Malaria transmission and individual variability of the naturally acquired IgG antibody against the Plasmodium vivax blood-stage antigen in an endemic area in Brazil
Introduction
Malaria is an infectious disease that is transmitted in many parts of the world, and most cases are caused by Plasmodium vivax or Plasmodium falciparum (World Health Organization 2018, World Health Organization 2015). P. vivax is geographically the most widely distributed parasite and is highly prevalent in Asia and South America (Mendis et al., 2001; Howes et al., 2016). In Brazil, malaria occurs in the Brazilian Amazon region, where approximately 85% of infections over the last two decades have been due to P. vivax (Oliveira-Ferreira et al., 2010; Siqueira et al., 2016). In 2017, the number of reported malaria cases caused by this species was 169,834 (World Health Organization, 2018). In general, there is no realistic plan for the complete elimination of its transmission in all endemic areas (World Health Organization, 2016).
Epidemiological and immunological studies have shown that after exposure, individuals living in P. vivax malaria-endemic areas may develop an effective immune response that controls parasitemia and induces minimal clinical symptoms (Luxemburger et al., 1999; Alves et al., 2002; Nogueira et al., 2006; White et al., 2014). Although immunity to malaria infection develops relatively slowly and is incomplete, the immune response can occur at any point in the parasite's life cycle after the entry of sporozoites (Greenwood et al., 2008; Riley and Stewart, 2013). The mechanism is not fully understood, but extensive evidence suggests that antibodies are important mediators of this process in humans (Cohen et al., 1961; Boyle et al, 2015; Cockburn and Seder, 2018). The acquired response is thought to predominantly target blood-stage parasites, though as immune targets, antigens expressed by sporozoites and malaria-infected hepatocytes are also involved (Riley and Stewart, 2013; Cockburn and Seder, 2018).
The erythrocytic stages of Plasmodium ssp trigger potent host responses by elevating antibody levels (Soares et al., 1997, Soares et al., 1999b; Riley and Stewart, 2013; Beenson et al., 2016; Longley et al., 2016). The main determinant of antibody acquisition is exposure to parasite antigens, which can be determined, in part, as a marker of malaria transmission intensity (Burattini et al., 1993; Drakeley et al., 2005; Zeyrek et al., 2011; Cunha et al., 2014; Folegatti et al., 2017). In Brazil, where transmission is usually low and seasonal, a detailed description of dynamic antibody acquisition in different areas, such as where P. vivax- and P. falciparum-caused malaria have equal or differing prevalence, is important for understanding how the humoral immune response is achieved and maintained (Cutts et al., 2014; Cunha et al., 2014).
Merozoite surface protein 1 (MSP1) is one of the most studied molecules on the surface of asexual blood-stage malaria parasites (Soares et al., 1997, 1999a,b; Holder, 2009; Beenson et al., 2016). This molecule is present in all Plasmodium species, and P. vivax MSP1 sequence determination has enabled detailed structural analyses and identified a sequence of approximately 100 amino acids in the C-terminal region, which comprises two epidermal growth factor (EGF) domains called MSP1-19 (Del Portillo et al., 1991). This protein is transported to the surface of the intracellular parasite, where it is retained as a result of its glycosylphosphatidylinositol (GPI) anchor. MSP1-19 is the C-terminal 19-kDa fragment synthesized at the end of schizogony, when merozoites are released from infected red blood cells (Babon et al., 2007).
Several immunoepidemiological studies have described the high antigenicity of the P. vivax C-terminal region (PvMSP1-19) and shown a high prevalence of IgG antibodies against this antigen in serum samples from populations living in countries with variations in malaria transmission intensities, including Brazil (Soares et al., 1997, 1999a; Cunha et al, 2001, 2014; Ladeia-Andrade et al., 2007; Fernandez-Becerra et al., 2010; Folegatti et al., 2017). Nonetheless, little is known about the homeostasis of these antibodies over a long period of time under conditions of possible reinfection.
Antibody kinetics involves a balance between production and decay. Antibody production can be sustained through the restimulation of memory B cells by persistent antigens or by nonproliferating long-lived plasma cells (Langhorne et al., 2008; Wipasa et al., 2010; Riley and Stewart, 2013; Cockburn and Seder, 2018) and there have been continuous efforts to develop malaria vaccines within this context. However, such efforts have not been matched by similar levels of investment in understanding the basic aspects of the immune response to malaria parasites, which are essential for vaccine research (Langhorne et al., 2008; Cockburn and Seder, 2018) as well as for serological approaches for epidemiological surveillance (Drakeley et al., 2005; Zeyrek et al., 2011; Cutts et al., 2014). For P. vivax in particular, this limitation is even greater considering the restrictions involved in the cultivation of this parasite for biological assay studies (Mueller et al., 2009; Bermúdez et al., 2018).
In the last three decades, PvMSP1-19 has been extensively analyzed as an immunological target against malaria parasites in a variety of studies in humans (Soares et al., 1997; Perera et al., 1998; Ladeia-Andrade et al., 2007; Mourão et al., 2012; Cunha et al., 2014; Beenson et al., 2016; Folegatti et al., 2017) and animal models (Perera et al., 1998; Cunha et al., 2001; Sachdeva et al., 2004). These include studies that have described antibody acquisition in individuals naturally exposed to malaria parasites, revealing a correlation between exposure and the acquisition of such antibodies (Soares et al., 1997; Ladeia-Andrade et al., 2007; Cunha et al., 2014; Folegatti et al., 2017). Regardless, a limitation of these studies is the lack of detailed information on the kinetics of these antibodies in the population.
We herein describe a profile of a naturally acquired IgG antibody response in individuals living in an unstable malaria transmission area in Pará state in Amazon region, Brazil, where an epidemic of P. vivax malaria was recorded and monitored over time. This epidemic was characterized by intense exposure and high circulating parasite levels over a short period of time. Individual differences in antibody responses against P. vivax MSP1-19 were observed, highlighting variation in the acquisition and decay of IgG antibodies that might be useful for understanding differences in antibodies and immunity acquisition in P. vivax malaria infection.
Section snippets
Study area, surveys and epidemiological data
The study area was selected based on the high incidence of malaria recorded in Goianésia do Pará municipality, which in 2010 was classified as a high-risk area for malaria by official malaria surveillance/Ministry of Health of Brazil (Sivep/Malaria). This area is located southwest of Pará state in the Brazilian Amazon region (Figure 1). The study was carried out with three cross-sectional surveys conducted once a year in 2010 (November), 2012 (August) and 2013 (July) before the rainy season.
Results
Epidemiological data confirmed natural exposure to the P. vivax antigen, with acquisition and decay of the IgG antibody. Malaria transmission occurred in this area between 2010 and 2014 as part of a focal epidemic, and 7,788 malaria cases were registered (Table 1). During this period, this area was maintained under intense surveillance, and consequently, exposure to malaria parasites decreased over time. The major species involved in this malaria epidemic was P. vivax, which in 2010 was
Discussion
We analyzed the acquisition and decay of the IgG response to the C-terminus of MSP1 (MSP1-19), which is the most immunogenic of antigens from the different P. vivax blood stages, as well as the impact of endemicity on the humoral immune response in malaria by monitoring the acquisition of IgG anti-PvMSP1-19 during an epidemic malaria outbreak. We described the temporal, spatial and individual variability, indicating the importance of the IgG as biomarker of P. vivax exposure.
The presence of IgG
CRediT statements for authors
Maristela G. Cunha: Conceive and design of the study, participated in the process of blood sample collection, coordinated laboratory work, data analyses and writing of the manuscript.
Edna Maria F. Costa: Performed laboratory work by ELISA and data analysis.
Ednei Charles C. Amador: Performed laboratory work by ELISA and data analysis.
Eliane S. Silva: Performed laboratory work by expression and purification of the recombinant protein.
Cassiana O. Alvarenga: Performed laboratory work by ELISA.
Pedro
Declaration of competing interest
The authors declare no conflict of interest.
Acknowledgments
Funding was provided by the National Research Council of Brazil (CNPq- Conselho Nacional de Desenvolvimento Científico e Tecnológico) and FAPESPA (Fundação Amazônia Paraense) program grant to Rede Paraense de Malária, Processo: 555654/2009-5, coordinated by MMP), and PPSUS/MS/FAPESPA, ICAAF 182/2012 coordinated by MGC. We thank João F. Guerreiro for support to collect samples, Regina Célia Guerreiro and Lauro Cunha for the medical attendance of the patients, Hailton Monteiro, Vilson Monteiro,
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