The risk of contracting an infection is inherent in the life of any living being. The same individual can encounter a variety of viruses, bacteria, helminths, fungi, or protozoa throughout a lifetime and often in the same period of time, increasing the chances of a co-infection (1, 2). Co-infection is defined as infection of the same host by two or more microorganisms belonging to different species or strains (1, 3).

The effect of co-infection on disease pathogenesis is related to the type of interaction that the parasites establish with each other and with the host, including the immune response triggered against these pathogens (3–5). In a co-infection, the parasites may cause a similar immune response profile (which may exacerbate this response) or a different one, bringing limitations to the immune response, with increased susceptibility and lack of control of the infection (6). Therefore, interactions between parasites that inhabit the same host simultaneously can be neutral, synergistic or antagonistic (1–3).

The order of arrival of pathogens in the host is another crucial factor to be considered. When we talk about co-infection, it is immediately assumed that at least two parasites infect the host simultaneously, but this only happens in specific cases, when a particular vector carries different pathogens and transmits them to the host at the same time (5). However, what is more feasible in nature is sequential co-infection, where the first parasite infects the host and then the second parasite, within a certain period (which can be from days to years), finds the same host and infects it (5). Therefore, at the time of co-infection, the host environment is metabolically and immunologically different compared to an uninfected host. Thus, the manifestation of a given disease is not only dependent on host susceptibility, pathogen virulence and environmental factors, but can also be directly influenced by co-infections ( Figure 1 ).

The geographical overlap of malaria and leishmaniasis has been reported through the presence of the parasites and specific vectors circulating in the same endemic regions (7, 8), showing that there is a great potential for interaction between these pathogens in the same host. Indeed, human co-infection with Plasmodium and Leishmania parasites has been described in nature (9–27). Despite that, and the impact that the coexistence of the two parasites in the same host can have on the course of the diseases, there are few studies in the literature that address this interaction. The purpose of this review is to provide an overview of the knowledge available in the literature on co-infection by the parasites that cause malaria and leishmaniasis. Articles detailing this interaction permeate natural co-infection in humans and experimental models of co-infection ( Table 1 ).

Malaria is an infectious parasitic disease caused by protozoa of the genus Plasmodium and transmitted by the bite of the Anopheles mosquito (7). Despite being an ancient disease, it remains a major public health problem worldwide. According to the World Malaria Report (37), an estimated 247 million cases of malaria occurred in 2021, with 619,000 deaths. In 2020, there was a significant increase in the numbers of malaria deaths (620,000) compared to the previous year (568,000). Overall, between 2019 and 2021, an estimated 13.4 million additional cases of malaria and 63,000 deaths can largely be attributed to the disruption of malaria prevention, diagnosis, and treatment program during the COVID-19 pandemic (37–39). Human malaria is mainly caused by five species of Plasmodium: P. falciparum, P. vivax, P. malariae and P. ovale curtisi and P. ovale wallikeri (7, 40, 41). However, there are three other zoonotically transmitted species that are also capable of infecting humans: P. knowlesi, P. cynomolgi and P. simium (40–45).

Plasmodium species show differences in their geographic distribution, pathological severity, and biology. P. falciparum is the predominant species on the African continent and is found in other tropical and subtropical regions. It is considered the species with the greatest impact on public health due to the high morbidity and mortality rates associated with severe forms of the disease, in addition to drug resistance (46). P. vivax is the most widely distributed species in the world. This parasite is the leading cause of malaria outside Africa and is found in regions of Asia and the Americas (46, 47). In the early stages, malaria has nonspecific symptoms, such as fever, chills, sweating, headache, and muscle pain. This set of symptoms is observed in most patients, but some cases, the disease can progress to more severe manifestations, such as pulmonary malaria, severe anemia, and cerebral malaria.

According to the WHO guidelines, the recommended treatment for adults (excluding pregnant women in their first trimester) and children with uncomplicated malaria caused by P. falciparum, P. vivax, P. ovale, P. malariae or P. knowlesi is with artemisinin-based combination therapies (ACT). This can include artemether + lumefantrine, artesunate + amodiaquine, artesunate + sulfadoxine–pyrimethamine (SP), and others (48). Chloroquine can also be used to treat uncomplicated non-P. falciparum malaria in areas with chloroquine-susceptible infections. In specific cases, to prevent P. vivax or P. ovale relapse, treatment should be carried out with primaquine, paying attention to the risk of G6PD deficiency. For severe malaria, the treatment of choice is intravenous or intramuscular administration of artesunate, followed by combination ACT therapy (48).

Leishmaniasis is a group of neglected infectious diseases caused by protozoan parasites of the genus Leishmania and transmitted by the bite of infected sand flies. It is estimated that 700,000 to 1 million new cases occur annually, and 1 billion people live in endemic areas and are at risk of infection (8) Endemic in 98 countries and 3 territories (49), in tropical and subtropical regions and in the Mediterranean basin, leishmaniasis is associated with lack of financial resources, precarious housing, climate change, population displacement, malnutrition and compromised immune system (8, 50, 51). More than 50 species of Leishmania have been identified, distributed in regions of the Old World (Europe, Asia, and Africa) and the New World (Americas). Of these, 20 species are known to infect humans (50, 52).

The disease, leishmaniasis, comprise a wide spectrum of clinical manifestations grouped in three main forms: Visceral Leishmaniasis (VL), Cutaneous Leishmaniasis (CL) and Mucocutaneous Leishmaniasis (ML) (8, 50). The VL form, also called kala-azar, is the most severe form of leishmaniasis. In the Old World, it is associated with infection by L. donovani and L. infantum, and in the New World by L. infantum. It is characterized as a systemic infection, with symptoms that include irregular fever, fatigue, abdominal pain, weight loss, splenomegaly and hepatomegaly (51, 52). Without treatment, VL is fatal in 95% of cases (8, 52). The CL form is the most common form of the disease. In the Old World, CL was mainly caused by L. major and L. tropica, and in the New World by more than eight different species of the L. (Leishmania) and L. (Viannia) subgenera, including L. (L.) amazonensis, L. (L.) mexicana, L. (V.) braziliensis, L. (V.) panamensis, L. (V.) peruviana and L. (V.) guyanensis (51, 53). The clinical presentation of CL varies according to the infecting species, the genetic background of the host, and immune response triggered. Typically, the lesions occur in the region of the sand fly bite and present as a single non-ulcerative and painless papule. However, multiple lesions can also occur as well as ulcerating dry or wet lesions with raised edges. Cutaneous lesions can heal spontaneously or after therapeutic interventions, but others can persist and be refractory to the treatment (51, 52, 54, 55). Between 2-14% of patients with CL caused by parasites of the L. (Viannia) subgenus develop ML (52, 56). In ML, the parasite disseminates from the skin to the oral and nasal mucosa through the lymphatic and hematogenous system, with slow and progressive destruction of these tissues (51, 52, 54, 57).

During the last six decades, the different forms of have been treated with a reduced option of drugs, including pentavalent antimonials, paromomycin, miltefosine, pentamidine isethionate and amphotericin B (52, 58, 59). Monotherapy with pentavalent antimonial was the first-line treatment for CL and VL worldwide, but due to the emergence of resistance or failure during treatment with this drug, its use is no longer recommended in some regions of the world (59, 60). Oral miltefosine monotherapy is being implemented by more countries in the last decade, as well as combination regimens of antimonial, paromomycin, liposomal amphotericin B, amphotericin B deoxycholate, pentoxifylline and miltefosine, according to the disease form and particular conditions of pediatric and adult patients (52, 58, 59).

It is well known that genetic factors influence resistance or susceptibility to infectious diseases, including malaria and leishmaniasis. However, few genome-wide association studies (GWAS) have been conducted to identify human gene polymorphisms associated with these diseases. Some genetic variations, such as those found in the hemoglobin subunit beta (HBB), ABO blood group (ABO), ATPase plasma membrane Ca2+ transporting 4 (ATP2B4), glucose-6-phosphate dehydrogenase (G6PD) and CD40 ligand (CD40LG) loci, have been associated with attenuation of severe malaria (61). In addition, polymorphism in the erythrocyte Duffy antigen/receptor for chemokines (DARC) gene is associated with resistance to P. vivax malaria (62, 63). Specific TNF and DDX39B haplotypes have also been linked to increased susceptibility to P. vivax infections in Brazil (64, 65). DDX39B encodes an RNA helicase that has been described as a negative regulator for the expression of TNF and IL-6.

Regarding leishmaniasis, recently, a robust GWAS identified lysosomal associated membrane protein 3 (LAMP3), Syntaxin 7 (STX7), Keratin 80 (KRT80), IFNG antisense RNA 1 (IFNG-AS1), Cytokine receptor like factor 3 (CRLF3), and Serpin family B member 10 (SERPINB10) as plausible genetic risk factors for CL caused by L. braziliensis (66). This study suggested that lower levels of IFN-γ and TNF, regulated by IFNG-AS1, increase the risk of CL. For VL, GWAS analysis identified a polymorphic HLA-DR-DQ region within the major histocompatibility complex of immune-related genes as the single major genetic determinant of VL (67). Interestingly, this association was found in three independent cohorts from India and Brazil, and represented infections caused by different parasite species, including L. donovani and L. infantum. Sakthianandeswaren A, et al. (68) and Bharati, K (69), have also described in their revisions several gene variations and their relationships with the course of different forms of leishmaniasis (68, 69). Despite the mentioned studies on genetic polymorphisms and parasitic diseases, to date, there has been no description of the association of certain polymorphisms with resistance or susceptibility to Plasmodium and Leishmania co-infection. This remains a challenging field for future studies.

The geographical distribution of countries with reported malaria cases (39) or VL and CL cases in the world (70) reveals an overlapping of malaria, VL and/or CL cases in the Americas (Central and South), Africa and Asia, and suggests that at least 38 countries are at risk of co-infection ( Figure 2 ). In brief, overlapping cases of malaria and CL are reported in Central America in countries such as Mexico, Costa Rica, Panama, Honduras, and Nicaragua, and in South America in Ecuador, Peru, Guyana, and Suriname. In addition, cases of malaria, CL and VL are observed in Guatemala, Colombia, Venezuela, Bolivia and Brazil (39, 56, 70, 71). On the African continent, cases of malaria and CL overlap mainly in the north of the continent, in countries with a predominantly tropical climate, such as Senegal, Burkina Faso and Nigeria. Also, countries in northeastern Africa, such as Somalia, Uganda, Djibouti, Tanzania, Eritrea, and South Sudan, have reported cases of malaria and VL (39, 70). And yet, cases of malaria, CL, and VL have been reported in Cameroon, Chad, Sudan, Ethiopia, and Kenya. In West Asia, malaria and CL are endemic in Saudi Arabia, while all three diseases are present in Yemen. In South Asia, cases of malaria and CL are found in Pakistan, and cases of malaria, CL and VL are found in Iran and Afghanistan (39, 71, 72). Malaria and VL cases have been reported only in India, Nepal, Bangladesh and Thailand (39, 70), while malaria and CL cases have been reported in Bhutan, a country located between China and India. Isolated cases of malaria or leishmaniasis are observed in several other countries, but without reports of co-endemicity.

The geographical overlapping of the Plasmodium and Leishmania parasites, their vectors, and cases of natural co-infection are more than proven. Studies on natural and experimental co-infection, discussed in this review, suggest that the co-occurrence of the two parasites in the same host interferes with the duration of infection, level of infectivity and/or clinical manifestations. Some of these factors can influence the transmission and compromise the control of one or both diseases. This review also evidences the dangers of co-infection for populations residing in areas where these diseases are co-endemic. As the search for co-infections is not usually performed in these regions, the diagnosis of one infection may compromise the accurate and timely diagnosis of the other, implying a delay in treatment and possibly leading to patient death. Thus, more efforts should be made in an attempt to reduce the lack of knowledge about concomitant infections, and encouragement for the creation of programs that seek to diagnose co-infections by Plasmodium spp. and Leishmania spp. in areas co-endemic for both diseases.

UO-G drafted the manuscript. UO-G, PC, and FL reviewed, edited, and prepared its final version. All authors contributed to the article and approved the submitted version.