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Plasmodium vivax msp1 42 Haplotypes in Southern Mexico
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This entry is adapted from the peer-reviewed paper 10.3390/microorganisms10010186

P. vivax msp1 42 polymorphism from parasites the control and pre-elimination phases in southern Mexico was analyzed. Nucleotide variation of pre-elimination parasites showed a population contraction. Four Haplogroups having specific B-cell epitopes displayed spatiotemporal fluctuations. 

Plasmodium vivax merozoite surface protein 1 (42 kD) haplotype diversity haplogroups B-cell epitopes genetic structure spatiotemporal changes

1. Introduction

There are approximately 241 million malaria cases per year worldwide and 627,000 related deaths, according to the estimates of the World Health Organization (WHO) [1]. In Mexico, the number of cases fluctuated between 20,000 and 130,000 per year in the 1980s. In the following decade, the anti-malaria measures of the intensified control programs caused a gradual decrease in cases.
Anti-malarial control measures are implemented when the burden of malaria infection becomes an important public health problem and the slide positivity rate of fever cases is above 5%. The latter rate is a method for analyzing changes in malaria incidence; if it drops below 5% and certain other requirements are met, a country may enter the pre-elimination phase, which consists of the evaluation and reorientation of anti-malaria policies and strategies [2]. Mexico has remained in the pre-elimination phase since 2007.
In Mexico, the number of malaria cases had declined to 514 by 2016 [3]. Nevertheless, in 2017 this country reported a 37% rise in cases—most notably in the states of Chiapas, Chihuahua, and Tabasco. Alarmingly, new cases began to appear in San Luis Potosi in the same year, a state formerly enjoying an absence of malaria transmission [1][3][4].
The multiple mosquito vectors implicit in Plasmodium vivax genetic and haplotype diversity contributes to successful transmission in distinct environments [5]. Such diversity potentially plays an important role in the development of parasite mechanisms for evasion of the vertebrate and invertebrate host immune response (even after the application of vaccines) and the selection of strains resistant to current drugs [6][7]. Various evolutionary forces act on genes that code for blood-stage antigens, resulting in high polymorphism and parasite diversity. Thus, it is necessary to distinguish between the different species of parasites and trace their haplotypes [8]. Additionally, this information is essential for designing effective vaccines and surveillance strategies [9]. For countries moving to the elimination phase, therefore, a key strategy is the use of genetic studies with polymorphic markers to understand transmission dynamics. They provide evidence of the weakening of parasite transmission when the number of cases is diminishing and aid in molecular surveillance.
The P. vivax merozoite surface protein 1 (PvMSP1) is a 200 kD protein coded by a gene located on chromosome 7 [10]. It is abundant on the surface of merozoites and, during the invasion, makes the first contact with human reticulocytes [11]. The carboxyl end of the 42 kDa peptide (PvMSP142) is processed into two segments of 33 and 19 kDa (PvMSP133 and PvMSP119, respectively). PvMSP119 is formed by two highly conserved epidermal growth factor-like domains that bind to reticulocytes [12]. According to immuno-epidemiological studies, PvMSP133 [13][14] and PvMSP119 [15][16][17] are highly immunogenic and, consequently, could be useful as vaccine candidates for P. vivax. However, a polymorphic segment of PvMSP133 is presumably involved in the evasion of the host antibody response, as suggested by evidence that PvMSP133 might be under balancing selection [18][19][20][21].

2. Pvmsp142 Polymorphism and Evaluation of Nucleotide and Haplotype Diversity

The processing of 217 samples afforded 163 msp142 sequences with a single nucleotide sequence and 936 base pairs (comprising nucleotides 4149–5085 or codons 1384–1695). None of the sequences were similar to the Sal-I strain (XM_001614792.1) [22]. In addition, 26 sequences exhibited double peaks in both forward and reverse sequences (the other samples did not amplify). Pherograms with double peaks were considered to be multiple genotype infections (MGIs), because double peaks occurred at two or more nucleotide positions in the polymorphic region of pvmsp133, while the pvmsp119 fragment was conserved. Thirty-five single sequences previously reported from the same geographic region (2006–2007) [23] were included in the current analysis, thus constituting a total of 198 sequences. In pvmsp133, 57 polymorphic sites and 64 mutations were identified (nucleotides 4093–4917 or codons 1364–1639), as were 7 synonymous substitutions (codons: 1476, acc→acg; 1509, gaa→gag; 1532, agt→agc; 1533, ctg→ttg; 1538, cca→ccg; 1564, gtc→gtt; and 1570, ctg→ctt) and 57 nonsynonymous substitutions. On the other hand, pvmsp119 (nucleotides 4918–5085 or codons 1640–1695) was conserved and similar to the Sal-I sequence.
The nucleotide (π) and genetic diversity (θ) of the 198 single nucleotide sequences were 0.0219 and 0.0104, respectively. The haplotype diversity was 0.802 ± 0.014, finding 17 haplotypes. The most common haplotypes were h1, h4, h5, and h9, found at 31.8%, 21.2%, 14.6%, and 18.6%, respectively. For these sequences, a minimum number of 12 recombination events was estimated, with a correlation coefficient index (R2) of 0.332 (LD = R2). The dN/dS and Tajima’s D values forpvmsp142 were positive, being 1.108 (p> 0.05) and 2.650 (p < 0.05).

3. Temporal Analysis of pvmsp142 Nucleotide Diversity, Recombination, and Natural Selection

Of 26 multiple genotype infections encountered presently, there were 22 (84.6%) in samples from the 1990s (Figure 1), and 29–75% of them in any particular year. In contrast, only one of these multiple genotype infections was discovered in the samples from 2001, two in 2009, and one in 2010. A comparison of the proportion of haplotypes was made for 2002–2011, as more than 10 single sequences were obtained per year. The proportion of the distinct haplotypes was similar in samples from 2002 and 2003. In the following years (2004–2007), however, h1 was observed in a lower proportion in those samples. The proportion of haplotypes was significantly different between samples from 2003 and 2004 (Pearson’s chi-squared value (χ2(5) = 14.5; p = 0.015)) and between samples from 2006 and 2007 (χ2(7) = 16.1; p = 0.024). H4 was detected in most of the samples in 2007. During the next four years (2008–2011), the haplotype pattern was similar to that observed in samples from 2002–2003, except for the scant number of parasites containing h9 (as in 2007). The comparison of samples from 2007 and 2008 showed a significant difference in the proportion of haplotypes (χ2(4) = 14.6; p = 0.005; Figure 1).
Figure 1. P. vivax msp142 haplotypes in infected blood samples from each year. Bars portray single sequences and multiple genotype infections (MGI) from southern Mexico. From 2002–2011, the proportion of the most common haplotypes varied over time.
The pvmsp142 sequences were grouped into four consecutive periods. For 1993–2001 samples, only 31 single sequences were obtained and were considered as one group that existed during the years of highest transmission. As this group included many years and few sequences, quantitative outcomes were not analyzed or compared to the other periods, all of which involved more than 50 P. vivax sequences: 2002–2004 (n = 57), 2005–2007 (n = 54), and 2008–2011 (n = 56). There was a subtle variation in nucleotide and genetic diversity between samples of these periods, finding π and θ values ranging from 0.0205–0.0210 and 0.0111–0.0126, respectively. In contrast, the R2 index of LD increased gradually in samples from 2002–2004 to 2008–2011, and the dN/dS and Tajima’s D values were positive. In samples from 2008–2011, Tajima’s D values were positive, although dN/dS values were not significant.

4. Haplotype Network, Temporal Changes, and Haplogroups

The haplotype network demonstrates that the P. vivax msp142 haplotypes of southern Mexico are separated by 1 to 75 mutational steps. When divided into four haplogroups (Hg: A, B, C, and D), they were visibly separated from each other by 17 to 20 mutational steps. Each Hg comprised at least one high-frequency haplotype and other closely-related low-frequency ones (Figure 2). HgA included the high-frequency haplotype h1 and three low-frequency haplotypes (h12>h6>h15) separated by two, one, and four mutational steps from h1, respectively. In HgB, the high-frequency haplotype h4 was followed by h2 and three low-frequency haplotypes (h8, h14, and h16), separated by three, three, one, and five mutational steps from h4, respectively. HgC contained the high-frequency haplotype h9 and three low-frequency haplotypes (h10, h17, and h13), which were separated by four, six, and four mutational steps from h9. Haplotype h3, detected in two parasites from 1993 and 1994, was classified as HgC even though it was separated by 15 mutational steps from h9. HgD consisted of the high-frequency haplotype h5 and two low frequent haplotypes (h7 and h11), separated by three and four mutational steps from h5 (Figure 2). The temporal network showed that the high-frequency haplotypes from each Hg were encountered in sequences from all periods, although changes in the proportion were observed in certain periods within 2002–2011. Some of the low-frequency haplotypes of each Hg were found in different periods (h12, h2, and h10), while others were detected in only one isolate.
Figure 2. The haplotype network of P. vivax msp142 from 1993–2011 in southern Mexico. Each color corresponds to one haplotype. The number of samples containing each haplotype is indicated by the size of the circle. Black dots represent existing or extinct haplotypes not found in the samples. The number of mutational steps between haplotypes, if higher than one, is denoted. Four haplogroups were formed (HgA, HgB, HgC, and HgD). In the 198 sequences analyzed, haplotypes h1, h4, h5, and h9 were the most common, found at 31.8%, 21.2%, 14.6%, and 18.7%, respectively. Pvmsp142 haplotypes displayed a similar pattern of colors as in Figure 1.

5. Spatiotemporal Distribution of the Haplogroups in Southern Mexico

The geographic pattern of haplogroups varied with time (Figure 3). Most sequences came from the municipality of Tapachula and its surrounding areas. The high-frequency haplotypes in each sample/period were detected in Tapachula City. In the 1990s, most sequences were from the city and fewer came from the outlying hilly and coastal regions. From 2002 on, most parasite sequences came from a combination of the outlying hilly areas and the city.
Figure 3. Geographic distribution of pvmsp142 haplotypes during four time periods from 1993–2011. The size of the circles is proportional to the number of isolates from each rural area and Tapachula City. Haplogroups are illustrated in the same colors and haplotypes in the same shades as in Figure 2. The spatial pattern of haplogroups varied from one period to another. The multiple genotype infections (MGIs) detected in 1993–2001 displayed a scattered distribution in the region. The largest circle on each map corresponds to Tapachula City (short arrow). A significant difference in the proportion of haplotypes existed when comparing samples from 2002 to 2004 and 2005 to 2007 [χ2 (11) = 27.2781; p = 0.004], 2005 to 2007 and 200 to 2011 [χ2 (12) = 38.4027; p = 0.000], and 2002 to 2004 and 2008 to 2011 [χ2 (7) = 18.5703; p = 0.010].
All haplogroups and the haplotypes in each group were scattered across the geographic area (Figure 3). In 1993–2001, haplotypes of the different haplogroups were present in the city and rural areas. Members of HgA, HgB, HgC, and HgD were found in Tapachula City in sequences from all periods. HgA haplotypes were identified in 7 rural areas in sequences from 2002 to 2004, 4 in 2005–2007, and 18 in 2008–2011. HgB constituents were encountered in 8 rural areas in 2002–2004, 16 in 2005–2007, and 7 in 2008–2011. HgC members were evidenced in 14 rural areas in 2002–2004, 8 in 2005–2007, and 3 in 2008–2011. Lastly, h5 in HgD was discovered in 3 rural areas in 2002–2004, 6 in 2005–2007, and 10 in 2008–2011. The city was the site with the highest number of sequences. It also showed the greatest variation in the composition of each Hg when comparing the sequences from 2002 to 2004, 2005 to 2007, and 2008 to 2011 (Figure 3).

6. Linear B-Cell Epitopes

In the polymorphic amino acid sequences, haplogroup-specific B epitopes were predicted (Figure 4). In HgA, one amino acid changed from a polar to a positive charge (Q1506R in h15). This Hg was similar to the Sal I sequence. In the highly variable region, the peptide SEVSQNSEKTQL in HgB and two peptides (EELKKIENEANK and NTQNEELKKIEN) in HgC were predicted to participate in B-cell epitopes. In HgD, the peptides IKKIGSGSTKTT and TQSMAKKAELEKY were predicted to participate in B-cell epitopes. Additionally, three peptides from the semi-conserved carboxyl region of the 33 kDa fragment between codons 1668 and 1730 (EEYKKSEKKNEV, NCQLEKKEAEIT, and SKLIKENESKEI) were predicted to participate in B-cell epitopes.
Figure 4. The P. vivax MSP1-42 kDa highly variable peptide segment (amino acids 1489–1536) and the predicted B-cell epitopes. Different B-cell epitopes were predicted for each haplogroup with the Bcpred web server (in the red boxes). The epitope prediction of ≥12 consecutive amino acids was obtained by using 85% specificity. The Sal-I sequence was similar to h1 from southern Mexico.

7. SplitsTree Analysis

Pvmsp142 sequences from parasites in southern Mexico were compared to 631 homologous sequences from other geographic regions of the world. In 829 sequences, 117 segregating sites and 206 haplotypes were observed. The SplitsTree analysis of all haplotypes showed four main clusters with distinct assemblies and branches that contained parasites from the different parts of the world (Figure 5). Eleven of the seventeen haplotypes were exclusive to southern Mexico, including all those in HgD. For HgC, the high-frequency h9 and low-frequency h3 were exclusive to southern Mexico, whereas low-frequency h10 and h13 were shared with Nicaragua, and low-frequency h17 was detected at various sites (e.g., South Korea). HgA was closely related to the Sal-I sequence, and its high-frequency h1 was found in southern Mexico and Nicaragua, while its low-frequency haplotypes (h6, h12, and h15) were exclusive to southern Mexico. The most common haplotypes of HgB, being high-frequency h4 and low-frequency h2, were shared with Brazil, Turkey, and South Korea. One of them was also discovered in Thailand. The low-frequency haplotypes of HgB (h8, h14, and h16) were exclusive to southern Mexico. Worldwide, the three most common haplotypes were identified in Asian parasites—h106 and h142 from Thailand and h77 in Sri Lanka and South Korea (Figure 5). Based on the complex network, no particular structure of the parasite population existed at the global level. Plasmodium cynomolgi was rooted in between the HgC and HgD networks (Figure 5).
Figure 5. SplitsTree analysis of the global distribution of P. vivax msp142. The four main clusters found with the NeighborNet method resembled haplogroups A, B, C, and D (established by the haplotype network). Only the most common worldwide haplotypes (≥29) are portrayed. P. cynomolgi served as the outgroup. The bar scale denotes the nucleotide substitution per site.

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