enzymes either work in prereplicative or postreplicative manner. In the first, they search DNA for unusual nucleotide structure and replace them before replication, whereas in the latter, they check newly synthesized DNA for errors and correct them. Therefore, ‘deficiency in DNA repair’ was introduced as a possible definition of mutation .
Overall, four types of gene mutations are known: hereditary, acquired, induced, and spontaneous. Hereditary mutations, known also as germline mutations, are inherited and present throughout all next generations in virtually every life cycle stage. Acquired (or somatic) mutations occur only in certain cells (or certain life cycle stages) owing to exposure to environmental factors, such as ultraviolet radiation, and are not inherited to the next generations . In contrast, the use of transgenic mosquitoes in malaria control is an example of the induced mutation, where induction of foreign genes into the mosquito germline blocks the development of parasitic life stages in their vector and blocks malaria transmission ,. Spontaneous mutations are caused because of depurination (loss of purine base from a nucleotide) or deamination (removal of an amine group from a base). Deamination of cytosine converts it to uracil, which will pair with adenine instead of guanine at the next replication, resulting in a base substitution .
Variants: Gene mutations either affect the function of a single gene (involving a single base pair or few base pairs) or cause a large scale change in the chromosomal structure resulting in alterations of the functions of several genes with major phenotypic consequences. The first variant occurs because of replacement of either one amino acid by another (missense mutation) or amino acid codon by a stop codon (nonsense mutation) in a single base pair. Deletion of few base pairs in a single gene causes what is known as frameshift mutation, in which there is change in the reading frame, leading to introduction of unrelated amino acids into the protein, followed by a stop codon. The second variant of mutation involving a chromosome includes deletion or insertion of several contiguous genes, inversion of genes on a chromosome, or the exchange of large segments of DNA between nonhomologous chromosomes . Several human diseases are due to single gene mutation, and most genetic diseases arise by spontaneous mutations in germ cells to be transmitted to future generations. Sickle-cell anemia is caused by a single missense mutation (glutamic acid is replaced by valine in the mutant protein at codon 6 of the β-globin gene). The disease commonly affects individuals of African origin, and it is characterized by RBCs rigidity. Although malaria is endemic in Africa, heterozygous individuals of African origin are resistant to the disease because the mutant allele is maintained by interbreeding .
Effects: Mutations in bacteria and yeast are described as loss or gain of function. However, with other microorganisms such as protozoa, detailed phenotype characters are described based on the growth properties of mutant cells in various culture media. For example, if the mutation occurred in one of the genes controlling tryptophan synthesis, the mutant microorganisms will grow only in media enriched with tryptophan as a nutrient. Another example is the temperature-sensitive mutants that behave like wild-type cells in culture media with low temperatures and exhibit their mutant phenotype when the temperature is raised. Apart from growth characters in various culture media, gene mutation might cause structural changes in the protein targeted by the inhibitory effect of a certain drug resulting in drug resistance .
Methods of detection: Two groups of tests, molecular and cytogenetic, are used in genetic syndromes. In general, single base pair mutations are identified by direct sequencing, DNA hybridization, and/or restriction enzyme digestion methods. However, there are two approaches for genetic diagnosis. The indirect approach depends on the results from a genetic linkage analysis using DNA markers such as short tandem repeat or variable number tandem repeat markers flanking or within the gene. The direct approach for diagnosis essentially depends on the detection of the genetic variations responsible for a disease .
In addition to genetic causes of disorders, predisposition to a disease or treatment options could be revealed by determining DNA variations. Molecular diagnostics provide a way for assessment of the genetic makeup of human; it combines laboratory medicine with molecular genetics to develop DNA/RNA-based analytical methods for monitoring human pathologies. A wide range of methods have been used for mutation detection. Molecular methods for identification of the disease-causing mutations could be classified as methods for known and methods for unknown mutations. Several criteria, however, have to be met for choosing a suitable method; for example, the following points should be considered: type of nucleic acid (DNA or RNA), kind of specimen (blood, tissues, etc.), the number of mutations, and reliability of the method. Pediatricians need to be specific when prescribing these tests to obtain an accurate diagnosis for the patients .
Mutation detection techniques include those testing for known mutations (genotyping) and those scanning for any mutation in a particular target region (mutation scanning). Broader aspects of mutation detection include identification of gene dosage alterations, gross rearrangements, and methylation. There are several well-known genotyping and scanning methods in routine diagnostic use .
Known mutations: Many different approaches, usually starting with the PCR, have been used for detection of known mutations. Additional assay steps are performed based on the type of mutation. DNA ‘chips’ or microarrays have been used for possible testing of multiple mutations, so that the sequences and their quantities in the sample are determined . DNA sequencing provides analysis of genes at the nucleotide level to determine the sequence of small regions of interest (∼1 kbp) using a PCR product as a template. Dideoxynucleotide sequencing or Sanger sequencing represents the most widely used technique for sequencing DNA . Multiplex ligation-dependent probe amplification is commonly applied to screen deletions and duplications of up to 50 different genomic DNA or RNA sequences which altogether account for up to 10% and in many disorders up to 30% of disease-causing mutations .
Unknown mutations: Single strand conformational polymorphism (SSCP) is one of the simplest screening techniques for detecting unknown mutations (microlesions) such as unknown single-base substitutions, small deletions, small insertions, or microinversions. A DNA variation causes alterations in the conformation of denatured DNA fragments. Denaturing and renaturing prevents the formation of double-stranded DNA and allows conformational structures to form in single-stranded fragments. The conformation is unique and results from the primary nucleotide sequence . Denaturing gradient gel electrophoresis (DGGE) has been used for screening of unknown point mutations. It is based on differences in the melting behavior of small DNA fragments (200–700 bp); even a single-base substitution can cause such a difference. Detection of mutated fragments is achieved by comparing the melting behavior of the DNA fragments. Approximately less than 100% of point mutations can be detected, and a maximum of a nearly 1000 bp fragment can be investigated . In heteroduplex analysis, a mixture of wild-type and mutant DNA molecules is denatured and renatured to produce heteroduplices. Homoduplices and heteroduplices show different electrophoretic mobilities with a fragment size ranging between 200 and 600 bp. Nearly 80% of point mutations have been estimated to be detected by heteroduplex analysis . Restriction fragment length polymorphism (RFLP) is used to detect mutations occurring in restriction sites. Point mutations can change restriction sites in DNA causing alteration in cleavage by restriction endonucleases which produce fragments with various sizes .
3. Gene mutation and parasitic diseases
3.1 Host gene mutations
3.1.1 Resistance and susceptibility
Malaria: Host genetic resistance to malaria occurs through either modifications of the host immune system to enhance immunity against the infection or changes in human RBCs to hinder Plasmodium spp. invasion and replication within these cells . Several publications clearly demonstrated an association between host genetic mutations and malaria protection. Deletion of the anion exchanger band 3 protein causes Melanesian ovalocytosis, and it was linked to protection against malaria morbidity . Host Duffy antigen/chemokine receptor or cluster of differentiation 234 (CD234) is the receptor on RBCs for P. vivax, and its absence owing to fy gene mutations prevents RBCs entry and protects against vivax malaria . A missense mutation within that gene is common in Africans with absence of glycoprotein receptors from RBCs resulting in increased resistance to P. vivax infection . There are two main polymorphisms in fy gene. In the first, Asp→Gly peptides substitution is associated with Fyb and Fya blood group antigens, correspondingly, whereas the second one leads to negative Duffy expression by silent erythrocytes . It was reported that individuals with Fya, common in Southeast Asian and several American populations, are more resistant to P. vivax infections. Accordingly, the investigators suggested that a vaccine based on P. vivax Duffy binding protein would show different efficacies among populations with different Fy phenotypes . In a preliminary report, not a single case of P. vivax was diagnosed by PCR in Haitian patients, 99% of whom had silent erythrocytes with no Duffy antigen expression (FYES allele carriers) . Glycophorins (GYPA, GYPB, and GYPC) bind to Plasmodium spp. surface proteins, and their absence was found to reduce invasion of RBCs with protection against malaria . Another correlation was found between the human gene encoding chitotriosidase (Chit) and resistance to malaria. Italian investigators analyzed gene mutation in Mediterranean and African populations and found that the high prevalence rate of chit gene mutation in the Mediterranean population was associated with the high resistance to malaria infections . In addition, mutant hemoglobin variants such as sickle-cell anemia  or thalassemia , were found to produce significant protection against malaria. Glucose-6-phosphate dehydrogenase (G6PD) is an essential enzyme for glutathione production and protects against hemoglobin degradation-induced oxidative stress damage. Its deficiency proved to be linked to protection against P. vivax but not against P. falciparum malaria .
Resistance to malaria was also demonstrated using an animal model with pyruvate kinase (PK) deficiency. However, the investigators recommended further studies in human to demonstrate the influence of gene mutations and malaria infections because there are more than 180 mutations responsible for PK deficiency . The same investigators conducted another study to determine the mechanism of resistance, and they found that hemolytic anemia which occurred in mice with mutant gene would be compensated by erythropoiesis resulting in mice protection against P. chabaudi infection . In human, two genes encode PK, the liver/erythrocyte-specific enzyme (PKLR) and the muscle-specific enzyme (PKM1/2). PKLR is essential for energy generation for mature RBCs, and its deficiency is the most common cause of nonspherocytic hemolytic anemia, which is inherited in an autosomal recessive manner. It was found that RBCs from PKLR-deficient patients are significantly associated with ex vivo reduction of RBCs invasion and increase of early phagocytosis of infected RBCs . In contrast, no associated link was detected between mutation in pklr gene and malaria infections in two case–control studies ,. Recently, investigators in a multinations team concluded that PKLR should be considered an important RBCs-specific factor whose partial or complete loss of function might produce some degree of protection against malaria .
In experimental animals, investigators showed that mice with spontaneous mutation of multidrug resistance-1a (mdr1a) gene coding for P-glycoprotein are more susceptible to cerebral malaria (CM) . Ankyrin-1 is a cytoskeletal protein found in RBCs membranes and is encoded by the ank-1 gene; previous studies demonstrated the role of its mutation in human-inherited hemolytic anemia disorders. In another experimental study, investigators demonstrated that ank-1 mutation increased resistance to malaria infection by reduction of P. chabaudi survival in affected RBCs . Recently, individuals with erythropoietic protoporphyria were found to be resistant to P. falciparum infections. These patients are characterized by low levels of ferrochelatase, which is the final enzyme in the heme biosynthetic pathway, rendering their RBCs unsuitable for P. falciparum blood stages .
Regarding genes controlling host immune response, a study was conducted to investigate the role of gene mutation resulting in CD36 deficiency and its influence on susceptibility and resistance to malaria infections. CD36 is a receptor on the surface of activated immune cells and vascular endothelial cells participating in phagocytosis and lipid metabolism. It was found that CD36 deficiency predisposed to significant decrease in IgG production and increased susceptibility to P. falciparum infections in children . In contrast, another study, also conducted on Indian children, the researchers found that CD36 deficiency (owing to host gene mutation) significantly protected children from severe anemia by reducing cytoadherence of infected RBCs . Another study investigated the role of apobec3b, a host gene involved in innate response. The distribution frequency of apobec3b gene mutation was significantly correlated with P. falciparum infections, where increased frequency of deleted allele was found to associate with greater susceptibility to P. falciparum malaria . The mannose-binding lectin (MBL) protein is essential for initiation of host innate immune response. It binds to pathogen oligosaccharides to activate the lectin pathway and forms a complex with mannan-binding lectin serine peptidase 2 (MASP2) to activate complement. Mutants mbl2 and masp2 were found to affect susceptibility to placental transmission and congenital malaria where placental malaria was detected in 39% of the women carrying no risk alleles for MBL2 or MASP2, compared with 65% of women with risk alleles at both loci . Finally, only one study denied any correlation between different mutations in three human genes [toll-like receptor 4 (TLR4), Duffy, and complement receptor type 1 genes] and resistance or suitability to P. vivax and P. falciparum infections .
Leishmaniasis: Several studies were published incriminating host gene mutations in host resistance or susceptibility to leishmaniasis. Mice susceptible to visceral leishmaniasis (VL) had nramp1 gene mutation at position 169, which controls innate immunity against intracellular parasites . Interestingly, mutation in the human nramp1 homolog was associated with susceptibility to tuberculosis and leprosy. A case–control study including resistant and susceptible dogs to VL was conducted to investigate allele 145 in canine slc11a1 gene that controls parasites replication in the macrophage. They found two gene mutations in susceptible dogs . The influence of host slc7a2 gene in immune response against leishmaniasis was also investigated. To differentiate between C57Bl/6 and BALB-C mice in their VL susceptibility, the investigators found that BALB-C macrophages are able to uptake arginine which is critical for their activation to resist infection. In contrast, macrophages of C57Bl/6 mice (with slc11a1 gene mutation) failed to uptake arginine with high VL susceptibility . Host op/op gene, controlling macrophage colony-stimulating factor, was also found to be associated with VL resistance. Mice with spontaneous point mutation in op/op gene showed profound macrophage deficiency and high VL susceptibility , while New Zealand black mice with mutations in both the C-lectin-binding domain and stalk region proved to be naturally resistant to VL owing to IgE overexpression . In an endemic area of VL in Brazil, genetic analysis of families having several VL cases suggested the presence of a major host gene that predisposes to infection. Because MBL is responsible for enhancing intracellular infections, the investigators found mutations in mbl2 gene in individuals who are able to resist VL or who present with asymptomatic disease . Another study was conducted also in Brazil to test for polymorphism of lpl gene controlling lipoprotein lipase in infected and noninfected individuals. It was found that those with high triglycerides levels were susceptible to VL, whereas those with low levels of high-density lipoproteins showed resistance to infection . Furthermore, mice that have inactivating knock-in mutation in p110δ gene showed resistance to VL. The researchers investigated the role of the hepatic stellate cells in VL pathogenesis. They found that VL caused expansion of these hepatic cells in a p110δ-dependent manner suggesting that mice resistance to VL was attributed, in part, to impaired expansion of their hepatic stellate cells . However, in cutaneous leishmaniasis, mice with a single mutation of fas apoptosis gene developed early mild cutaneous lesions, which later progressed rapidly. The investigators observed significant high IL-12 and IFN-γ levels as well as more nitric oxide (NO) in mutant mice than control wild-type mice. It was suggested that fas apoptosis gene is essential in resistance to infection, and that high concentration of NO was not enough for resistance, though IL-12 and IFN-γ released in early infection are responsible for mild lesions . A study conducted in Iran found that mutation in the host gene controlling TLR4 might lead to the increased susceptibility and severity of cutaneous leishmaniasis , but not VL . Searching in Brazilian families for il2ra gene mutation controlling IL-2 pathway revealed its association with susceptibility to cutaneous leishmaniasis .
Schistosomiasis: In Egyptian patients, a research was conducted in 2008 to study single-nucleotide polymorphisms (SNPs) in the human gene encoding the lymphotoxin-α gene among 3 groups of patients; schistosomiasis alone, hepatitis C virus (HCV) alone and schistosomiasis co-infected with HCV, compared to a fourth normal control group. On testing for polymorphism in the gene encoding the lymphotoxin-α gene, patients of the second and third groups were found significantly more likely to carry the mutation than the control participants . Another study related to schistosomiasis published in 2011 indicated that a genetic mutation that confers protection to individuals from schistosomiasis may increase their risk for asthma . In the same year, Barnes  published a review article documenting that people living in Bahia, Brazil, had a genetic mutation that protects against schistosomiasis by allowing the immune system to produce abundant IgE. The researcher added that although IgE binds to the worm and labels it for expulsion from the body, it also sets off swelling of the airways that puts those individuals at higher risk for asthma.
Amoebiasis: It was observed that children with genetic polymorphism in the leptin receptor were more susceptible to amoebic cytotoxicity . Host gene mutation in stat3 gene resulted in an error of leptin signaling, which is a well-characterized antiapoptotic factor. In addition, an experimental study showed that mice without leptin receptor developed severe amoebiasis . The investigators concluded that leptin has an essential role in protection of infected cells from apoptosis .
Trypanosomiasis: Gene mutation in apoL-I alleles results in human susceptibility to infection with trypanosomes that is closely related to T. evansi. It was found that normal human serum includes a trypanosome lytic factor which is found in association with high-density lipoproteins containing both haptoglobin-related protein and apoL-I. Therefore, individuals with serum devoid of apoL-I (owing to gene mutation) are more susceptible to animal trypanosomiasis .
Toxoplasmosis: It was found that B10.Q/J mice were susceptible to toxoplasmosis, and at the same time, highly resistant to autoimmune arthritis. The investigators observed that host tyk2 gene mutation was incriminated in this association .
Chagas disease: Mutations in host genes encoding placental expression enzymes (adam12 and mmp2 genes) were associated with susceptibility of children to acquire the infection from their infected mothers .
3.1.2 Carcinogenesis complicating parasitic infections
It is well known that change of gene expression patterns is an important feature of cancer cells. These alterations are caused directly or indirectly by genetic or epigenetic events . Meanwhile, infection was perceived as one of the most important causes of cancer and that infection-associated cancers are increasing at an alarming rate .
Schistosomiasis: In 1995, research was conducted including 25 Egyptian patients with bladder cancer (both types; transitional and squamous) to study tumor suppressor gene (p53) mutations using immunohistochemistry. The investigators detected p53 mutation in 40% of patients, which was associated with late stages in both carcinomas . In the same year, another study investigated the genetic defects behind the development of squamous cell carcinoma in association with schistosomiasis haematobium in Africa. Overall, two genes (cdkn2 and p53) were analyzed in patients of both types of cancer bladder, and the investigators observed significant contribution of the first gene in these patients . A later study, also in Egyptian patients, confirmed the high frequency of cdkn2 gene mutations in schistosomal cancer bladder . In another record, types of p53 mutations were reviewed in patients with schistosomal and nonschistosomal bladder cancers by British investigators who reported a significantly high proportion of base pair substitution at CpG dinucleotides in the first group. They attributed this mutation to NO production by the inflammatory response against S. haematobium eggs. They also explained NO direct and indirect mechanisms that led to significant rates of G:C→A:T transitions .
A search in the new century literature also confirmed the strong correlation between schistosomiasis and p53 gene mutation . An Egyptian research studied the relation between S. mansoni and gene mutation in codon 249 of p53 gene in patients with hepatocellular carcinoma. The investigators detected high frequency of p53 gene mutation in those patients than in patients without schistosomiasis. They observed that the association of schistosomiasis and aflatoxin B1 dietary intake would increase the incidence of hepatocellular carcinoma and its progression at an early age . In a study conducted in Portugal, the investigators detected kras gene mutation in 20% of patients with schistosomal cancer bladder. Investigators recommended further studies to address the relation between kras gene mutation and schistosomiasis-associated cancer bladder .
In addition, the relation between chromosomal alterations and prognosis of schistosomal cancer bladder was studied in Kingdom of Saudi Arabia. The cytogenetic profile was studied in 41 patients, and the investigators found a significant relation between gain of chromosome 4 and the overall survival rate . Another point of view related to schistosomal cancer bladder was investigated. As imatinib is a chemotherapeutic drug that specifically inhibits tyrosine kinase receptor (c-KIT or CD117) and is used in the management of squamous cell cancer bladder after radical cystectomy, Egyptian investigators studied the expression and mutation frequency of the gene encoding c-KIT and its relation with schistosomiasis. Interestingly, there was significantly high c-KIT expression without kit gene mutations in S. haematobium-infected patients. Therefore, the investigators recommended further studies investigating imatinib’s therapeutic effects in c-KIT schistosomal bladder cancer-positive patients .
Opisthorchiasis: Host gene mutation was also incriminated as a major factor for occurrence of cholangiocarcinoma (CCA) as a sequel complication of liver flukes infections. It was found that O. viverrini induces prolonged inflammatory reactions causing continuous production of host free radicals that act as carcinogens leading to gene mutations and CCA. In 2006, a group of investigators from Thailand published three studies, the first of which dealt with the relation of gene deletion to CCA prognosis. They found that patients with deletion at regions covering some specific genes had better prognosis than patients without these deletions . Results of the second study revealed that development of CCA in O. viverrini-infected patients is a multistep process that requires accumulated gene alteration and/or mutation of oncogenes and tumor suppressor genes . In the last study, the incidence of loss of heterozygosity and microsatellite instability in patients with O. viverrini-related CCA was investigated. Loss of heterozygosity and microsatellite instability are phenotypes of genetic abnormalities of tumor suppressor and DNA mismatch repair genes. The obtained results indicated the importance of investigating both phenotypes to predict the clinical, pathological, and prognostic parameters (survival, lymphatic, and nerve invasion). The investigators recommended assessment of tumor suppressor genes (riz, cdc42, and dffb) in infected patients to predict development and progression of CCA . Furthermore, runx3 gene (RUNT-related transcription factor) is essential for normal tissue development, and meanwhile it is involved in carcinogenesis. Although its mutation was not reported as a major cause of CCA, a study conducted in Thailand showed loss of 1p36 harboring runx3 gene in patients with O. viverrini-related CCA . However, a study conducted in Canada attributed its frequent increase in O. viverrini-infected patients to the frequent mutation rate of a tumor suppressor gene (e.g. tp53) . Another study conducted in patients from Europe and Asia showed significant difference in gene mutation patterns. Their results showed significant frequency of tp53 mutations in O. viverrini-related carcinoma, whereas other genes (bap1, idh1, and idh2) mutations were recorded in non-O. viverrini-related carcinomas .
Cryptosporidiosis: It was postulated that host p53 gene mutation was involved in the development of ileocecal oncogenesis in C. parvum-experimentally infected mice . In contrast, Benamrouz et al.  failed to demonstrate either oncogenic β-catenin mutations in tumor samples, or mice p53 gene mutation. They attributed carcinogenesis to a combination of several pathways, the most important of which is Rho GTPase pathway, which regulates many aspects of intracellular actin dynamics.
3.1.3 Pathogenesis and clinical manifestations
Malaria: It was found that mutation in the gene encoding human intercellular adhesion molecule 1 (ICAM-1, CD54) was associated with increased severity of P. falciparum malaria and cerebral complications in Africans . Two mutations in mbl gene, which is responsible for host innate immune response, were detected in African children from Gabon who presented with severe clinical manifestations of malignant malaria . In another study conducted in Gabon two years later, the investigators studied several RBCs genetic polymorphisms (blood group, sickle-cell trait, and G6PD) as well as mbl gene and promoter regions of tumor necrosis factor-α (TNF-α) and nitric oxide synthesis 2 (NOS2) as contributing factors in clinical manifestations of malignant malaria. The investigators concluded that children with blood group O and hemoglobin AA and girls without mutation in the gene encoding G6PD are associated with mild malaria manifestations. Investigating the role of polymorphisms of genes encoding inflammatory response products, they found that mutation related only to TNF-α was associated with severe clinical manifestations, whereas neither the promoter regions of NOS2 nor mbl gene was correlated with clinical manifestations . However, individuals with point mutation in NOS2 had significant higher NO production and were associated with protection against severe malignant malaria in Gabon . Similar results were obtained in Indian patients protected from CM . However, the results of another case–control study among children from Ghana revealed the association of mbl gene mutation and severe P. falciparum clinical manifestations .
As mentioned previously, G6PD deficiency protects against P. vivax infections . The results of another study conducted in Gambia, including a larger sample size of infected children and controls, revealed that both heterozygous females and hemizygous males are protected from severe malaria. The investigators attributed their results to several unrecognized G6PD-deficiency alleles . Similar results were obtained in two different areas in Thailand, and further studies on larger sample sizes from different endemic areas were recommended for accurate genetic data aiming to map G6PD-deficiency variants and its relation to malaria infections . In addition, another study was conducted in Thailand with correlation to antimalarial treatment. The investigators recommended further studies to characterize the hemolytic risk of antimalarial treatment in different mutations that occurred in G6PD-deficiency variants . Recently, 17 G6PD genetic variants were detected, but the common mutations previously detected in South Asia were absent or rare in their sample size. Because few of these genetic variations showed association with malaria severity, they recommended further studies to map G6PD-deficiency variants in Sri Lanka population aiming to understand their functional significance in malaria infections . A year later, a case–control study was conducted in Gambia to investigate the association between malaria severity and the major functional alleles contributing to G6PD deficiency. The investigators concluded that G6PD deficiency is protective against severe malaria but with certain limitation to CM and with possible increased risk conferred on severe malaria anemia .
A mutation in the gene encoding TNF-α was a risk factor for frequent P. falciparum reinfections . Children with mutation in the gene encoding the anion-exchange protein 1 experienced severe clinical manifestations of malignant malaria. It was found that anion-exchange protein prevents adhesion of infected RBCs to endothelial cells . Several observations suggested that host heparan sulfate proteoglycans bind with circumsporozoite protein in both hosts: mammalian and vector. Any variation in host genes (hs3st3a1 and hs3st3b1) encoding the enzymes involved in host heparan sulfate proteoglycans biosynthesis might influence clinical outcome of malaria infection . Another host genetic factor involved in malaria pathogenesis is FcγRIIa (cd32 gene) whose mutation affects the affinity of the receptor for human IgG subclasses. The investigators assessed total IgG and subclass profiles to P. falciparum merozoite surface protein 1 in infected patients. No difference was detected in total IgG levels, whereas there was a significant difference between the frequency of positive responders for total IgG and IgG1 antibodies in patients with gene mutation. Therefore, the investigators suggested the occurrence of severe clinical manifestations in mutant patients . Increased levels of TNF-α and IL-6 are associated with severe malarial manifestations, and DDX39B (bat1 gene) regulates expression of these two cytokines. Brazilian investigators analyzed the frequency distribution of mutations that occurred at G and C alleles of bat1 gene in four groups (uninfected, asymptomatic, mild, and complicated P. vivax infections). They found that G and C allele mutations were associated with asymptomatic or mild clinical manifestations and disease complications, respectively. Levels of cytokines as determined by ELISA were correlated according to patients’ clinical manifestations . In a study to investigate polymorphisms in host tlr2 gene and its influence in development of CM, the investigators found that reduced TLR2 expression attenuated proinflammatory response and resulted in protection from CM only in patients with heterozygous gene mutation . Another study detected mutations in host genes encoding CD8+ and Janus-associated kinase 3 (Jak3) which mediates Th1 responses in patients with CM .
Other parasites: A collaborative group from France and Sudan demonstrated the role played by a locus on chromosome 6 (6q22-q23) near the gene encoding IFN-γ receptor on the increased susceptibility of periportal fibrosis (PPF) in Sudanese patients living in highly endemic areas in Gezira . Later on, the same group of researchers investigated the relationship between IFN-γ locus polymorphisms and PPF, and they confirmed the association of two polymorphisms with PPF . A recent study was conducted in India to screen host flt4 and foxc2 genes in patients with lymphatic filariasis, nonendemic individuals, and endemic control individuals. The investigators hypothesized a synergistic interaction of both gene mutations in lymphangiogenesis process caused by filarial parasites . In Chagas disease, patients with ccr5  or ikbl  or actc1  gene mutation are more susceptible to cardiomyopathy. In contrast, no association was detected between cardiomyopathy and host gene encoding angiotensin-converting enzyme .
3.1.4 Insecticide resistance
As a result of extensive use of insecticides (DDT and pyrethroids), the investigators detected increased frequency of kdr mutation and emergence of new mutation to ace-1R (organophosphates) in A. gambiae population in Africa. As change in malaria vectors population structure requires modification of malaria control strategy, the investigators recommended further studies to map the dynamic changes in vector distribution for malaria transmission . Similar results were obtained with detection of high frequency of kdr mutations . The influence of both mutations (kdr and ace-1R) on the outcome of malaria transmission was studied in three A. gambiae strains (one susceptible and two resistant). The mosquitoes were experimentally infected by P. falciparum, and the investigators found that both resistant strains increased the prevalence of infection. Interestingly, it was found that kdr resistant strain was associated with reduced parasite burden, compared with the susceptible strain, whereas such reduction was not observed in the other mutation ace-1R. This observation warned the authorities for malaria control regarding the extensive use of DDT and pyrethroid . Detection of gene mutation at kdr locus also increased the susceptibility of A. gambiae to P. falciparum infection, and the investigators emphasized the importance of development of new strategy for malaria control based on these results . In a review article, kdr mutations were found in 13 Anopheles spp. from African, Asian, and American continents. The reviewers also discussed the course of Plasmodium spp. infection in kdr mutant mosquitoes and suggested that continuous monitoring of insecticide resistance programs in endemic regions should be considered to complete malaria eradication . Recently, two studies were conducted in two African countries, and the results revealed increased frequency of kdr mutations in mosquitoes: A. funestus in Mali  and A. arabiensis in Senegal . On the other hand, it was found that the vector transmitter of Chagas disease, Triatoma infestans, developed gene mutation in the domain II region of voltage-gated sodium channel, the main target of pyrethroid insecticides .
3.1.5 Drug toxicity
Canadian investigators studied the serious adverse events reported in a small percent of patients administered with ivermectin for treatment of Loa loa infections. It was found that patients with high microfilariaemia develop fatal encephalopathy after treatment. The investigators analyzed mdr-1 gene polymorphism in dogs and mice with and without post-treatment toxicity and found gene mutations in ivermectin toxicity. Although they did not detect any mutation in human, they hypothesized the effect of mdr-1 gene mutation in ivermectin toxicity .
3.1.6 Control of vector-transmitted diseases
It was reported that altering mosquito genome to diminish Plasmodium spp. transmission through transgenesis or using genetic engineering tools can offer new strategy in malaria eradication. One of these tools is the use of transcription activator-like effector nuclease (TALEN) to induce mutation in the vector genome. To obtain hypersusceptible vector mutant lines, the investigators used TALEN to target tep1 gene, which is the principal component of their immune system. It was concluded that this approach could be applied to induce mutation in vector genes, essential for Plasmodium spp. development . Meanwhile, it was found that mosquitoes secrete phospholipase A2 in their midgut to prevent invasion of Plasmodium spp. ookinete. The investigators developed transgenic mosquito lines that impaired rodent malaria parasites, and these lines became fertile. In addition, the investigators found increased percentage of transgenic mosquitoes over the nontransgenic mosquitoes when they were placed together in one cage and the transgenic mosquitoes were fed on Plasmodium spp.-infected blood . Regarding leishmaniasis, of 700 sand fly species, only 10% are specific in its transmission, and galactose-binding protein (PpGalec) was found to have a role in this specificity. A study was conducted to explore sequence of the gene controlling PpGalec in sandflies collected from endemic and nonendemic areas of cutaneous leishmaniasis in Morocco. The investigators detected a mutation involved in substrate recognition by galectin, and they suggested that induction of this mutation in sandflies might influence the capacity of the vector PpGalec to recognize and bind with L. major lipophosphoglycan. The investigators concluded that this approach (induced mutation) might be one of the strategies used in control of cutaneous leishmaniasis .
3.1.7 Drug resistance
Investigating the frequency of host gene mutations is also applicable to obtain relevant data related to drug resistance in malaria. Cytochrome P450 is involved in artemisinin metabolism which is recommended in therapy-based combinations in many African countries. Frequency distribution of cytochrome P450 mutation variants was determined in patients infected with P. falciparum in Tanzania. Based on the detected frequencies (ranging from 10 to 78%), the investigators recommended further evaluation of the drugs used in the treatment of malignant malaria in Tanzania . Because the ability to clear P. falciparum depends on drug regimen and host immune response, the investigators determined frequency distribution of 62 mutations on 17 human chromosomes (candidate immune genes). Genes encoding immune response factors and involved in clearance of drug resistant mutant parasites were determined in Cameroonian children. The investigators found that IL-22, IL-4, IL-10, IL-17, CD36, and TNF-α are essential in clearance of resistant parasites but without significant distribution, owing to small sample size .
Gene mutation is a change in nucleotide sequence of a short region of DNA genome resulting in structural and functional changes of the encoded protein. It occurs in either the parasite or the host, which may be beneficial or harmful for either one. Mutations arise either spontaneously or on exposure to certain environmental factors such as ultraviolet light, radiation, and chemical carcinogens. Scientifically, they are classified into four types: hereditary, acquired, induced, and spontaneous. Most commonly, they affect a single gene; however, in some instances, they alter the functions of several genes with major phenotypic consequences. Molecular techniques are the most common tools used to identify gene mutation(s) such as DNA microarray and sequencing, RFLP, single-strand conformational polymorphism, multiplex ligation-dependent probe amplification, denaturing gradient gel electrophoresis, and heteroduplex analysis.
The most common and important applications of host gene mutations in parasitic diseases are resistance and susceptibility to diseases, carcinogenesis, and vector control.
Resistance or susceptibility to malaria is linked to mutations in host genes related to blood receptors (Duffy antigen/chemokine, glycophorins, and chitotriosidase), hemoglobin or RBCs disorders (sickle-cell anemia, thalassemia, G6PD or PK deficiency, and Melanesian ovalocytosis), and immune response such as CD36 deficiency and MBL, which activates complement.
Resistance or susceptibility to VL is linked to host mutations in several genes related to immune response such as nramp1, slc7a2, op/op, and mbl2 genes controlling innate immunity against intracellular parasites, macrophage activation, macrophage colony-stimulating factor, and MBL responsible for enhancing intracellular infections, respectively. Other genes related to metabolic disorders were also incriminated such as lpl gene controlling lipoprotein lipase, whereas mutations in the genes encoding cytokines production (IL-12, IFN-γ) and TLR4 and fas apoptosis gene were linked to resistance or susceptibility to cutaneous leishmaniasis.
In most studies, two host genes were incriminated in the development of cancer bladder in urinary schistosomiasis: p53 and cdkn2 genes. Development of CCA as sequel complication of O. viverrini is a multistep process requiring accumulated gene alteration and/or mutation of host tumor suppressor genes (riz, cdc42, and dffb).
Generations of transgenic mosquitoes with mutant tep1 gene, a principal component in their immune system for Plasmodium spp. development, proved a novel approach to prevent Plasmodium spp. transmission to the vector. Similarly, induced mutations to sandflies influencing their capacity to recognize and bind to L. major lipophosphoglycan would decrease disease transmission.
Authors are equally contributed in writing the review article.
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Conflicts of interest
There are no conflicts of interest.
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