ABSTRACT

Unlike for major bacterial and viral pathogens, established and readily available vaccines do not exist to prevent parasitic protozoan infections. A better understanding of the factors that influence immunity to these diseases may provide a foundation to design novel public health interventions. Transmission of the enteric protozoa typically occurs through the fecal-oral route. The intestine is densely populated by commensal bacteria well situated to influence the behavior of the protozoan parasites with which they directly interact (1). The potential influence of the microbiota on parasites is not, however, limited to the intestinal protozoa. Protozoa that live in the blood or tissue of humans may also be affected by the interplay between the gut microflora and the host metabolism and immune system (1,–6). The focus of this review will therefore be the impact of the human microbiota on the parasitic protozoa that infect the intestine (Entamoeba histolytica, Giardia, Cryptosporidium, Blastocystis hominis) or vagina (Trichomonas vaginalis) or cause systemic infections (Plasmodium falciparum) (7). Changes in the composition of the intestinal microbiota may increase resistance to infection at mucosal sites, as well as alter systemic immunity to these parasites (Fig. 1).

PARASITIC PROTOZOANS AND THE SCOPE OF THE PUBLIC HEALTH IMPACT

Worldwide, diarrhea is currently the second leading cause of death in children younger than 5 years of age and is associated with around 500,000 deaths per year (8,–10). Although diarrhea can be caused by many pathogens, in a large proportion of cases, the causal organism is a parasitic protozoan (11). In 2010, an estimated 357 million cases of illness with at least one of three enteric protozoa, Entamoeba, Cryptosporidium, and Giardia, resulted in 33,900 deaths and the loss of 2.94 million disability-adjusted life years (12). In a recent study of moderate-to-severe diarrhea in African and Asian children, Cryptosporidium spp. were some of the top diarrhea-associated pathogens (13).

Despite the significant health burden that protozoans cause, infections can be asymptomatic. For instance, in a Bangladeshi childhood cohort, Entamoeba histolytica, the causative agent of amebiasis, was found to be associated with diarrhea in only 1 of 4 infections (14, 15). Overview Of Protozoan Parasite – A Cause Of Malaria Essay. Cryptosporidium and Giardia infections are also marked by wide variations in clinical presentation (16,–19). Plasmodium infections result in clinical presentations that range from asymptomatic to severe malaria and result in ∼1 million deaths annually. Despite this toll, the factors that determine disease severity remain poorly understood (20). Host genetics and variation in immune response contribute to protection from parasites; however, it is increasingly clear that the intestinal microbiota may have a significant influence on the disease progression of both the enteric protozoa (1) and blood-borne malaria parasites (4).

INTESTINAL MICROBIOTA

The intestinal bacterial microbiota (21, 22) is a complex community of bacteria which is comprised of at least several hundred species. These organisms form a symbiotic relationship that influences human physiology and disease progression (23, 24). Epidemiological studies have shown that the composition of the intestinal bacterial microbiota can correlate with the development of, or resistance to, obesity (25), malnutrition (26, 27), and allergic disease (28) and may also influence cognitive function and development (29). The intestinal microbiota is not limited to prokaryotes (30), with archaea and eukaryotes potentially contributing to clinical variation (31, 32).

Microbiota compositions can vary significantly from one person to the next (33), even within healthy individuals or twins in the same household (34). Several studies have noted that the bacterial microbiota may influence the virulence of individual pathogens and potentially add variability to the outcomes of parasitic protozoan infections (1, 22). For example, coculture with Escherichia coli strains can augment or attenuate the virulence of Entamoeba histolytica (35, 36). Recently reported studies highlight the impact of the microbiota on infections with enteric protozoa and on infection with extraintestinal Plasmodium parasites. Overview Of Protozoan Parasite – A Cause Of Malaria Essay.

MUCOSAL PARASITES AND MICROBIOTA INTERACTIONS IN HUMAN POPULATIONS

Mucosal infection with the enteric protozoa Entamoeba, Giardia, Cryptosporidium, and Blastocystis can be asymptomatic or cause diarrhea, abdominal pain, and/or weight loss. The infecting parasites reside in the intestinal mucosa and therefore are surrounded by the mucosa-associated microbiota. It has been proposed that the dynamic interplay that occurs between the protozoan parasite, host microbiota, and host immune system shapes the clinical outcome of enteric infections (1, 37).

Infection with the gut parasite Entamoeba was significantly correlated with fecal microbiome composition and diversity. Entamoeba species infection was predicted by the composition of an individual’s gut microbiota with 79% accuracy in a study of the farming and fishing populations in southwest Cameroon (38). One of the most important taxa in predicting an infection with Entamoeba was Prevotellaceae. In a separate independent study focused on the E. histolytica-associated diarrhea that is common in Bangladeshi infants, levels of Prevotella copri, a member of the Prevotellaceae, were found to be elevated in patients with diarrheagenic E. histolytica infections (39) (Table 1). The Cameroonian study was focused on infected adults who were not experiencing symptomatic amebiasis; therefore, it is interesting that both P. copri and Prevotella stercorea were significantly downregulated in infected individuals (38, 40, 41). Both studies suggest that microbiota composition may play a significant role during an E. histolytica infection. Overview Of Protozoan Parasite – A Cause Of Malaria Essay. These studies also highlight the potential influence of inflammation driven by the gut microbiome in altering parasite infection outcomes (37, 39). Elevated levels of P. copri have been associated with severe inflammation and an increased risk of autoimmune disease and colitis, suggesting that the organism is proinflammatory (41).

Cryptosporidium, Giardia, Blastocystis, and Trichomonas infections may also be influenced by the gut microbiota. A retrospective study of volunteers who were originally enrolled in Cryptosporidium infectivity studies (42) examined the relationship between the relative abundances of several bacterial taxa commonly found in adults prior to or within 48 h of infection and infection outcomes. The patients that were protected from infection had a greater abundance of Proteobacteria and lower Bacteriodetes and Verrucomicrobia levels than infected subjects. There was a higher ratio of Firmicutes to Bacteriodetes in uninfected subjects than in infected subjects. Seven specific taxa had differences of at least 2.5-fold between the two groups. Specifically, uninfected subjects had increased relative abundances of the indole-producing bacteria Escherichia coli CFT073 and Bacillus spp., as well as Clostridiumspp. In contrast, infected subjects had increased relative abundances of Bacteroides fragilis, Bacteroides pyogenes, and Prevotella bryantii, as well as Akkermansia muciniphila (Table 1). Presently, the mechanism by which increased indole production may protect from Cryptosporidium is unknown. Indole may directly adversely affect the parasite or perhaps alter host tissues to enhance the innate response by increasing epithelial integrity (43) and/or stimulating anti-inflammatory pathways (42, 44).

A study of intestinal parasite infection in individuals in southern Côte d’Ivoire utilizing PCR-temporal temperature gel electrophoresis (TTGE) and quantitative PCR demonstrated that TTGE profiles clustered into four significantly different groups, i.e., groups that are positive for Giardia duodenalis, positive for Entamoeba spp. and Blastocystis hominis, negative for protozoa, and positive for all three parasites. Quantitative PCR of selected bacterial species in these four groups showed that there was a significant increase in the relative abundance of Bifidobacterium in G. duodenalis-positive patients. This study suggested that the tested intestinal protozoans can induce significant changes in the microbiome which result in substantially different bacterial communities (Table 1). Overview Of Protozoan Parasite – A Cause Of Malaria Essay.

The relative abundances of Faecalibacterium prausnitzii and E. coli have been used as a marker of the inflammatory bowel disease (IBD)-induced dysbiosis associated with increased E. coli levels (45, 46). Application of this tool to samples from a patient cohort in Côte d’Ivoire suggested that the Côte d’Ivoire and Cameroonian study results were in agreement and that an increase in microbiome diversity occurs in asymptomatic Entamoeba species infections. The Côte d’Ivoire results also suggest that this observation may be extended and that an increase in microbiome diversity also occurred during Blastocystis hominis infections (47). It is controversial, however, whether Blastocystis can cause diarrhea (48). Part of the reason for this controversy might be due to the tremendous genetic diversity within Blastocystis spp. Blastocystis hominis consists of at least seven morphologically identical but genetically distinct organisms (49). The gut microbiome which Blastocystis encounters upon infecting a human host may also influence clinical outcomes. Audebert et al. compared the microbiomes of Blastocystis-colonized and Blastocystis-free patients in a case-control study design that controlled for environmental and clinical risk factors, such as seasonal variation (50). The authors also reported a higher bacterial diversity in the fecal microbiota of Blastocystis-colonized patients, with a higher abundance of Clostridia as well as a lower abundance of Enterobacteriaceae (Table 1). These results suggested that Blastocystis colonization may be associated with expansion of members of the intestinal microbiota generally associated with a healthy gut microbiota, rather than with expansion of bacteria associated with gut dysbiosis.

Trichomonas vaginalis, the causative agent of trichomoniasis and an extracellular parasite of the human urogenital tract, is the most common nonviral sexually transmitted infection globally (51). Women are disproportionally impacted by trichomoniasis, with symptomatic infection primarily impacting the vaginal mucosa. Variation in clinical presentation of disease may be impacted by the composition of the vaginal microbiota. In a study of the vaginal microbiota of T. vaginalis-positive and T. vaginalis-negative women, infection was associated with vaginal microbiota consisting of low proportions of lactobacilli (52) (Table 1). T. vaginalis interactions with various Lactobacillus species inhibit parasite interactions with human cells (53).

In summary, the referenced human studies suggest that there is a strong link between the composition of the intestinal bacterial microbiota and mucosa-associated enteric protozoa (Table 1). Future studies are needed to understand the nature of the connection and how it can be utilized for disease prevention. Overview Of Protozoan Parasite – A Cause Of Malaria Essay.

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PLASMODIUM AND GUT MICROBIOTA

Approximately 60% of the world’s population is at risk of infection with Plasmodium(54, 55). However, the distribution of clinical malaria is highly heterogeneous. In studies in Kenya and Senegal, the number of clinical episodes of disease ranged from 0 to 40 per child over a 5-year period in the same community (56, 57). Clinical variation has been attributed to genetic differences. For example, heterozygous carriers of the hemoglobin variant HbS, associated with sickle cell disease, are healthy and are protected from severe forms of malaria, including cerebral malaria (58). Variation in exposure and variance in immune response are also implicated. However, these factors may not completely explain such a large clinical variation (55, 59). The intestinal bacterial microbiota might represent an environmental factor that may contribute to this variability.

In a recent study, stool samples were collected from a cohort of Malian children and adults just before the P. falciparum transmission season (4). The compositions of gut bacterial communities in these individuals were determined and compared to the risks of acquiring P. falciparum infection and febrile malaria. A significant association was found between microbiota composition and the prospective risk of P. falciparuminfection. The intestinal microbiota of subjects who did not become infected had a significantly higher proportion of Bifidobacterium and Streptococcus species than subjects who became infected with P. falciparum. However, no relationship was observed between microbiota composition and the risk of developing febrile malaria once P. falciparum infection was established. The authors note that this is possibly due to a lack of statistical power. The preliminary finding of an association between gut microbiota composition and P. falciparum infection risk suggests that alteration of the composition of the intestinal microbiota may decrease the risk of P. falciparum infection in areas where malaria is endemic and may potentially augment partially effective malaria vaccines (4) (Table 1). Overview Of Protozoan Parasite – A Cause Of Malaria Essay.