Intracellular Pathogens: Infection, Immunity, and Intervention.

Intracellular pathogens comprise a diverse group of pathogens that all share a required location in a host cell to infect, survive, and replicate. Intracellular location allows pathogens to hide from host immune responses, avoid competition with other pathogens, mediate host cellular functions, replicate safely, and cause infection that is difficult to target with therapeutics. All intracellular pathogens have varying routes of infiltration into host cells and different host cell preferences. For example, bacteria Mycobacterium tuberculosis chooses to invade antigen-presenting cells, which allows them to moderate host antigen presentation to memory cells, whereas rabies virus prefers to invade neurons because they have pre-existing innate immunity protection systems. Regardless of the pathway that each intracellular pathogen follows, all share the capacity to cause disease if they succeed in entering host cells. Here, we give an overview of selected intracellular pathogens and infections they cause, immune responses they induce, and intervention strategies used to treat and control them.

Antimalarial prophylaxis failure: Malaria in a returning traveler despite mefloquine prophylaxis.

This case report presents a perplexing case of Plasmodium malariae breakthrough infection despite prophylaxis with appropriate antimalarial prophylactic regimen of mefloquine in a compliant patient. A 78-year-old missionary who travels each year to the African subcontinent for multiple weeks to months, over 25 years, adheres to stringent antimalarial prophylaxis with Mefloquine as prescribed, starting prior to the trip and continuing after the return to the U.S.A. She gave no prior history of malaria during her 25 years of travel to Africa and back. Since she had no prior history of malaria and due to her excellent compliance with antimalarial regiment, despite her presentation which were suggestive of malaria, neither the patient nor her providers recognized the onset of malaria in this case. Infectious diseases physicians approached this case with an open mind, investigated appropriately, requested appropriate tests, found the presence of malarial parasite, identified as P. malariae species thereafter. She was started on antimalarial treatment in a timely fashion and showed an excellent response. This intriguing recovery of malarial parasite and response to treatment despite the patient being on antimalarial prophylaxis raised the possibility of mefloquine failure as an antimalarial prophylactic agent against P. malariae species.

Prevalence of non-falciparum malaria infections among asymptomatic individuals in four regions of Mainland Tanzania.

BACKGROUND: Recent studies point to the need to incorporate the detection of non-falciparum species into malaria surveillance activities in sub-Saharan Africa, where 95% of the world's malaria cases occur. Although malaria caused by infection with Plasmodium falciparum is typically more severe than malaria caused by the non-falciparum Plasmodium species P. malariae, P. ovale spp. and P. vivax, the latter may be more challenging to diagnose, treat, control and ultimately eliminate. The prevalence of non-falciparum species throughout sub-Saharan Africa is poorly defined. Tanzania has geographical heterogeneity in transmission levels but an overall high malaria burden. METHODS: To estimate the prevalence of malaria species in Mainland Tanzania, we randomly selected 1428 samples from 6005 asymptomatic isolates collected in previous cross-sectional community surveys across four regions and analyzed these by quantitative PCR to detect and identify the Plasmodium species. RESULTS: Plasmodium falciparum was the most prevalent species in all samples, with P. malariae and P. ovale spp. detected at a lower prevalence (< 5%) in all four regions; P. vivax was not detected in any sample. CONCLUSIONS: The results of this study indicate that malaria elimination efforts in Tanzania will need to account for and enhance surveillance of these non-falciparum species.

One hundred malaria attacks since birth. A longitudinal study of African children and young adults exposed to high malaria transmission.

Background: Despite significant progress in malaria control over the past twenty years, malaria remains a leading cause of child morbidity and mortality in Tropical Africa. As most patients do not consult any health facility much uncertainty persists about the true burden of the disease and the range of individual differences in susceptibility to malaria. Methods: Over a 25-years period, from 1990 to 2015, the inhabitants of Dielmo village, Senegal, an area of intense malaria transmission, have been monitored daily for their presence in the village and the occurrence of diseases. In case of fever thick blood films were systematically examined through microscopy for malaria parasites and patients received prompt diagnosis and treatment. Findings: We analysed data collected in 111 children and young adults monitored for at least 10 years (mean 17.3 years, maximum 25 years) enrolled either at birth (95 persons) or during the two first years of life. A total of 11,599 episodes of fever were documented, including 5268 malaria attacks. The maximum number of malaria attacks in a single person was 112. Three other persons suffered one hundred or more malaria attacks during follow-up. The minimum number of malaria attacks in a single person was 11. The mean numbers of malaria attacks in children reaching their 4th, 7th, and 10th birthdays were 23.0, 37.7, and 43.6 attacks since birth, respectively. Sixteen children (14.4%) suffered ten or more malaria attacks each year at ages 1-3 years, and six children (5.4%) each year at age 4-6 years. Interpretation: Long-term close monitoring shows that in highly endemic areas the malaria burden is higher than expected. Susceptibility to the disease may vary up to 10-fold, and for most children childhood is an endless history of malaria fever episodes. No other parasitic, bacterial or viral infection in human populations has such an impact on health. Funding: The Pasteur Institutes of Dakar and Paris, the Institut de Recherche pour le Développement, and the French Ministry of Cooperation provided funding.

Malaria Species Positivity Rates Among Symptomatic Individuals Across Regions of Differing Transmission Intensities in Mainland Tanzania.

BACKGROUND: Recent data indicate that non-Plasmodium falciparum species may be more prevalent than thought in sub-Saharan Africa. Although Plasmodium malariae, Plasmodium ovale spp., and Plasmodium vivax are less severe than P. falciparum, treatment and control are more challenging, and their geographic distributions are not well characterized. METHODS: We randomly selected 3284 of 12 845 samples collected from cross-sectional surveys in 100 health facilities across 10 regions of Mainland Tanzania and performed quantitative real-time PCR to determine presence and parasitemia of each malaria species. RESULTS: P. falciparum was most prevalent, but P. malariae and P. ovale were found in all but 1 region, with high levels (>5%) of P. ovale in 7 regions. The highest P. malariae positivity rate was 4.5% in Mara and 8 regions had positivity rates ≥1%. We only detected 3 P. vivax infections, all in Kilimanjaro. While most nonfalciparum malaria-positive samples were coinfected with P. falciparum, 23.6% (n = 13 of 55) of P. malariae and 14.7% (n = 24 of 163) of P. ovale spp. were monoinfections. CONCLUSIONS: P. falciparum remains by far the largest threat, but our data indicate that malaria elimination efforts in Tanzania will require increased surveillance and improved understanding of the biology of nonfalciparum species.

Epidemiological characteristics of Plasmodium malariae malaria in China: a malaria that should not be neglected post elimination.

BACKGROUND: Plasmodium malariae was always neglected compared with P. falciparum and P. vivax. In the present study, we aimed to describe the epidemiology of reported cases infected with P. malariae in the past decade to raise awareness of the potential threat of this malaria parasite in China. METHODS: Individual data of malaria cases infected with P. malariae reported in China in the past decade were collected via the China Information System for Disease Control and Prevention and Parasitic Diseases Information Reporting Management System, to explore their epidemiological characteristics. Pearson Chi-square tests or Fisher's Exact Test was used in the statistical analysis. RESULTS: From 2013 to 2022, a total of 581 P. malariae cases were reported in China, and mainly concentrated in 20-59 years old group (P < 0.001), and there was no significant trend in the number of cases reported per month. Moreover, four kinds of P. malariae cases were classified, including 567 imported cases from 41 countries in 8 regions and distributed in 27 provinces (autonomous regions, municipalities) in China, six indigenous cases in a small outbreak in Hainan, seven recurrent cases in Guangdong and Shanghai, and one induced case in Shanghai, respectively. In addition, only 379 cases (65.2%) were diagnosed as malaria on the first visit (P < 0.001), and 413 cases (71.1%) were further confirmed as P. malariae cases (P = 0.002). Meanwhile, most cases sought healthcare first in the health facilities at the county and prefectural levels, but only 76.7% (161/210) and 73.7% (146/198) cases were diagnosed as malaria, and the accuracy of confirmed diagnosis as malaria cases infected with P. malariae was only 77.2% (156/202) and 69.9% (167/239) in these health facilities respectively. CONCLUSIONS: Even though malaria cases infected with P. malariae didn't account for a high proportion of reported malaria cases nationwide, the threat posed by widely distributed imported cases, a small number of indigenous cases, recurrent cases and induced case cannot be ignored in China. Therefore, it is necessary to raise awareness and improve the surveillance and response to the non-falciparum species such as P. malariae, and prevent the reestablishment of malaria transmission after elimination.

Epidemiology of Plasmodium malariae and Plasmodium ovale spp. in a highly malaria-endemic country: a longitudinal cohort study in Kinshasa Province, Democratic Republic of Congo.

Background: Increasing reports suggest that non-falciparum species are an underappreciated cause of malaria in sub-Saharan Africa, but their epidemiology is not well-defined. This is particularly true in regions of high P. falciparum endemicity such as the Democratic Republic of Congo (DRC), where 12% of the world's malaria cases and 13% of deaths occur. Methods and Findings: The cumulative incidence and prevalence of P. malariae and P. ovale spp. infection detected by real-time PCR were estimated among children and adults within a longitudinal study conducted in seven rural, peri-urban, and urban sites from 2015-2017 in Kinshasa Province, DRC. Participants were sampled at biannual household survey visits (asymptomatic) and during routine health facility visits (symptomatic). Participant-level characteristics associated with non-falciparum infections were estimated for single- and mixed-species infections. Among 9,089 samples collected from 1,565 participants over a 3-year period, the incidence of P. malariae and P. ovale spp. infection was 11% (95% CI: 9%-12%) and 7% (95% CI: 5%-8%) by one year, respectively, compared to a 67% (95% CI: 64%-70%) one-year cumulative incidence of P. falciparum infection. Incidence continued to rise in the second year of follow-up, reaching 26% and 15% in school-age children (5-14yo) for P. malariae and P. ovale spp., respectively. Prevalence of P. malariae, P. ovale spp., and P. falciparum infections during household visits were 3% (95% CI: 3%-4%), 1% (95% CI: 1%-2%), and 35% (95% CI: 33%-36%), respectively. Non-falciparum malaria was more prevalent in rural and peri-urban vs. urban sites, in school-age children, and among those with P. falciparum co-infection. A crude association was detected between P. malariae and any anemia in the symptomatic clinic population, although this association did not hold when stratified by anemia severity. No crude associations were detected between non-falciparum infection and fever prevalence. Conclusions: P. falciparum remains the primary driver of malaria morbidity and mortality in the DRC. However, non-falciparum species also pose an infection risk across sites of varying urbanicity and malaria endemicity within Kinshasa, DRC, particularly among children under 15 years of age. As P. falciparum interventions gain traction in high-burden settings like the DRC, continued surveillance and improved understanding of non-falciparum infections are warranted.

The public health response to a Plasmodium malariae outbreak in Penampang district, Sabah during a COVID-19 movement control order.

BACKGROUND: Since 2018, no indigenous human malaria cases has been reported in Malaysia. However, during the recent COVID-19 pandemic the World Health Organization is concerned that the pandemic might erode the success of malaria control as there are reports of increase malaria cases in resource limited countries. Little is known how the COVID-19 pandemic has impacted malaria in middle-income countries like Malaysia. Here the public health response to a Plasmodium malariae outbreak occurred in a village in Sabah state, Malaysia, during a COVID-19 movement control order is reported. METHODS: An outbreak was declared following the detection of P. malariae in July 2020 and active case detection for malaria was performed by collecting blood samples from residents residing within 2 km radius of Moyog village. Vector prevalence and the efficacy of residual insecticides were determined. Health awareness programmes were implemented to prevent future outbreaks. A survey was conducted among villagers to understand risk behaviour and beliefs concerning malaria. RESULTS: A total of 5254 blood samples collected from 19 villages. Among them, 19 P. malariae cases were identified, including the index case, which originated from a man who returned from Indonesia. His return from Indonesia and healthcare facilities visit coincided with the movement control order during COVID-19 pandemic when the healthcare facilities stretched its capacity and only serious cases were given priority. Despite the index case being a returnee from a malaria endemic area presenting with mild fever, no malaria test was performed at local healthcare facilities. All cases were symptomatic and uncomplicated except for a pregnant woman with severe malaria. There were no deaths; all patients recovered following treatment with artemether-lumefantrine combination therapy. Anopheles balabacensis and Anopheles barbirostris were detected in ponds, puddles and riverbeds. The survey revealed that fishing and hunting during night, and self-treatment for mild symptoms contributed to the outbreak. Despite the index case being a returnee from a malaria-endemic area presenting with mild fever, no malaria test was performed at local healthcare facilities. CONCLUSION: The outbreak occurred during a COVID-19 movement control order, which strained healthcare facilities, prioritizing only serious cases. Healthcare workers need to be more aware of the risk of malaria from individuals who return from malaria endemic areas. To achieve malaria elimination and prevention of disease reintroduction, new strategies that include multisectoral agencies and active community participation are essential for a more sustainable malaria control programme.

Poor performance of malaria rapid diagnostic tests for the detection of Plasmodium malariae among returned international travellers in China.

BACKGROUND: Malaria is a worldwide infectious disease. For countries that have achieved malaria elimination, the prevention of re-establishment due to infections in returned travellers has become important. The accurate and timely diagnosis of malaria is the key in preventing re-establishment, and malaria rapid diagnostic tests (RDTs) are frequently used due to their convenience. However, the RDT performance in Plasmodium malariae (P. malariae) infection diagnosis remains unknown. METHODS: This study analysed epidemiological features and diagnosis patterns of imported P. malariae cases from 2013 to 2020 in Jiangsu Province and evaluated the sensitivity of four parasite enzyme lactate dehydrogenase (pLDH)-targeting RDTs (Wondfo, SD BIONLINE, CareStart and BioPerfectus) and one aldolase-targeting RDT(BinaxNOW) for P. malariae detection. Furthermore, influential factors were investigated, including parasitaemia load, pLDH concentration and target gene polymorphisms. RESULTS: The median duration from symptom onset to diagnosis among patients with P. malariae infection was 3 days, which was longer than that with Plasmodium falciparum (P. falciparum) infection. The RDTs had a low detection rate (39/69, 56.5%) among P. malariae cases. All tested RDT brands had poor performance in P. malariae detection. All the brands except the worst-performing SD BIOLINE, achieved 75% sensitivity only when the parasite density was higher than 5000 parasites/µL. Both pLDH and aldolase showed relatively conserved and low gene polymorphism rates. CONCLUSIONS: The diagnosis of imported P. malariae cases was delayed. The RDTs had poor performance in P. malariae diagnosis and may threaten the prevention of malaria re-establishment from returned travellers. The improved RDTs or nucleic acid tests for P. malariae cases are urgently needed for the detection of imported cases in the future.

Similar Prevalence of Plasmodium falciparum and Non-P. falciparum Malaria Infections among Schoolchildren, Tanzania1.

Achieving malaria elimination requires considering both Plasmodium falciparum and non-P. falciparum infections. We determined prevalence and geographic distribution of 4 Plasmodium spp. by performing PCR on dried blood spots collected within 8 regions of Tanzania during 2017. Among 3,456 schoolchildren, 22% had P. falciparum, 24% had P. ovale spp., 4% had P. malariae, and 0.3% had P. vivax infections. Most (91%) schoolchildren with P. ovale infections had low parasite densities; 64% of P. ovale infections were single-species infections, and 35% of those were detected in low malaria endemic regions. P. malariae infections were predominantly (73%) co-infections with P. falciparum. P. vivax was detected mostly in northern and eastern regions. Co-infections with >1 non-P. falciparum species occurred in 43% of P. falciparum infections. A high prevalence of P. ovale infections exists among schoolchildren in Tanzania, underscoring the need for detection and treatment strategies that target non-P. falciparum species.

The Intersection Between Malaria Treatment and Chemoprophylaxis and Their Potential Adverse Dermatologic Manifestations: A Narrative Review.

Malaria is a life-threatening parasitic disease caused by various forms of the protozoa Plasmodium and is transmitted by the female Anopheles mosquito. The parasitic infection is endemic in 90 countries, with approximately 500 million cases reported annually and an estimated annual mortality of 1.5-2.7 million individuals. Historically, the use of antimalarial drugs has been promising for the chemoprophylaxis and treatment of malaria, mitigating the annual mortality rate. Notably, these antimalarial drugs have been associated with various adverse effects, including gastrointestinal upset and headaches. However, the adverse cutaneous manifestations these antimalarial drugs may lead to are poorly documented and understood. We aim to describe the lesser-studied adverse cutaneous pathologies of malaria treatment to better educate physicians on the proper treatment of their patients. Our narrative review describes the skin manifestations associated with specific antimalarial treatments and their associated prognoses and treatments. The cutaneous pathologies discussed include aquagenic pruritus (AP), palmoplantar exfoliation, Steven-Johnson syndrome, toxic epidermal necrolysis, cutaneous vasculitis, psoriasis, ecchymosis, and tropical lichenoid dermatitis. Further studies and vigilant documentation of the cutaneous adverse events of antimalarial drugs need to be performed and emphasized to prevent potential life-threatening adverse outcomes.

Plasmodium malariae: the persisting mysteries of a persistent parasite.

Plasmodium malariae is a 'neglected malaria parasite' in as much as the amount of research conducted on it pales into insignificance when compared to that pertaining to Plasmodium falciparum and Plasmodium vivax, its more notorious and pathogenic cousins. There has, however, been an increase in interest in this parasite over the past decade. Principally, this is because of the increasing use of sensitive molecular detection techniques that have revealed a wider than previously recorded prevalence in some regions (particularly in Africa), and high numbers of chronic, asymptomatic infections.

False-positive fourth-generation HIV test result in a woman with Plasmodium malariae malaria.

BACKGROUND: False positive results on fourth-generation human immunodeficiency virus (HIV) diagnostic tests have previously been reported in infections with Plasmodium falciparum and Plasmodium ovale but not with Plasmodium malariae. METHODS: We report a false positive fourth-generation HIV test result in a patient with P. malariae infection. The patient's symptoms improved rapidly with antimalarial treatment and the confirmatory and repeated HIV tests were eventually negative. RESULTS: False positive results may add a variety of unnecessary burden. CONCLUSIONS: One must be aware of false positive results even with fourth-generation tests in patients with malaria, including P. malariae malaria.

Malaria species prevalence among asymptomatic individuals in four regions of Mainland Tanzania.

Recent studies point to the need to incorporate non-falciparum species detection into malaria surveillance activities in sub-Saharan Africa, where 95% of malaria cases occur. Although Plasmodium falciparum infection is typically more severe, diagnosis, treatment, and control for P. malariae, P. ovale spp., and P. vivax may be more challenging. The prevalence of these species throughout sub-Saharan Africa is poorly defined. Tanzania has geographically heterogeneous transmission levels but an overall high malaria burden. In order to estimate the prevalence of malaria species in Mainland Tanzania, 1,428 samples were randomly selected from 6,005 asymptomatic isolates collected in cross-sectional community surveys across four regions and analyzed via qPCR to detect each Plasmodium species. P. falciparum was most prevalent, with P. malariae and P. ovale spp. detected at lower prevalence (<5%) in all four regions. P. vivax was not detected. Malaria elimination efforts in Tanzania will need to account for these non-falciparum species.

Metagenomic Sequencing for the Diagnosis of Plasmodium spp. with Different Levels of Parasitemia in EDTA Blood of Malaria Patients-A Proof-of-Principle Assessment.

Molecular diagnostic approaches are increasingly included in the diagnostic workup and even in the primary diagnosis of malaria in non-endemic settings, where it is difficult to maintain skillful microscopic malaria detection due to the rarity of the disease. Pathogen-specific nucleic acid amplification, however, bears the risk of overlooking other pathogens associated with febrile illness in returnees from the tropics. Here, we assessed the discriminatory potential of metagenomic sequencing for the identification of different Plasmodium species with various parasitemia in EDTA blood of malaria patients. Overall, the proportion of Plasmodium spp.-specific sequence reads in the assessed samples showed a robust positive correlation with parasitemia (Spearman r = 0.7307, p = 0.0001) and a robust negative correlation with cycle threshold (Ct) values of genus-specific real-time PCR (Spearman r = -0.8626, p ≤ 0.0001). Depending on the applied bioinformatic algorithm, discrimination on species level was successful in 50% (11/22) to 63.6% (14/22) instances. Limiting factors for the discrimination on species level were very low parasitemia, species-depending lacking availability of reliable reference genomes, and mixed infections with high variance of the proportion of the infecting species. In summary, metagenomic sequencing as performed in this study is suitable for the detection of malaria in human blood samples, but the diagnostic detection limit for a reliable discrimination on species level remains higher than for competing diagnostic approaches like microscopy and PCR.

A Case of Plasmodium malariae in Bangladesh: A Representation of the Suboptimal Performance of Rapid Diagnostic Approaches in Malaria Elimination Settings.

Plasmodium malariae is a neglected human malaria parasite with low parasitemia that often results in the misdiagnosis and underestimation of the actual disease burden of this pathogen. Microscopy is the best diagnostic tool, despite the fact that rapid diagnostic tests (RDTs) are the best surveillance tool for malaria diagnosis in many rural areas for their ease of use in elimination settings. For parasite antigen detection other than P. falciparum, RDTs depend on essential glycolytic Plasmodium proteins, i.e., Plasmodium lactate dehydrogenase (pLDH) and Plasmodium aldolase (pAldo) antigens. There is a lack of species-specific test kits for P. malariae, and overall, its rapid antigenic test accuracy is questionable. False negative results can accelerate the burden of asymptomatic malaria infection and transmission. Here, we report a case of a malaria patient in Bangladesh infected with P. malariae who tested negative on pLDH and pAldo based RDTs. This case provides useful information for health providers to be aware of possible RDT failure and also for the future development of analytically sensitive test kits for P. malariae.

Plasmodium malariae Detected by Microscopy in the International Bordering Area of Mizoram, a Northeastern State of India.

Northeastern states of India share international borders with Myanmar, China, Bangladesh, and Bhutan, contributing 7.45% of the overall malaria cases in the country. Mizoram accounts for the highest malaria burden in the northeastern states, with perennial transmission in the hilly and deep-forested areas. Plasmodium falciparum (93%) is the most prevalent human Plasmodium species, followed by P. vivax; however, information on P. ovale and P. malariae is negligible. Rapid diagnostic tests (RDTs) are the most preferred malaria diagnostic tool followed by microscopy in this high malaria-endemic region. The present epidemiological study was carried out in July and August 2019 to assess the malaria burden in and around the Chawngte primary health center, Lawngtlai District of Mizoram, using RDTs and microscopy as diagnostic tools. World Health Organization-certified level I microscopists examined the blood smears. Diagnosis using RDTs resulted in 151 malaria cases (P. falciparum: 136; P. vivax: 15) out of 948 screened fever cases. However, blood smear examination detected 179 cases (P. falciparum: 154; P. vivax: 17; mixed P. falciparum + P. vivax infection: 3; P. malariae: 5). Analysis revealed that the risk of malaria infection was higher in the ≥5-year-old subjects than in the under-5 age group. The mean parasite density of P. malariae (1455.00/µL blood) was the lowest; cf. with P. falciparum: 12,275.08/µL blood. Surveillance at the point-of-care level using microscopy was able to detect all the four human Plasmodium species and their mixed infections, including P. malariae, which were missed with RDTs. Thus, the quality of microscopy along with trained manpower should be strengthened to diagnose all human malaria parasite species (particularly P. malariae and P. ovale) until the molecular tools are deployed at the field level to achieve malaria elimination by 2030.

Inhibitor of Cysteine Protease of Plasmodium malariae Regulates Malapains, Endogenous Cysteine Proteases of the Parasite.

Cysteine proteases of malaria parasites have been recognized as potential targets in antimalarial drug development as they play pivotal roles in the biology of these parasites. However, strict regulation of their activities is also necessary to minimize or prevent deleterious damage to the parasite and the host. Previously, we have characterized falcipain family cysteine proteases of Plasmodium malariae, named as malapains (MPs). MPs are active hemoglobinases. They also may participate in the release of merozoites from mature schizonts by facilitating remodeling of erythrocyte skeleton proteins. In this study, we identified and characterized an endogenous inhibitor of cysteine protease of P. malariae (PmICP). PmICP shared similar structural and biochemical properties with ICPs from other Plasmodium species. Recombinant PmICP showed a broad range of inhibitory activities against diverse cysteine proteases such as falcipain family enzymes (MP-2, MP-4, VX-3, VX-4, and FP-3), papain, and human cathepsins B and L, with stronger inhibitory activities against falcipain family enzymes. The inhibitory activity of PmICP was not affected by pH. PmICP was thermo-labile, resulting in rapid loss of its inhibitory activity at a high temperature. PmICP effectively inhibited hemoglobin hydrolysis by MPs and regulated maturation of MPs, suggesting its role as a functional regulator of MPs.

The primate malaria parasites Plasmodium malariae, Plasmodium brasilianum and Plasmodium ovale spp.: genomic insights into distribution, dispersal and host transitions.

During the twentieth century, there was an explosion in understanding of the malaria parasites infecting humans and wild primates. This was built on three main data sources: from detailed descriptive morphology, from observational histories of induced infections in captive primates, syphilis patients, prison inmates and volunteers, and from clinical and epidemiological studies in the field. All three were wholly dependent on parasitological information from blood-film microscopy, and The Primate Malarias" by Coatney and colleagues (1971) provides an overview of this knowledge available at that time. Here, 50 years on, a perspective from the third decade of the twenty-first century is presented on two pairs of primate malaria parasite species. Included is a near-exhaustive summary of the recent and current geographical distribution for each of these four species, and of the underlying molecular and genomic evidence for each. The important role of host transitions in the radiation of Plasmodium spp. is discussed, as are any implications for the desired elimination of all malaria species in human populations. Two important questions are posed, requiring further work on these often ignored taxa. Is Plasmodium brasilianum, circulating among wild simian hosts in the Americas, a distinct species from Plasmodium malariae? Can new insights into the genomic differences between Plasmodium ovale curtisi and Plasmodium ovale wallikeri be linked to any important differences in parasite morphology, cell biology or clinical and epidemiological features?