Plasmodium knowlesi and global changes: socio-ecological drivers and challenges

Abstract

Plasmodium knowlesi, a malaria species predominantly found in Southeast Asia, is influenced by climate change in its transmission dynamics. Variations in temperature and precipitation impact both mosquito vectors and the parasites they carry. Additionally, deforestation and alterations in land use, often driven by climate change, facilitate the zoonotic transmission of the disease from simian hosts to humans. Climatic fluctuations also influence human and community behaviours, potentially altering exposure risks. Although increased awareness of climate risks may prompt behavioural changes, the attitude behaviour gap—where awareness does not necessarily translate into action—remains a significant challenge. Environmental alterations can transform mosquito habitats and breeding patterns, thereby influencing disease transmission. Community responses may create new transmission zones or modify existing ones. Furthermore, climate change may alter the distribution of natural hosts for Plasmodium knowlesi, affecting its transmission dynamics. Understanding these interconnections is crucial for addressing the impact of climate change on malaria transmission in general and specifically P. knowlesi. This review examines the spread of P. knowlesi in the context of climate change, land use changes, human behaviour and activities, human-macaque-mosquito interaction, other contributing factors, and challenges to provide insight for future research on controlling P. knowlesi in regions where interactions among humans, monkeys, and mosquitoes are intensifying due to environmental and developmental changes.

Background

Plasmodium knowlesi is an emerging zoonotic malaria in Southeast Asia (SEA), primarily associated with long-tailed macaques (Macaca fascicularis) and pig-tailed macaques (Macaca nemestrina) as its natural hosts [1, 2]. Its transmission is facilitated by mosquito species such as Anopheles leucosphyrus and Anopheles dirus [3, 4]. Initially identified in infected macaques in 1932 and a man who returned to the USA after visiting peninsular Malaysia was reported as the first natural infection of P. knowlesi in human in 1965 [5, 6]. Although P. knowlesi is related to Plasmodium vivax, it presents differently and has a shorter asexual cycle without a dormant liver stage characteristic of relapsing P. vivax [2, 7]. Since the first documented large focus of human cases reported in 2004, the incidence of P. knowlesi infections has significantly increased, rendering it the most prevalent form of malaria in Malaysia and presenting challenges to disease control efforts across the region [1, 8]. The rapid increase in incidence complicates malaria control strategies not only in Malaysia [1, 8], but also in various SEA countries, including Indonesia, Thailand, and the Philippines, due to its 24-h asexual erythrocytic cycle [9].

Changes in temperature, rainfall patterns, and extreme weather events due to climate change contribute to the dynamics of vector-borne diseases such as malaria, affecting the survival and reproduction of Plasmodium species in vector habitats [10, 11]. Populations in regions experiencing rising temperatures and increased humidity face a heightened risk of malaria infection, as these conditions promote behaviours such as outdoor sleeping, which increases exposure to mosquito bites and the risk of malaria infection [12]. Additionally, climate change is influencing the distribution and behaviour of vector-borne diseases, including malaria [10]. Plasmodium knowlesi naturally infects wild macaque populations in SEA, thereby serving as an ongoing reservoir [13]. The zoonotic nature of this complex and evolving disease poses significant challenges to its control [14].

This review synthesize evidence and present a comprehensive review to aid a more nuanced understanding of the impact of climate change, land-use alterations, and biodiversity loss on the interactions among macaques, mosquitoes, humans, and transmission of P. knowlesi (Fig. 1). The review examines the interplay between epidemiology, environmental changes, and human activities, including current knowledge on the socio-ecological drivers of zoonotic malaria. Challenges and gaps in current knowledge are identified to inform future research, public health policies, and support targeted interventions to mitigate the impact of climate change on zoonotic malaria transmission.

Fig. 1.

Conceptual framework diagram showing how environmental disruptions and climate changes influence vectors, monkeys, and humans, which in turn contribute to P. knowlesi infection

Climate change and mosquito vector behaviour

Plasmodium knowlesi is largely transmitted in the jungles of Southeast Asia (SEA) by sylvan anopheline species [15]. The transmission of P. knowlesi occurs primarily in forest and forest fringes area where the natural host of P. knowlesi are commonly found [16]. A study found that M. fascicularis and M. nemestrina are the natural hosts of P. knowlesi [2]. Macaca fascicularis is widely distributed in southern Southeast Asia (SEA), such as Bangladesh, Myanmar, Thailand, Laos, Vietnam, Cambodia, and Malaysia, as well as on several Indonesian Islands, such as Kalimantan, Sumatera, and Java [17]. The Kapit Division's wild macaques had the highest prevalence of P. knowlesi, with 87% of 83 long-tailed macaques and 50% of 26 pig-tailed macaques confirmed P. knowlesi positive in Sarawak, Malaysian Borneo [18]. The close genetic relationship between humans and macaques may explain the similar immunological responses of both species as biological factors in the P. knowlesi transmission [19].

Anthropogenic activities in forested areas contribute to the variability of P. knowlesi vectors [20]. The variability refers to differences or changes in distribution, abundance, and behaviour of P. knowlesi vectors due to human-driven changes to forest environments [20]. Research findings highlight that land use changes, particularly deforestation and agricultural activities, can create more favorable breeding habitats for P. knowlesi anopheline vectors. The alteration of natural habitats into disturbed forests, vegetation mosaics, and cropland increases the probability of vector occurrence in these areas. For example, the Leucosphyrus Complex of Anopheles mosquitoes, which are key vectors for P. knowlesi, are more likely to inhabit disturbed forests rather than intact ones. The An. leucosphyrus group, including Anopheles latens and Anopheles balabacensis, has been identified as the primary vector group, particularly in regions where human and macaque habitats overlap. Studies conducted in Malaysia reported that An. latens and An. balabacensis can bite both macaques and humans and responsible for the zoonotic transmission of P. knowlesi [4, 21, 22]. Biting intensity and differential degree of attraction to humans and/or macaques impacts transmission of P. knowlesi. For example, An. latens exhibited a preference for feeding on long-tailed macaques in forested areas between 7 and 10 p.m. at higher elevations [18]. Anopheles cracens, another vector of P. knowlesi malaria, has peak biting hours between 8 and 9 p.m. and has been observed to feed on humans at ground level and macaques at the canopy level due to its high zoophilia [23, 24]. Therefore, the time when humans enter the forest will impact the risk of contracting P. knowlesi; indeed, some studies have reported that staying overnight in the jungle is associated with P. knowlesi transmission to humans [25, 26].

Climate change has been reported to exert a substantial influence on the distribution and management of Anopheles mosquitoes, which act as vectors for malaria [27, 28]. Deforestation alters local microclimates, climate variability, and climate change affect the biology and vectoring capacity of Anopheles mosquitoes, thereby influencing their potential for disease transmission due to rising temperatures, changes in precipitation and rainfall patterns, and increased humidity [29–31] Similar to other living organisms, mosquitoes, classified as insects within the arthropod group, are directly affected by ambient temperature, which is essential for their survival [32]. In addition to impacting the behaviour and ecology of Anopheles mosquitoes, climate change is expected to elevate temperatures at higher latitudes and altitudes [30, 33]. Anopheles mosquitoes, as poikilothermic organisms, have life cycle characteristics, including biting rate, reproductive cycle, fertility, and survival skills, that are dependent on ambient temperatures [30, 34]. Within P. knowlesi transmission areas, Anopheline vectors feed on monkeys in the canopy and at ground level; those on the ground present the most risk to humans entering the jungle. The level of risk will depend on how anthropogenic the vectors are; some have been found to favour humans, if present [4, 24, 35].

Environmental modifications can result in increased global temperatures and decreased humidity in open areas, leading to the elimination of canopy cover [36, 37]. These changes, along with changes in water level and quality can create or enhance suitable aquatic habitats, such as shallow, shaded, and stagnant water due to the removal of canopy and land clearing that support larval habitats development, thereby increasing potential human contact and facilitating the spread of malaria. For example, low temperatures can significantly delay larval development and mortality, whereas elevated temperatures can accelerate development and enhance reproductive fitness, resulting in smaller larval size and reduced hatching and pupation durations [38]. Anopheles gambiae, one of the primary vector of malaria, experiences a cessation of larval development at temperatures below 16 °C and mortality at 14 °C [38]. However, warmer climates lead to shorter maturation periods and increased offspring production [30]. Environmental changes can also modify the biting patterns of mosquitoes that transmit malaria. Anopheles mosquitoes of the leucosphyrus group typically exhibit outdoor biting activity, with peak activity occurring from afternoon to evening [4, 24, 39]. As such environmental changes may result in mosquito bites occurring while humans are still active, leading to an increased risk of transmission and heightened contact between mosquitoes and humans, particularly in regions with agricultural activities, plantations, and areas undergoing deforestation [30, 40].

The impact of climate change on mosquito vectors in the Philippines, particularly An. balabacensis, is of concern [41]. The expansion of habitats, such as forests and agricultural areas, creates optimal environments for these vectors, potentially increasing their densities due to climate-induced alterations in rainfall patterns and temperatures [37, 41–43]. The climate changes enable mosquitoes to expand their geographic ranges, increase their population densities, and potentially extend their breeding seasons [38, 44, 45]. For instance, studies have demonstrated that mosquitoes may develop more rapidly at elevated temperatures, reducing the duration of their life cycle and increasing the number of generations per year, thereby elevating the risk of disease transmission [46–49]. Optimal ambient temperatures, particularly in the range of 22–30 °C, can increase flight frequency and malaria transmission [38]. Other factors, such as high humidity > 60% and substantial rainfall, support mosquito range by providing a larger breeding habitat [50]. A positive correlation has also been found between high precipitation and increased risk of malaria transmission, as light to moderate rain can increase breeding sites for mosquitoes, while extreme rain can wash larvae away [51, 52]. The increased humidity level provides optimal conditions for vector breeding, leading to an increase in vector populations in areas where they were not previously prevalent. This results in additional transmissions, cases, and potentially fatalities due to the low immunity of formerly malaria naive populations [53]. Exposure to heavy rain can decrease malaria transmission by washing away mosquito breeding sites [44]. Furthermore, climate change is predicted to lead to more frequent natural disasters, which may increase vector growth due to available breeding sites and suitable conditions [54]. A study conducted in Gambella, Ethiopia, found that increased temperature and rainfall can create suitable conditions for malaria transmission by extending the rainy season and creating more new breeding sites for Anopheles spp. [55].

Climate change has the potential to alter the geographical distribution of malaria cases, extending their incidence even to highland regions. This phenomenon occurs because elevated temperatures can accelerate the larval development cycle and broaden the habitat range of Anopheles mosquitoes [56]. Furthermore, variations in temperature and humidity can modify the life cycle of mosquitoes, leading to spatial or seasonal shifts in malaria transmission patterns. This is particularly critical in regions with low herd immunity, where a rapid increase in vector populations can result in a surge in cases and fatalities [57]. Moreover, global warming may cause the expansion of saline and brackish water bodies, affect salt-tolerant mosquito species and potentially increase their populations [48, 58]. This is especially pertinent in coastal areas of the Philippines, where rising sea levels and climate change influence the ecology of mosquito habitats, resulting in higher densities of salinity-tolerant vectors, including certain Anopheles species [48].

Moreover, climate change has the potential to intensify conditions conducive to the transmission of mosquito-borne diseases by modifying the vectors' active periods due to alterations in daylight and temperature patterns. The timing of biting activity, such as the peak activity period of An. leucosphyrus group from over 7 p.m. until 10 p.m., may increasingly align with human activity times, thereby elevating the likelihood of human-vector contact and malaria transmission [59, 60]. Consequently, climate change is a pivotal factor in the ecology of mosquito vectors in SEA which has tropical climate [61]. Comprehending these dynamics is crucial for the development of effective vector control strategies and the mitigation of public health impacts. It is imperative for stakeholders to concentrate on monitoring and adaptation strategies to address these challenges within the context of a warming planet.

Climate change and ecological impacts

Human activities that impact forests, such as deforestation, changes in land use, logging, and agricultural expansion, have the potential to elevate the risk of P. knowlesi outbreaks [62]. This contrasts with the climate change effects, such as shifting temperature zones, increasing fire risk, or altering rainfall patterns which also impact forests as the primary habitat for macaque monkeys, the natural hosts of P. knowlesi [62]. Alterations in forest cover can influence the population dynamics of macaque monkeys, which are integral to the life cycle of P. knowlesi [63, 64]. The reduction in forest cover due to climate change has been linked to a shift in P. knowlesi infections to higher altitudes, given the negative correlation between infection incidence and deforestation [65].

Temperature and environmental changes influence land conversion and forest vulnerability. Land conversion of land of agricultural, urban development, and deforestation results in forest fragmentation that creating edge habitats which can result in the spillover of P. knowlesi malaria into human population in fragmentated areas [66]. Furthermore, another factors such as low topography also contribute in the transmission process [66]. A study demonstrated a risk of protozoal parasite infection from the red colobus primates (Procolobus rufomitratus) wild population inhabiting fragmented habitats to those in undisturbed habitats [67]. Additionally, the characteristics of dwellings with open spaces, slit walls, and tall grass in their vicinity also heighten the risk of infection [64].

Studies in Indonesia and Malaysia shows forest workers, including workers that involving deforestation to expand agricultural land and settlements enhance the potential for vector mosquito habitat development, contributing to the rising number of P. knowlesi cases [26, 37, 68]. The study indicates that the highest risk areas are in Malaysia and Indonesia, followed by the Greater Mekong Subregion, the Philippines, and Northeast India. The risk of infection increases significantly in regions with altitudes of 75–345 m above sea level, extensive tree cover (< 82%), and settlements adjacent to forest areas (< 200) metres [62, 69].

Land use changes play a significant role in the spread of P. knowlesi, posing substantial public health challenges. The primary environmental factor influencing malaria infections by P. knowlesi is forest degradation resulting from human activities related to land use [70]. Alterations in land use, such as the conversion of primary forests into plantations and agricultural land, can affect mosquito populations and facilitate the spread of malaria [4, 37]. Deforestation for the establishment of plantations and agricultural activities has caused considerable damage to the forests of Indonesia and Malaysia. Changes in land use associated with deforestation force macaques to leave their forest habitats and migrate to farms and semi-urban areas. Additionally, deforestation alters microclimatic conditions and may make them favourable to mosquito breeding [43, 65]. The distribution patterns of P. knowlesi vectors have likely been modified as land use changes have increased larval habitats [71]. Consequently, some members of the Leucosphyrus group have proliferated due to deforestation and are frequently observed in agricultural areas and villages, which are recognized as deforested regions [72]. Furthermore, this process has facilitated the expansion of mosquitoes from the Leucosphyrus group into populated areas that increase human contact and may facilitate human-to-human transmission of P. knowlesi [13].

Research has demonstrated that fluctuations in vector population abundance are associated with changes in forested areas, and the risk of P. knowlesi malaria to human populations escalates when new residential developments are established within these forested regions [73]. Empirical studies conducted in Malaysia, Indonesia, Singapore, Brunei, and the Philippines have shown that mosquito species, particularly those within the Leucosphyrus group, inhabit areas characterized by plantations, concessions, deforested land, and agricultural zones, which are linked to high yields [74]. These findings indicate that varying rates of vector reproduction, survival, and biting behaviour are observed in environments altered by human activity [75–77]. Consequently, the proximity of these species to human activities increases the risk of P. knowlesi transmission to humans due to heightened contact with P. knowlesi within the population.

Climate change, human behaviour and socio-economic factors

Climate change exerts a profound influence on human behaviour, which may subsequently elevate the risk of P. knowlesi infection through environmental changes, migration, and altered human-macaque interactions [78, 79]. The alterations in human behaviour, such as some people sleeping outdoors or wear, more revealing clothing because of the hot weather to reduce the feeling of heat [80]. Humans contract the disease when bitten by an infected Anopheles mosquito, typically of the Leucosphyrus species, which tends to bite outdoors during the night. The processes of deforestation and environmental transformation increase human exposure to vector mosquitoes and macaques, the primary hosts and vectors for P. knowlesi [81]. Human behaviours and activities into forested region contributing to the spread of P. knowlesi malaria are notably similar across Malaysia, Thailand, Indonesia, and the Philippines. The activities encompass forestry-related endeavours, such as entering forests, and occupational activities, including plantation, farming, and construction work. Empirical studies indicate that individuals residing on the forest periphery or engaged in forestry work face an elevated risk of P. knowlesi infection [68, 82]. The impacts of climate change are anticipated to further intensify these environmental alterations. As mosquitoes and macaques adapt their habitats in response to climatic shifts, humans entering these altered landscapes encounter increased risks of P. knowlesi exposure [83]. Furthermore, as human populations settle or work in proximity to dense forests due to socio-economic factors often influenced by environmental changes, interactions between humans and the natural reservoirs of P. knowlesi are augmented [84, 85]. This proximity facilitates the transmission of the parasite from macaques to humans via mosquito vectors [62, 86]. Males aged 15 to 45 years are particularly susceptible due to occupational requirements related to deforestation and farming necessitating forest exposure, especially overnight stays. Consequently, the nature of work serves as a significant predictor of infection risk, with men disproportionately affected [87]. Population mobility for employment, particularly toward malaria-endemic regions, also increases exposure and accelerates the dissemination of P. knowlesi. Tourists partaking in forest-based activities such as hiking or camping in endemic areas are similarly at risk [68].

In addition to occupational exposure, anthropogenic environmental changes—particularly deforestation, forest fragmentation, and agricultural expansion—have modified vector habitats and increased human-vector interactions [16, 88]. Deforestation in SEA creates edge environments that are ecologically favourable for An. leucosphyrus group mosquitoes, thereby enhancing their population density in disturbed areas [37]. Fragmented forests increase the edge-to-interior ratio, where species such as Anopheles donaldi, which is significantly more prevalent in the edge-interior ratio, indicating that forest fragmentation creates ecological conditions that favour this species. Consequently, An. donaldi is very important in the dynamics of zoonotic malaria transmission in fragmented landscapes, thereby elevating transmission risk [89]. Agricultural practices, including the expansion of rubber plantations or livestock areas near forests, generate ecotopes conducive to mosquito breeding [90]. These land-use changes have also caused shifts in macaque movement patterns, bringing them closer to human settlements and increasing opportunities for zoonotic spillover of P. knowlesi [91]. In Indonesia, particularly in Southeast Sulawesi, the overlap between deforestation and settlement expansion has been linked to the presence of several competent Anopheles vectors, suggesting a heightened risk of transmission in disturbed landscapes [92]. Moreover, behaviours such as going out at night due to high indoor temperatures have also been shown to increase the risk of malaria. Research indicates that rising temperatures due to climate change correlate with spikes in malaria cases in certain areas [79]. Additionally, studies have found that hot weather exacerbates malaria risk by increasing outdoor sleeping time and hindering the use of ITNs [93].

Climate change and human-primate interactions

The interplay between climate change and human-non-human primate interactions, particularly concerning hunting and the transmission of P. knowlesi, is intricate, encompassing both environmental and behavioural dimensions. As forest are cleared for agriculture or urban development, macaques and mosquitoes carrying P. knowlesi migrate closer to human settlements, thereby elevating the risk of transmission that affect human-primate contact. The hunting activity and consumption of monkey meat, specifically that of the macaque monkey (M. fascicularis), has been documented in Indonesia, confirms interaction between macaques and humans [94]. These studies propose that ecological disturbances drive macaques and their mosquito vectors into areas populated by humans, thereby increasing the potential for disease spillover [62]. The transmission dynamics of P. knowlesi are further affected by the behavioural adaptations of macaques and mosquitoes in these modified environments. Notably, macaques may adapt by foraging on farms, which could elevate human infection rates if they frequently interact with human-dominated areas [73]. Additionally, the increase in monkey hunting and human interaction due to habitat loss further disrupts ecological balance and complicates disease dynamics [13, 81].

Ecological challenges for P. knowlesi

The ecological shifts create conditions that may either favour or impede the survival and proliferation of anopheline mosquitoes, which serve as vectors for P. knowlesi. Forested areas, where both macaques and their mosquito vectors thrive, exhibit higher infection rates. Deforestation has further complicated control efforts by facilitating the adaptation of these vectors to human settlements [95]. The causes for deforestation are divided into two types: direct and indirect. The direct factors are growing agriculture, building new roads and railways, and logging activities. The indirect factors are social, economic, demographic, cultural, institutional, political, and technological [96]. Deforestation has been a common issue in most SEA countries, primarily driven by the expansion of plantations and infrastructure development [97]. Additionally, the rapid urban growth resulted in the reduction of forested areas in recent years [98].

Urbanization is acknowledged as a major contributor to the deforestation of tropical forests since the beginning of the twenty-first century [99]. This phenomenon has resulted in deforestation due to an increase in demand for agricultural goods and encouragement of urban growth [99]. Economic and population growth can lead to the emergence of new and diverse land-cover types [100, 101]. In numerous countries in SEA, such as Vietnam, Cambodia, Indonesia, Malaysia, and Thailand, changes in demographics and economic development are leading to changes in land use [98]. Agriculture is vital component of the economy and as a primary cause of deforestation in this region [98]. The reduction in forested areas amounted to 376,000 km², which exceeds the combined land area of Thailand, Myanmar, and Cambodia between 1990 and 2020 [102].

In Indonesia, particularly the regions of Sumatra, Kalimantan, and Papua, along with Malaysia's Sabah and Sarawak, have emerged as the geographical areas most affected by tropical forest loss on a global scale [103, 104]. The islands of Kalimantan and Sumatra have environmental changes that directly affect the spread of vector-borne diseases [105]. Sumatra has lost 1.53 million hectares (Mha) of primary wetland forest and 1.21 Mha of lowland forest, while Kalimantan has seen a reduction of 0.99 Mha of primary wetland forest and 1.33 Mha of lowland forest. Between 2000 and 2008, Sumatra and Kalimantan together lost approximately 5.39 Mha or 5.3% of their total forest cover. Specifically, in 2001, there were 45 Mha of primary forest, and by 2019, only 37 Mha remained that representing an average loss of 0.43 Mha per year. This primary drivers of deforestation include the expansion of plantations, such as palm oil and rubber, mining, urbanization, and human migration for economic activities. Both Sumatra and Kalimantan are undergoing rapid deforestation and experiencing climatic variability, resulting in landscapes that are becoming warmer, drier, and more urbanized [103, 106].

Subsequently, due to Java Island’s overpopulation, congestion, and severe environmental degradation, Indonesia is relocating its capital from Jakarta to North Penajam Paser and parts of the Kutai Kartanegara regencies, East Kalimantan. The relocation aims to promote economic growth and infrastructure development, as well as reduce the urban pressures on Jakarta [105]. However, the project poses multiple challenges, such as conflicting location decisions, cultural and demographic factors, economic and political complexities, and environmental issues such as deforestation, biodiversity loss, and a higher risk of vector-borne diseases [105]. Over the past decade, land use in East Kalimantan has fluctuated, with deforestation rates peaking at 1,086.82 km² before declining to 137,588 km² by 2021–2022, which reflects some conservation success [107].

The relocation of Indonesia's capital city to Borneo, where zoonotic malaria is evident, exemplifies the unpredictable regulatory and policy pathways that complicate P. knowlesi malaria control and prevention strategies. Studies indicate the potential for this newly populated area to become a hotspot for P. knowlesi transmission due to the presence of both host and vector and now humans [108].

Furthermore, deforestation has emerged as a critical driver of P. knowlesi transmission dynamics, with patterns observed in Palawan, The Philippines, offering compelling parallels to the situation in Myanmar. Previous studies conducted in Palawan revealed that deforestation may significantly contribute to the increase of P. knowlesi prevalence in macaque populations through a complex ecological cascade. As forest habitats are systematically destroyed, macaques, the natural reservoir hosts of P. knowlesi, are also forced into closer proximity with human populations, fundamentally altering the spatial relationship between wildlife, vectors, and humans. This habitat destruction creates conditions that facilitate the spillover of the parasite from its natural primate hosts to humans, transforming what was once a primarily simian malaria into an increasingly significant zoonotic threat [82]. Long-tailed macaques have demonstrated a remarkable behavioural and demographic response to deforestation, with studies indicating that these primates increase in population density as their forest habitat becomes fragmented and degraded [109]. This counterintuitive increase in macaque density in response to deforestation intensifies the possibility of contact between individual macaques, potentially amplifying parasite transmission within the primate population itself, while simultaneously increasing the likelihood that these displaced primates will encroach upon human settlements in search of food and shelter.

However, deforestation represents only one dimension of this multifaceted public health challenge, as land use changes that involve human mobilization into forested areas and the establishment of settlements at the forest fringe play an equally significant role in facilitating the spillover of P. knowlesi from macaque monkeys to human populations in these settlements [110]. This pattern of human encroachment into previously intact forest ecosystems places people in direct and sustained contact with forest environments, where they engage in activities that increase their exposure risk, including conducting forest chores, working in outdoor occupations that require forest access, and maintaining primary employment in the logging and plantation industries that are themselves drivers of deforestation in Myanmar. These occupational and livelihood activities create repeated opportunities for human-macaque-vector interactions, effectively establishing ecological bridges for pathogen transmission.

Beyond the immediate ecological impacts on species distributions and contact patterns, deforestation and land use change generate broader environmental consequences that may further amplify P. knowlesi transmission risk, particularly through their implications for local and regional temperature regimes. Increases in local temperature resulting from deforestation have demonstrated bidirectional causal relationships that contribute to elevated mosquito populations and malaria transmission rates [111]. The zoonotic nature of this complex relationship between pathogens, reservoirs such as macaques, and vectors, all of which contribute to the cycle of transmission. In addition, it is influenced by dynamic ecological changes and genetics, and evolving disease renders its control particularly challenging [112]. Vegetation, including trees, plays a crucial role in the hydrological cycle by influencing precipitation partitioning and runoff, as well as creating breeding habitats for mosquitoes. This situation indicates an increased likelihood of zoonotic infections spreading to humans, animal hosts, and wildlife when mosquitoes inhabit forested areas and regions where human-animal-environment interactions occur [113, 114].

To mitigate these ecological impacts, the establishment of robust and enforceable environmental governance is crucial, particularly through the strengthened implementation of Environmental Impact Assessments (EIA) and Strategic Environmental Assessments (SEAs), ensuring that every project undertakes proper mitigation measures, independent monitoring, and is subject to strict sanctions for non-compliance [115]. The integration of environmental policies across all development sectors through the Environmental Policy Integration (EPI) approach is also crucial, as it reinforces the mainstreaming of sustainability within public policy and reduces policy fragmentation, often a root cause of environmental degradation in developing countries [116]. In addition, participatory frameworks such as Community-Based Natural Resource Management and Nature-based Solutions (NbS) for instance, post-mining land rehabilitation and forest restoration, have proven effective in restoring ecosystem functionality [117, 118]. Furthermore, the implementation of green economic instruments, including Payments for Ecosystem Services (PES) and environmental fiscal incentives, can encourage industries to internalize ecological accountability. With adaptive governance and cross-border collaboration, these mitigation strategies can become more integrated, resilient, and sustainable.

Diagnostic and therapeutic challenges of P. knowlesi malaria

Plasmodium knowlesi infections are frequently misidentified or misdiagnosed as Plasmodium falciparum or Plasmodium malariae due to the limitations of traditional diagnostic methods, such as microscopy. Specifically, P. knowlesi is often mistaken for P. malariae when using light microscopy because of their morphological similarities [119–122]. Various approaches have been employed to detect malaria, with Polymerase Chain Reaction-based assays (PCR-based assays) being the most reliable and accurate for identifying P. knowlesi. Some studies in Malaysian Borneo show that many cases that were initially diagnosed as P. malariae were found to be P. knowlesi through molecular techniques upon re-examination using nested PCR assays with specific Plasmodium primers [123, 124]. On the other hand, a study has shown high rates of misidentification of P. knowlesi cases that being misdiagnosed as P. malariae, with up to 87% and 85% in Sarawak and Sabah, respectively [125]. Another study in Sabah, Malaysia, also confirmed that misdiagnosis also extends to other species, such as P. falciparum and P. vivax. Furthermore, rapid diagnostic tests (RDTs) which detect parasite antigens using monoclonal antibodies also show cross-reactivity that further complicate diagnosis, potentially giving false-positive results to others Plasmodium species [126]. Plasmodium knowlesi cross-reacted with parasite lactate dehydrogenase (pLDH) of both P. falciparum and P. vivax due to amino acid sequence homology similarity between them [126]. However, their high cost, time-consuming nature, and requirement for specialized equipment render them suboptimal for routine diagnostics in standard peripheral or district-level laboratories within P. knowlesi-endemic regions of SEA, such as Malaysia and Indonesia [127].

Addressing the diagnostic challenges associated with P. knowlesi is essential for effective malaria management and surveillance. Misidentification in diagnostic methods poses a significant challenge as it impedes appropriate treatment and reliable data collection for mapping transmission chains. The limitations in data collection also hinder the analysis of transmission clusters due to unpublished cases and surveillance records [128]. The absence of surveillance records is also evident outside SEA, contributing to diagnostic challenges, as isolated cases of P. knowlesi that have been detected in travellers returning from endemic areas [128]. A similar issue is observed in the lack of empirical data on P. knowlesi presence in SEA [68, 129]. The challenges associated with the development of malaria vaccines and treatments are also true for P. knowlesi inherent characteristics, including antigenic variation [130]. The development of P. knowlesi vaccines is low priority, as existing research primarily focuses on P. falciparum and P. vivax [131]. Additionally, the remote and forested regions where P. knowlesi is endemic would present technical and logistical challenges, for the use of a vaccine [132].

A multidimensional strategy is needed to address P. knowlesi misdiagnosis. Implementing enhanced molecular diagnostic, such as nested PCR, real-time PCR, and Loop-mediated Isothermal Amplification (LAMP), can improve the detection and differentiation of P. knowlesi due to its high sensitivity and specificity [127]. Then, multiplex high-resolution melting (hexaplex-PCR-HRM) assay is also another method that can simultaneously detect and differentiate five Plasmodium species, including P. knowlesi. A study has shown that Hexaplex-PCR-HRM diagnostic development is highly sensitive, specific, practical, and straightforward to use [133]. Development of specific RDTs, such as phosphoethanolamine-N-methyltransferase (PMT) and pLDH RDTs improvement, also could constitute an alternative solution [134]. PMT protein has potential as a P. knowlesi-specific biomarker for RDTs, which could improve rapid diagnosis at the point of care, while combining different RDT, for example the use of CareStart RDT and OptiMAL-IT RDT that can detect specific species of Plasmodium, specifically P. falciparum and P. vivax by immunochromatographic assays, which can reduce P. knowlesi misdiagnosis risk [126, 134]. However, regular training and proficiency testing for microscopists are crucial to reduce misdiagnosis rates [135]. Routine molecular testing for both zoonotic and non-zoonotic Plasmodium species also important to better monitor and manage this P. knowlesi malaria [136].

Socio-demographic challenges

A qualitative investigation among forestry workers in Indonesia has identified that beliefs, misconceptions, negative perceptions, and a limited understanding of malaria risks significantly influence treatment-seeking behaviours and the adoption of preventive measures [84]. The study confirmed many workers attributed the disease to supernatural causes, such as malevolent curses or spirits encountered during forest activities, prompting them to seek assistance from a Shaman [84]. Shaman provided written prayers, charms, or ritual objects believed to offer protection. Supernatural beliefs, including the presence of evil spirits in the forest, frequently result in a preference for traditional healers over medical professionals [84]. The study also found that forest workers often rely on traditional remedies (in Bahasa, it is called “jamu”) or talismans, such as magic stones, for protection against malaria. Upon the onset of symptoms, many forest workers opted to ignore them or self-medicated with over-the-counter drugs obtained from local pharmacies typically analgesics, antipyretics, or antimalarial tablet to enable uninterrupted work [84].

The study also confirmed forest workers often choose to sleep outdoors, perceiving the cool temperature as harmless while disregarding the potential risk of mosquito bites and subsequent malaria transmission [84]. The practice of outdoor sleeping, common in communities such as those in Sabah, Malaysia, further exacerbates exposure [84]. The adoption of preventive measures such as long-lasting insecticidal nets (LLINs), repellents, or protective clothing, was inconsistency due to discomfort, limited access, perceived expense, or distrust of chemically treated materials [84, 137]. Moreover, the transmission of P. knowlesi is confined to deep forest regions, which consequently leads to an underestimation of the risks present in residential or peri-forest areas [137]. Additionally, certain forest workers engage in feeding or capturing macaques and bringing them near human habitation, which potentially facilitates cross-species transmission of P. knowlesi [84]. Low socio-economic status is correlated with reduced educational attainment, which subsequently influences the adoption of malaria prevention behaviours. Individuals with limited formal education often exhibit lower awareness of transmission risks and may not engage in protective practices [84]. Conversely, higher educational attainment is associated with a better understanding of malaria symptoms, transmission pathways, and the importance of timely treatment. In Indonesia, where male-dominated sectors prevail in the labour market, men are at a higher risk of P. knowlesi malaria infection and incur greater associated healthcare costs—averaging US$141.90 per episode compared to US$126.13 for women [64, 138].

Communities impacted by P. knowlesi malaria frequently encounter obstacles in accessing healthcare services and malaria interventions, which can intensify the severity of infections. Factors such as poverty, inadequate housing, and socio-economic disparities have been linked to heightened susceptibility to malaria [139]. Malaria imposes a substantial economic burden on health systems, as well as on individuals, families, and communities affected by the disease [140]. A study conducted in Sabah, Malaysia, indicated that the average total cost per malaria case per household amounted to US$137.96, encompassing both direct and indirect costs [138]. Direct costs, including diagnosis, hospitalization, follow-up visits, medical care, food and drink in the hospital, over-the-counter medications, and transportation expenses during medical treatment, constituted approximately 41% of the total, or about US$56.96 per person. Conversely, indirect costs—comprising lost productivity, missed workdays, and caregiver expenses—accounted for 58%, averaging US$80.15 per household [138]. Additionally, malaria patients experience reduced mobility due to hospitalization, with the average duration of hospital stay for malaria patients being 4 to 5 days [138].

These socio-economic constraints not only increase the clinical and economic burden of malaria at the household level, but also shape the real-world performance of control programmes. Cross-country evidence shows that the success of malaria control and elimination is influenced more by socio-demographic factors, that have a greater impact, than the presence of intervention instruments. Despite the availability of interventions, such as long-lasting insecticidal nets (LLINs), indoor residual spraying (IRS), artemisinin-based combination therapy (ACT), mass drug administration (MDA), and vaccination of at-risk groups, their effectiveness depends on whether they can be consistently implemented within communities facing poverty, mobility, and service-access gaps [141]. Evidence indicates that a combination of interventions is more effective when tailored to local social characteristic and transmission levels, as evidenced by the success of Guangzhou, China, in achieving elimination through a phased strategy that followed population dynamics and service capacity, and in sub-Saharan African countries that implemented different control methods according to their respective social context [142, 143].

These intervention strategies align with the socio-ecological model framework, which emphasizes the importance of behavioural change in individuals, family-based education, and community leader involvement to increase programme acceptance at the community level, as well as fair policies, strong infrastructure, and real-time monitoring systems at the organizational to be truly effective in the field [144]. Consequently, malaria elimination requires a multi-pronged strategy specifically designed to address socio-demographic barriers at all levels of society, as opposed to the mere distribution of intervention tools in a non-contextualized manner.

Conclusion

Plasmodium knowlesi, a zoonotic malaria parasite predominantly found in Southeast Asia, is significantly influenced by climate change and various socio-ecological factors. Climate change impacts the transmission dynamics of P. knowlesi by altering the behaviour and habitats of mosquito vectors and macaque hosts. Deforestation and land use changes, often driven by climate change, create edge habitats that facilitate zoonotic transmission from simian hosts to humans. Human behaviours, such as occupational activities in forested areas and proximity to macaque habitats, increase exposure risk. Socio-economic factors, including poverty and limited healthcare access, further complicate the risk landscape. Diagnostic challenges, such as misidentification of P. knowlesi for other Plasmodium species, and the lack of effective vaccines and targeted interventions pose additional hurdles in controlling the spread of zoonotic malaria. Understanding the complex interplay between climate change, ecological factors, human activities, and public health challenges is crucial for developing effective strategies to mitigate the impact of P. knowlesi on human health in regions where human-host-vector interactions are intensifying due to ongoing environmental and developmental changes. More research is needed to fully understand how climate change will impact P. knowlesi transmission dynamics across different ecosystems in Southeast Asia. This knowledge is crucial for developing effective prevention and control strategies.

Abbreviations

SEA

Southeast Asia

PCR

Polymerase chain reaction

IRS

Indoor residual spraying

ITNs

Insecticide-treated nets

Mha

Million hectares

EIA

Environmental impact assessments

SEAs

Strategic environmental assessments

EPI

Environmental policy integration

NbS

Nature-based solutions

PES

Payments for ecosystem services

RDTs

Rapid diagnostic tests

pLDH

Parasite lactate dehydrogenase

LAMP

Loop-mediated isothermal amplification

LLINs

Long-lasting insecticidal nets

IRS

Indoor residual spraying

ACT

Artemisinin-based combination therapy

MDA

Mass drug administration

Author contributions

FM, JHH—conceptualization, methodology, writing original draft, review and editing, supervision, funding acquisition; NGQ, MRY, ADW, AAR, FAA—writing original draft, writing—review and editing; JHH—writing—review and editing, supervision, funding acquisition; MERF, NKDC—writing—review and editing.

Funding

This research was funded by the Institute for Research and Community Services, Universitas Diponegoro (No. 222-030/UN7.D2/PP/IV/2025) (FM). This work was also supported by the National Research Foundation of Korea (NRF), funded by the Ministry of Education (RS-2023-00240627) and the Ministry of Science and ICT (RS-2025-16069701) (J-HH).

Availability of data and materials

Not applicable.

Declarations

Ethics approval and consent to participate

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Consent of publication

Not applicable.

Competing interest

The authors declare no competing interests.